Leukemia, Myelodysplasia, Transplantation

Older patients with newly diagnosed acute myeloid leukemia who were unsuitable for intensive chemotherapy had significantly longer overall survival with gemtuzumab ozogamicin, compared with best supportive care, according to phase III trial results published Jan. 25.

The phase III EORTC-GIMEMA AML-19 trial randomly assigned 118 patients to receive gemtuzumab ozogamicin and 119 to receive best supportive care, including hydroxyurea. The median age was 77 years. In total, 104 of 118 patients in the gemtuzumab ozogamicin arm received the full induction course, and the median number of gemtuzumab ozogamicin infusions was three (range: 1 to 10).

Median overall survival (OS) for patients who received gemtuzumab ozogamicin was 4.9 months, compared with 3.6 months for those who received best supportive care, including hydroxyurea (hazard ratio, 0.69; 95% confidence interval, 0.53-0.90; P = .005).

One-year survival rates were 24.3% (95% CI, 16.9 to 32.4) for gemtuzumab ozogamicin and 9.7% (5.1 to 15.9) for best supportive care (J Clin Onc. 2016 Jan 25. doi: 10.1200/JCO.2015.64.0060).

The low intensity gemtuzumab ozogamicin regimen was generally well tolerated, with comparable toxicity between arms. Pancytopenia was observed in nearly all patients during gemtuzumab ozogamicin induction, however.

“Of importance, liver toxicity, a hallmark of [gemtuzumab ozogamicin] safety profile, was not increased in [gemtuzumab ozogamicin] recipients. Furthermore, it appeared to be less frequent and severe than previously reported by our group in a first-line trial, in which a more intensive [gemtuzumab ozogamicin] regimen was used in elderly patients with AML unfit for intensive chemotherapy,” wrote Dr. Sergio Amadori of the Tor Vergata University, Rome, and his colleagues.

Gemtuzumab ozogamicin therapy resulted in an overall complete response (CR) rate of 27% (15.3% CR and 11.7% CRi [incomplete recovery of peripheral blood counts]). The overall clinical benefit rate (CR + CRi+ partial response + stable disease for 30 days) was 56.7%.

Gemtuzumab ozogamicin combines a human monoclonal antibody specific for CD33 on myeloid cells with the DNA intercalator calicheamicin.

Patient characteristics that influenced gemtuzumab ozogamicin treatment effect were CD33 expression status, sex, and cytogenic profile. In patients with more than 80% CD33-positive blasts, gemtuzumab ozogamicin resulted in greater improvements over best supportive care (HR, 0.49; 95% CI, 0.32 to 0.76).

In women, OS was significantly improved (HR, 0.53; 95% CI, 0.35 to 0.79), whereas in men the hazard ratio was near 1. Patients with favorable/intermediate cytogenetic risk profiles had significant gemtuzumab ozogamicin benefit (HR, 0.52; 95% CI, 0.34 to 0.77), and those with adverse risk profiles had no treatment difference between arms.

The research was supported by Wyeth (Pfizer) and by the European Organisation for Research and Treatment of Cancer . Dr. Amadori reported having no disclosures. Several of his coauthors reported ties to industry.

Older patients with newly diagnosed acute myeloid leukemia who were unsuitable for intensive chemotherapy had significantly longer overall survival with gemtuzumab ozogamicin, compared with best supportive care, according to phase III trial results published Jan. 25.

The phase III EORTC-GIMEMA AML-19 trial randomly assigned 118 patients to receive gemtuzumab ozogamicin and 119 to receive best supportive care, including hydroxyurea. The median age was 77 years. In total, 104 of 118 patients in the gemtuzumab ozogamicin arm received the full induction course, and the median number of gemtuzumab ozogamicin infusions was three (range: 1 to 10).

Median overall survival (OS) for patients who received gemtuzumab ozogamicin was 4.9 months, compared with 3.6 months for those who received best supportive care, including hydroxyurea (hazard ratio, 0.69; 95% confidence interval, 0.53-0.90; P = .005).

One-year survival rates were 24.3% (95% CI, 16.9 to 32.4) for gemtuzumab ozogamicin and 9.7% (5.1 to 15.9) for best supportive care (J Clin Onc. 2016 Jan 25. doi: 10.1200/JCO.2015.64.0060).

The low intensity gemtuzumab ozogamicin regimen was generally well tolerated, with comparable toxicity between arms. Pancytopenia was observed in nearly all patients during gemtuzumab ozogamicin induction, however.

“Of importance, liver toxicity, a hallmark of [gemtuzumab ozogamicin] safety profile, was not increased in [gemtuzumab ozogamicin] recipients. Furthermore, it appeared to be less frequent and severe than previously reported by our group in a first-line trial, in which a more intensive [gemtuzumab ozogamicin] regimen was used in elderly patients with AML unfit for intensive chemotherapy,” wrote Dr. Sergio Amadori of the Tor Vergata University, Rome, and his colleagues.

Gemtuzumab ozogamicin therapy resulted in an overall complete response (CR) rate of 27% (15.3% CR and 11.7% CRi [incomplete recovery of peripheral blood counts]). The overall clinical benefit rate (CR + CRi+ partial response + stable disease for 30 days) was 56.7%.

Gemtuzumab ozogamicin combines a human monoclonal antibody specific for CD33 on myeloid cells with the DNA intercalator calicheamicin.

Patient characteristics that influenced gemtuzumab ozogamicin treatment effect were CD33 expression status, sex, and cytogenic profile. In patients with more than 80% CD33-positive blasts, gemtuzumab ozogamicin resulted in greater improvements over best supportive care (HR, 0.49; 95% CI, 0.32 to 0.76).

In women, OS was significantly improved (HR, 0.53; 95% CI, 0.35 to 0.79), whereas in men the hazard ratio was near 1. Patients with favorable/intermediate cytogenetic risk profiles had significant gemtuzumab ozogamicin benefit (HR, 0.52; 95% CI, 0.34 to 0.77), and those with adverse risk profiles had no treatment difference between arms.

The research was supported by Wyeth (Pfizer) and by the European Organisation for Research and Treatment of Cancer . Dr. Amadori reported having no disclosures. Several of his coauthors reported ties to industry.

Older patients with newly diagnosed acute myeloid leukemia who were unsuitable for intensive chemotherapy had significantly longer overall survival with gemtuzumab ozogamicin, compared with best supportive care, according to phase III trial results published Jan. 25.

The phase III EORTC-GIMEMA AML-19 trial randomly assigned 118 patients to receive gemtuzumab ozogamicin and 119 to receive best supportive care, including hydroxyurea. The median age was 77 years. In total, 104 of 118 patients in the gemtuzumab ozogamicin arm received the full induction course, and the median number of gemtuzumab ozogamicin infusions was three (range: 1 to 10).

Median overall survival (OS) for patients who received gemtuzumab ozogamicin was 4.9 months, compared with 3.6 months for those who received best supportive care, including hydroxyurea (hazard ratio, 0.69; 95% confidence interval, 0.53-0.90; P = .005).

One-year survival rates were 24.3% (95% CI, 16.9 to 32.4) for gemtuzumab ozogamicin and 9.7% (5.1 to 15.9) for best supportive care (J Clin Onc. 2016 Jan 25. doi: 10.1200/JCO.2015.64.0060).

The low intensity gemtuzumab ozogamicin regimen was generally well tolerated, with comparable toxicity between arms. Pancytopenia was observed in nearly all patients during gemtuzumab ozogamicin induction, however.

“Of importance, liver toxicity, a hallmark of [gemtuzumab ozogamicin] safety profile, was not increased in [gemtuzumab ozogamicin] recipients. Furthermore, it appeared to be less frequent and severe than previously reported by our group in a first-line trial, in which a more intensive [gemtuzumab ozogamicin] regimen was used in elderly patients with AML unfit for intensive chemotherapy,” wrote Dr. Sergio Amadori of the Tor Vergata University, Rome, and his colleagues.

Gemtuzumab ozogamicin therapy resulted in an overall complete response (CR) rate of 27% (15.3% CR and 11.7% CRi [incomplete recovery of peripheral blood counts]). The overall clinical benefit rate (CR + CRi+ partial response + stable disease for 30 days) was 56.7%.

Gemtuzumab ozogamicin combines a human monoclonal antibody specific for CD33 on myeloid cells with the DNA intercalator calicheamicin.

Patient characteristics that influenced gemtuzumab ozogamicin treatment effect were CD33 expression status, sex, and cytogenic profile. In patients with more than 80% CD33-positive blasts, gemtuzumab ozogamicin resulted in greater improvements over best supportive care (HR, 0.49; 95% CI, 0.32 to 0.76).

In women, OS was significantly improved (HR, 0.53; 95% CI, 0.35 to 0.79), whereas in men the hazard ratio was near 1. Patients with favorable/intermediate cytogenetic risk profiles had significant gemtuzumab ozogamicin benefit (HR, 0.52; 95% CI, 0.34 to 0.77), and those with adverse risk profiles had no treatment difference between arms.

The research was supported by Wyeth (Pfizer) and by the European Organisation for Research and Treatment of Cancer . Dr. Amadori reported having no disclosures. Several of his coauthors reported ties to industry.

Blood samples

Photo by Graham Colm

New research indicates that chronic lymphocytic leukemia (CLL) can develop during nearly any stage of B-cell maturation.

However, CLL that arises from more progressive maturation stages responds better to therapy.

The study also suggests that most methylation events that were previously thought to be tumor-specific are normally present in non-malignant B cells.

These findings were published in Nature Genetics.

Christoph Plass, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, and his colleagues conducted this study to determine which development stage of B cells marks the origin of B-cell CLL.

The team took blood samples from 268 CLL patients, separated the blood cells using specific B-cell maturation markers and analyzed the methylation patterns of each individual maturation stage.

The investigators were surprised to find that CLL can develop from almost all maturation stages. They also found that maturation was associated with “increasingly favorable clinical outcomes.”

In addition, methylation patterns that were previously regarded as cancer-specific actually reflect the characteristic patterns of the development stages at the moment of cancerous transformation.

The investigators found that the cell “freezes” this methylation pattern, and this is followed by only a few changes that are truly cancer-specific.

The team said they used advanced bioinformatic methods to calculate the small percentage of cancer-specific methylation patterns from the wealth of maturation-related variations.

“Up until recently, it was technically impossible to study the various maturation stages in such detail as we have done,” Dr Plass said. “It took the advanced sequencing technology and the powerful bioinformatic methods that we have available now to make such a detailed comparison possible.”

The investigators said their findings differ from those of prior studies because, with the current study, they compared CLL cells with the whole pool of B-cell maturation stages.

“All differences found were attributed to cancer,” Dr Plass said, adding that some previous works on the cancer epigenome will need to be re-interpreted in the light of the current results.

Next, Dr Plass and his colleagues want to examine other cancer types to determine whether methylation patterns that are thought to be cancer-specific also arise from the normal cellular maturation program. In particular, they plan to study other hematologic malignancies and prostate cancer.

Blood samples

Photo by Graham Colm

New research indicates that chronic lymphocytic leukemia (CLL) can develop during nearly any stage of B-cell maturation.

However, CLL that arises from more progressive maturation stages responds better to therapy.

The study also suggests that most methylation events that were previously thought to be tumor-specific are normally present in non-malignant B cells.

These findings were published in Nature Genetics.

Christoph Plass, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, and his colleagues conducted this study to determine which development stage of B cells marks the origin of B-cell CLL.

The team took blood samples from 268 CLL patients, separated the blood cells using specific B-cell maturation markers and analyzed the methylation patterns of each individual maturation stage.

The investigators were surprised to find that CLL can develop from almost all maturation stages. They also found that maturation was associated with “increasingly favorable clinical outcomes.”

In addition, methylation patterns that were previously regarded as cancer-specific actually reflect the characteristic patterns of the development stages at the moment of cancerous transformation.

The investigators found that the cell “freezes” this methylation pattern, and this is followed by only a few changes that are truly cancer-specific.

The team said they used advanced bioinformatic methods to calculate the small percentage of cancer-specific methylation patterns from the wealth of maturation-related variations.

“Up until recently, it was technically impossible to study the various maturation stages in such detail as we have done,” Dr Plass said. “It took the advanced sequencing technology and the powerful bioinformatic methods that we have available now to make such a detailed comparison possible.”

The investigators said their findings differ from those of prior studies because, with the current study, they compared CLL cells with the whole pool of B-cell maturation stages.

“All differences found were attributed to cancer,” Dr Plass said, adding that some previous works on the cancer epigenome will need to be re-interpreted in the light of the current results.

Next, Dr Plass and his colleagues want to examine other cancer types to determine whether methylation patterns that are thought to be cancer-specific also arise from the normal cellular maturation program. In particular, they plan to study other hematologic malignancies and prostate cancer.

Blood samples

Photo by Graham Colm

New research indicates that chronic lymphocytic leukemia (CLL) can develop during nearly any stage of B-cell maturation.

However, CLL that arises from more progressive maturation stages responds better to therapy.

The study also suggests that most methylation events that were previously thought to be tumor-specific are normally present in non-malignant B cells.

These findings were published in Nature Genetics.

Christoph Plass, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, and his colleagues conducted this study to determine which development stage of B cells marks the origin of B-cell CLL.

The team took blood samples from 268 CLL patients, separated the blood cells using specific B-cell maturation markers and analyzed the methylation patterns of each individual maturation stage.

The investigators were surprised to find that CLL can develop from almost all maturation stages. They also found that maturation was associated with “increasingly favorable clinical outcomes.”

In addition, methylation patterns that were previously regarded as cancer-specific actually reflect the characteristic patterns of the development stages at the moment of cancerous transformation.

The investigators found that the cell “freezes” this methylation pattern, and this is followed by only a few changes that are truly cancer-specific.

The team said they used advanced bioinformatic methods to calculate the small percentage of cancer-specific methylation patterns from the wealth of maturation-related variations.

“Up until recently, it was technically impossible to study the various maturation stages in such detail as we have done,” Dr Plass said. “It took the advanced sequencing technology and the powerful bioinformatic methods that we have available now to make such a detailed comparison possible.”

The investigators said their findings differ from those of prior studies because, with the current study, they compared CLL cells with the whole pool of B-cell maturation stages.

“All differences found were attributed to cancer,” Dr Plass said, adding that some previous works on the cancer epigenome will need to be re-interpreted in the light of the current results.

Next, Dr Plass and his colleagues want to examine other cancer types to determine whether methylation patterns that are thought to be cancer-specific also arise from the normal cellular maturation program. In particular, they plan to study other hematologic malignancies and prostate cancer.

Fruit fly retina

Image courtesy of

Northwestern University

In studying the fruit fly equivalent of an oncogene implicated in human leukemias, researchers have gained insight into how developing cells switch to a specialized state and how that process might go awry in cancers.

The team found that levels of the protein Yan start fluctuating wildly when a cell is switching from a stem-like state to a more specialized state. If the levels of Yan don’t or can’t fluctuate, the cell doesn’t differentiate.

The Yan protein is called Tel-1 in humans, and the gene that produces the Tel-1 protein, the Tel-1 oncogene, is frequently mutated in human leukemias.

Richard W. Carthew, PhD, of Northwestern University in Evanston, Illinois, and his colleagues conducted this research and reported the results in eLife.

The researchers studied cell behavior in the eye of Drosophila melanogaster, the common fruit fly, which has many of the same oncogenes as humans.

The team was surprised to discover that fluctuating levels of Yan were needed for cell differentiation.

“This mad fluctuation, or noise, happens at the time of cell transition,” Dr Carthew explained. “For the first time, we see there is a brief time period as the developing cell goes from point A to point B. The noise is a state of ‘in between’ and is important for cells to switch to a more specialized state. This limbo might be where normal cells take a cancerous path.”

He noted that it takes 15 to 20 hours for a fruit fly cell to transition from an unspecialized to a specialized state. The researchers found the Yan protein is “noisy,” or fluctuating, for 6 to 8 of those hours.

The team also found that a molecular signal received by the cell receptor EGFR is important for turning the noise off. If that signal is not received, the cell remains in an uncontrolled state.

The EGFR protein that turns off the noise in flies is called Her-2 in humans, and the Her-2 oncogene is known to play an important role in breast cancer.

“On the surface, flies and humans are very different, but we share a remarkable amount of infrastructure,” Dr Carthew noted. “We can use fruit fly genetics to understand how humans work and how things go wrong in cancer and other diseases.”

Fruit fly retina

Image courtesy of

Northwestern University

In studying the fruit fly equivalent of an oncogene implicated in human leukemias, researchers have gained insight into how developing cells switch to a specialized state and how that process might go awry in cancers.

The team found that levels of the protein Yan start fluctuating wildly when a cell is switching from a stem-like state to a more specialized state. If the levels of Yan don’t or can’t fluctuate, the cell doesn’t differentiate.

The Yan protein is called Tel-1 in humans, and the gene that produces the Tel-1 protein, the Tel-1 oncogene, is frequently mutated in human leukemias.

Richard W. Carthew, PhD, of Northwestern University in Evanston, Illinois, and his colleagues conducted this research and reported the results in eLife.

The researchers studied cell behavior in the eye of Drosophila melanogaster, the common fruit fly, which has many of the same oncogenes as humans.

The team was surprised to discover that fluctuating levels of Yan were needed for cell differentiation.

“This mad fluctuation, or noise, happens at the time of cell transition,” Dr Carthew explained. “For the first time, we see there is a brief time period as the developing cell goes from point A to point B. The noise is a state of ‘in between’ and is important for cells to switch to a more specialized state. This limbo might be where normal cells take a cancerous path.”

He noted that it takes 15 to 20 hours for a fruit fly cell to transition from an unspecialized to a specialized state. The researchers found the Yan protein is “noisy,” or fluctuating, for 6 to 8 of those hours.

The team also found that a molecular signal received by the cell receptor EGFR is important for turning the noise off. If that signal is not received, the cell remains in an uncontrolled state.

The EGFR protein that turns off the noise in flies is called Her-2 in humans, and the Her-2 oncogene is known to play an important role in breast cancer.

“On the surface, flies and humans are very different, but we share a remarkable amount of infrastructure,” Dr Carthew noted. “We can use fruit fly genetics to understand how humans work and how things go wrong in cancer and other diseases.”

Fruit fly retina

Image courtesy of

Northwestern University

In studying the fruit fly equivalent of an oncogene implicated in human leukemias, researchers have gained insight into how developing cells switch to a specialized state and how that process might go awry in cancers.

The team found that levels of the protein Yan start fluctuating wildly when a cell is switching from a stem-like state to a more specialized state. If the levels of Yan don’t or can’t fluctuate, the cell doesn’t differentiate.

The Yan protein is called Tel-1 in humans, and the gene that produces the Tel-1 protein, the Tel-1 oncogene, is frequently mutated in human leukemias.

Richard W. Carthew, PhD, of Northwestern University in Evanston, Illinois, and his colleagues conducted this research and reported the results in eLife.

The researchers studied cell behavior in the eye of Drosophila melanogaster, the common fruit fly, which has many of the same oncogenes as humans.

The team was surprised to discover that fluctuating levels of Yan were needed for cell differentiation.

“This mad fluctuation, or noise, happens at the time of cell transition,” Dr Carthew explained. “For the first time, we see there is a brief time period as the developing cell goes from point A to point B. The noise is a state of ‘in between’ and is important for cells to switch to a more specialized state. This limbo might be where normal cells take a cancerous path.”

He noted that it takes 15 to 20 hours for a fruit fly cell to transition from an unspecialized to a specialized state. The researchers found the Yan protein is “noisy,” or fluctuating, for 6 to 8 of those hours.

The team also found that a molecular signal received by the cell receptor EGFR is important for turning the noise off. If that signal is not received, the cell remains in an uncontrolled state.

The EGFR protein that turns off the noise in flies is called Her-2 in humans, and the Her-2 oncogene is known to play an important role in breast cancer.

“On the surface, flies and humans are very different, but we share a remarkable amount of infrastructure,” Dr Carthew noted. “We can use fruit fly genetics to understand how humans work and how things go wrong in cancer and other diseases.”

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

Blood samples

Photo by William Weinert

A test measuring minimal residual disease (MRD) can help predict relapse in patients with acute myeloid leukemia (AML), according to a study published in NEJM.

Investigators used the test to detect MRD in samples from patients with NPM1-mutated AML who were deemed standard-risk by conventional methods.

The team said the presence of MRD after treatment provided powerful prognostic information independent of other risk factors.

“What we have been able to identify is a group of patients who otherwise would be thought to do quite well, who, in fact, have a very poor prognosis, and who are not well served currently,” said study author Robert Hills, DPhil, of Cardiff University School of Medicine in the UK.

“This opens up the exciting prospect that we can do the same for other groups of patients as well.”

For this study, Dr Hills and his colleagues used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect MRD in 2569 samples (902 bone marrow samples and 1667 peripheral blood samples) from 346 patients with NPM1-mutated AML.

The patients had received 2 cycles of chemotherapy as part of the National Cancer Research Institute AML17 trial. They were treated at centers in the UK, Denmark, and New Zealand. All patients were shown to be at standard risk of relapse using conventional tests.

The investigators found that NPM1-mutated transcripts persisted in the blood of 15% of patients after the second cycle of chemotherapy.

This finding was associated with a greater risk of relapse after 3 years of follow-up.

Eighty-two percent of patients with NPM1-mutated transcripts had relapsed within 3 years, compared to 30% of patients who had no detectable NPM1. The hazard ratio was 4.80 (P<0.001).

Patients with traces of NPM1 also had a lower rate of survival—24%, compared to 75% for patients without detectable NPM1. The hazard ratio was 4.38 (P<0.001).

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse or death. The hazard ratios were 5.09 and 4.84, respectively (P<0.001 for both).

The investigators validated these findings in a cohort of 91 patients with NPM1-mutated AML.

The presence of MRD in the blood of these patients was associated with a higher cumulative incidence of relapse—70% vs 31% (P=0.001)—and a lower rate of survival—40% vs 87% (P=0.001)—at 2 years.

The investigators also found that, with sequential monitoring of MRD, a rising level of NPM1-mutated transcripts could predict relapse.

“Conventional methods for guiding treatment for this aggressive type of leukemia are inadequate,” said study author David Grimwade, PhD, of King’s College London in the UK.

“The MRD test is an invaluable tool to assess treatment response and identify those patients for whom chemotherapy is not sufficient and require stem cell transplantation or new treatments.”

Blood samples

Photo by William Weinert

A test measuring minimal residual disease (MRD) can help predict relapse in patients with acute myeloid leukemia (AML), according to a study published in NEJM.

Investigators used the test to detect MRD in samples from patients with NPM1-mutated AML who were deemed standard-risk by conventional methods.

The team said the presence of MRD after treatment provided powerful prognostic information independent of other risk factors.

“What we have been able to identify is a group of patients who otherwise would be thought to do quite well, who, in fact, have a very poor prognosis, and who are not well served currently,” said study author Robert Hills, DPhil, of Cardiff University School of Medicine in the UK.

“This opens up the exciting prospect that we can do the same for other groups of patients as well.”

For this study, Dr Hills and his colleagues used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect MRD in 2569 samples (902 bone marrow samples and 1667 peripheral blood samples) from 346 patients with NPM1-mutated AML.

The patients had received 2 cycles of chemotherapy as part of the National Cancer Research Institute AML17 trial. They were treated at centers in the UK, Denmark, and New Zealand. All patients were shown to be at standard risk of relapse using conventional tests.

The investigators found that NPM1-mutated transcripts persisted in the blood of 15% of patients after the second cycle of chemotherapy.

This finding was associated with a greater risk of relapse after 3 years of follow-up.

Eighty-two percent of patients with NPM1-mutated transcripts had relapsed within 3 years, compared to 30% of patients who had no detectable NPM1. The hazard ratio was 4.80 (P<0.001).

Patients with traces of NPM1 also had a lower rate of survival—24%, compared to 75% for patients without detectable NPM1. The hazard ratio was 4.38 (P<0.001).

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse or death. The hazard ratios were 5.09 and 4.84, respectively (P<0.001 for both).

The investigators validated these findings in a cohort of 91 patients with NPM1-mutated AML.

The presence of MRD in the blood of these patients was associated with a higher cumulative incidence of relapse—70% vs 31% (P=0.001)—and a lower rate of survival—40% vs 87% (P=0.001)—at 2 years.

The investigators also found that, with sequential monitoring of MRD, a rising level of NPM1-mutated transcripts could predict relapse.

“Conventional methods for guiding treatment for this aggressive type of leukemia are inadequate,” said study author David Grimwade, PhD, of King’s College London in the UK.

“The MRD test is an invaluable tool to assess treatment response and identify those patients for whom chemotherapy is not sufficient and require stem cell transplantation or new treatments.”

Blood samples

Photo by William Weinert

A test measuring minimal residual disease (MRD) can help predict relapse in patients with acute myeloid leukemia (AML), according to a study published in NEJM.

Investigators used the test to detect MRD in samples from patients with NPM1-mutated AML who were deemed standard-risk by conventional methods.

The team said the presence of MRD after treatment provided powerful prognostic information independent of other risk factors.

“What we have been able to identify is a group of patients who otherwise would be thought to do quite well, who, in fact, have a very poor prognosis, and who are not well served currently,” said study author Robert Hills, DPhil, of Cardiff University School of Medicine in the UK.

“This opens up the exciting prospect that we can do the same for other groups of patients as well.”

For this study, Dr Hills and his colleagues used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect MRD in 2569 samples (902 bone marrow samples and 1667 peripheral blood samples) from 346 patients with NPM1-mutated AML.

The patients had received 2 cycles of chemotherapy as part of the National Cancer Research Institute AML17 trial. They were treated at centers in the UK, Denmark, and New Zealand. All patients were shown to be at standard risk of relapse using conventional tests.

The investigators found that NPM1-mutated transcripts persisted in the blood of 15% of patients after the second cycle of chemotherapy.

This finding was associated with a greater risk of relapse after 3 years of follow-up.

Eighty-two percent of patients with NPM1-mutated transcripts had relapsed within 3 years, compared to 30% of patients who had no detectable NPM1. The hazard ratio was 4.80 (P<0.001).

Patients with traces of NPM1 also had a lower rate of survival—24%, compared to 75% for patients without detectable NPM1. The hazard ratio was 4.38 (P<0.001).

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse or death. The hazard ratios were 5.09 and 4.84, respectively (P<0.001 for both).

The investigators validated these findings in a cohort of 91 patients with NPM1-mutated AML.

The presence of MRD in the blood of these patients was associated with a higher cumulative incidence of relapse—70% vs 31% (P=0.001)—and a lower rate of survival—40% vs 87% (P=0.001)—at 2 years.

The investigators also found that, with sequential monitoring of MRD, a rising level of NPM1-mutated transcripts could predict relapse.

“Conventional methods for guiding treatment for this aggressive type of leukemia are inadequate,” said study author David Grimwade, PhD, of King’s College London in the UK.

“The MRD test is an invaluable tool to assess treatment response and identify those patients for whom chemotherapy is not sufficient and require stem cell transplantation or new treatments.”

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a small study suggest that adolescent and young adult (AYA) cancer survivors have a range of concerns regarding their fertility.

The female cancer survivors studied were more likely than males to describe feeling distressed and overwhelmed about their fertility.

Females also tended to worry about pregnancy-related health risks and cancer recurrence.

However, AYA cancer survivors of both sexes expressed concerns about genetic risk factors and how infertility might impact their future lives.

Catherine Benedict, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and her colleagues conducted this research and reported the results in the Journal of Adolescent and Young Adult Oncology.

The researchers assessed fertility concerns in 43 AYA cancer survivors. They were 16 to 24 at the time of the study, had been diagnosed with cancer between ages 14 and 18, and were at least 6 months post-treatment.

The subjects either completed an individual interview (n=26) or participated in 1 of 4 focus groups (n=17).

Before treatment, 5 of the males had banked sperm, but none of the females took steps to preserve their fertility. More males (50%) than females (39%) reported uncertainty about their fertility.

The researchers identified 3 themes when discussing fertility with the study subjects: fertility concerns, emotions raised when discussing fertility, and strategies used to manage fertility concerns.

Concerns

Some subjects expressed concerns about how potential infertility could affect dating and relationships with partners (8% of males and 20% of females).

Some subjects were concerned about the health risks associated with having children—both risks to the subjects themselves and to any potential children (39% of males and 30% of females).

And some subjects were concerned about how potential infertility would affect their lives going forward (31% of males and 20% of females).

Emotions

When it came to emotions associated with fertility discussions, some subjects said they felt distressed and overwhelmed (23% of males and 30% of females).

However, some subjects said they weren’t concerned about their fertility (31% of males and 15% of females) or they felt hopeful despite the risk of infertility (8% of males and 20% of females).

Managing concerns

The subjects also mentioned a few strategies for managing fertility concerns. Some said they had accepted infertility (23% of males and 15% of females).

Some subjects said they weren’t going to worry about their fertility until they were older and actually wanted to have children (23% of males and 20% of females).

And some subjects said they would rely on assisted reproductive technology if necessary (31% of males and 20% of females).

Dr Benedict and her colleagues said this study suggests AYA cancer survivors may have a number of reproductive concerns and fertility-related distress, which may affect other areas of psychosocial functioning.

So future research should explore how to best incorporate fertility-related informational and support services more fully into survivorship care.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a small study suggest that adolescent and young adult (AYA) cancer survivors have a range of concerns regarding their fertility.

The female cancer survivors studied were more likely than males to describe feeling distressed and overwhelmed about their fertility.

Females also tended to worry about pregnancy-related health risks and cancer recurrence.

However, AYA cancer survivors of both sexes expressed concerns about genetic risk factors and how infertility might impact their future lives.

Catherine Benedict, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and her colleagues conducted this research and reported the results in the Journal of Adolescent and Young Adult Oncology.

The researchers assessed fertility concerns in 43 AYA cancer survivors. They were 16 to 24 at the time of the study, had been diagnosed with cancer between ages 14 and 18, and were at least 6 months post-treatment.

The subjects either completed an individual interview (n=26) or participated in 1 of 4 focus groups (n=17).

Before treatment, 5 of the males had banked sperm, but none of the females took steps to preserve their fertility. More males (50%) than females (39%) reported uncertainty about their fertility.

The researchers identified 3 themes when discussing fertility with the study subjects: fertility concerns, emotions raised when discussing fertility, and strategies used to manage fertility concerns.

Concerns

Some subjects expressed concerns about how potential infertility could affect dating and relationships with partners (8% of males and 20% of females).

Some subjects were concerned about the health risks associated with having children—both risks to the subjects themselves and to any potential children (39% of males and 30% of females).

And some subjects were concerned about how potential infertility would affect their lives going forward (31% of males and 20% of females).

Emotions

When it came to emotions associated with fertility discussions, some subjects said they felt distressed and overwhelmed (23% of males and 30% of females).

However, some subjects said they weren’t concerned about their fertility (31% of males and 15% of females) or they felt hopeful despite the risk of infertility (8% of males and 20% of females).

Managing concerns

The subjects also mentioned a few strategies for managing fertility concerns. Some said they had accepted infertility (23% of males and 15% of females).

Some subjects said they weren’t going to worry about their fertility until they were older and actually wanted to have children (23% of males and 20% of females).

And some subjects said they would rely on assisted reproductive technology if necessary (31% of males and 20% of females).

Dr Benedict and her colleagues said this study suggests AYA cancer survivors may have a number of reproductive concerns and fertility-related distress, which may affect other areas of psychosocial functioning.

So future research should explore how to best incorporate fertility-related informational and support services more fully into survivorship care.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a small study suggest that adolescent and young adult (AYA) cancer survivors have a range of concerns regarding their fertility.

The female cancer survivors studied were more likely than males to describe feeling distressed and overwhelmed about their fertility.

Females also tended to worry about pregnancy-related health risks and cancer recurrence.

However, AYA cancer survivors of both sexes expressed concerns about genetic risk factors and how infertility might impact their future lives.

Catherine Benedict, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and her colleagues conducted this research and reported the results in the Journal of Adolescent and Young Adult Oncology.

The researchers assessed fertility concerns in 43 AYA cancer survivors. They were 16 to 24 at the time of the study, had been diagnosed with cancer between ages 14 and 18, and were at least 6 months post-treatment.

The subjects either completed an individual interview (n=26) or participated in 1 of 4 focus groups (n=17).

Before treatment, 5 of the males had banked sperm, but none of the females took steps to preserve their fertility. More males (50%) than females (39%) reported uncertainty about their fertility.

The researchers identified 3 themes when discussing fertility with the study subjects: fertility concerns, emotions raised when discussing fertility, and strategies used to manage fertility concerns.

Concerns

Some subjects expressed concerns about how potential infertility could affect dating and relationships with partners (8% of males and 20% of females).

Some subjects were concerned about the health risks associated with having children—both risks to the subjects themselves and to any potential children (39% of males and 30% of females).

And some subjects were concerned about how potential infertility would affect their lives going forward (31% of males and 20% of females).

Emotions

When it came to emotions associated with fertility discussions, some subjects said they felt distressed and overwhelmed (23% of males and 30% of females).

However, some subjects said they weren’t concerned about their fertility (31% of males and 15% of females) or they felt hopeful despite the risk of infertility (8% of males and 20% of females).

Managing concerns

The subjects also mentioned a few strategies for managing fertility concerns. Some said they had accepted infertility (23% of males and 15% of females).

Some subjects said they weren’t going to worry about their fertility until they were older and actually wanted to have children (23% of males and 20% of females).

And some subjects said they would rely on assisted reproductive technology if necessary (31% of males and 20% of females).

Dr Benedict and her colleagues said this study suggests AYA cancer survivors may have a number of reproductive concerns and fertility-related distress, which may affect other areas of psychosocial functioning.

So future research should explore how to best incorporate fertility-related informational and support services more fully into survivorship care.

Doctor examines patient

in the intensive care unit

A study of end-of-life cancer care practices in 7 countries suggests the US has the lowest proportion of deaths in the hospital and the lowest number of days in the hospital for patients in their last 6 months of life.

However, the US performed poorly in other aspects of care, particularly intensive care unit admissions and hospital expenditures.

The other countries included in the study were Belgium, Canada, England, Germany, the Netherlands, and Norway.

The research was published in JAMA.

Ezekiel J. Emanuel, MD, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues examined patterns of care, healthcare utilization, and expenditures for dying cancer patients in the 7 aforementioned countries.

The researchers first analyzed data from 2010 that included subjects older than 65 years of age who died with cancer.

The proportion of patients who died in the hospital was 22.2% in the US, 29.4% in the Netherlands, 38.3% in Germany, 41.7% in England, 44.7% in Norway, 51.2% in Belgium, and 52.1% in Canada.

In the last 180 days of life, the mean number of days in the hospital per capita was 27.7 in Belgium, 24.8 in Norway, 21.7 in Germany, 19 in Canada, 18.3 in England, 17.8 in the Netherlands, and 10.7 in the US.

The proportion of patients admitted to the intensive care unit in their last 180 days of life was 40.3% in the US, 18.5% in Belgium, 15.2% in Canada, 10.2% in the Netherlands, and 8.2% in Germany. Data were not available for England and Norway.

In the last 180 days of life, average per capita hospital expenditures (in USD) were higher in Canada ($21,840), Norway ($19,783), and the US ($18,500), intermediate in Germany ($16,221) and Belgium ($15,699), and lowest in the Netherlands ($10,936) and England ($9342).

Analyses that included decedents of any age, decedents older than 65 years of age with lung cancer, and decedents older than 65 years in the US and Germany from 2012 showed similar results.

The researchers said this suggests the differences observed were driven more by end-of-life care practices and organization rather than differences in cohort identification.

Doctor examines patient

in the intensive care unit

A study of end-of-life cancer care practices in 7 countries suggests the US has the lowest proportion of deaths in the hospital and the lowest number of days in the hospital for patients in their last 6 months of life.

However, the US performed poorly in other aspects of care, particularly intensive care unit admissions and hospital expenditures.

The other countries included in the study were Belgium, Canada, England, Germany, the Netherlands, and Norway.

The research was published in JAMA.

Ezekiel J. Emanuel, MD, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues examined patterns of care, healthcare utilization, and expenditures for dying cancer patients in the 7 aforementioned countries.

The researchers first analyzed data from 2010 that included subjects older than 65 years of age who died with cancer.

The proportion of patients who died in the hospital was 22.2% in the US, 29.4% in the Netherlands, 38.3% in Germany, 41.7% in England, 44.7% in Norway, 51.2% in Belgium, and 52.1% in Canada.

In the last 180 days of life, the mean number of days in the hospital per capita was 27.7 in Belgium, 24.8 in Norway, 21.7 in Germany, 19 in Canada, 18.3 in England, 17.8 in the Netherlands, and 10.7 in the US.

The proportion of patients admitted to the intensive care unit in their last 180 days of life was 40.3% in the US, 18.5% in Belgium, 15.2% in Canada, 10.2% in the Netherlands, and 8.2% in Germany. Data were not available for England and Norway.

In the last 180 days of life, average per capita hospital expenditures (in USD) were higher in Canada ($21,840), Norway ($19,783), and the US ($18,500), intermediate in Germany ($16,221) and Belgium ($15,699), and lowest in the Netherlands ($10,936) and England ($9342).

Analyses that included decedents of any age, decedents older than 65 years of age with lung cancer, and decedents older than 65 years in the US and Germany from 2012 showed similar results.

The researchers said this suggests the differences observed were driven more by end-of-life care practices and organization rather than differences in cohort identification.

Doctor examines patient

in the intensive care unit

A study of end-of-life cancer care practices in 7 countries suggests the US has the lowest proportion of deaths in the hospital and the lowest number of days in the hospital for patients in their last 6 months of life.

However, the US performed poorly in other aspects of care, particularly intensive care unit admissions and hospital expenditures.

The other countries included in the study were Belgium, Canada, England, Germany, the Netherlands, and Norway.

The research was published in JAMA.

Ezekiel J. Emanuel, MD, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues examined patterns of care, healthcare utilization, and expenditures for dying cancer patients in the 7 aforementioned countries.

The researchers first analyzed data from 2010 that included subjects older than 65 years of age who died with cancer.

The proportion of patients who died in the hospital was 22.2% in the US, 29.4% in the Netherlands, 38.3% in Germany, 41.7% in England, 44.7% in Norway, 51.2% in Belgium, and 52.1% in Canada.

In the last 180 days of life, the mean number of days in the hospital per capita was 27.7 in Belgium, 24.8 in Norway, 21.7 in Germany, 19 in Canada, 18.3 in England, 17.8 in the Netherlands, and 10.7 in the US.

The proportion of patients admitted to the intensive care unit in their last 180 days of life was 40.3% in the US, 18.5% in Belgium, 15.2% in Canada, 10.2% in the Netherlands, and 8.2% in Germany. Data were not available for England and Norway.

In the last 180 days of life, average per capita hospital expenditures (in USD) were higher in Canada ($21,840), Norway ($19,783), and the US ($18,500), intermediate in Germany ($16,221) and Belgium ($15,699), and lowest in the Netherlands ($10,936) and England ($9342).

Analyses that included decedents of any age, decedents older than 65 years of age with lung cancer, and decedents older than 65 years in the US and Germany from 2012 showed similar results.

The researchers said this suggests the differences observed were driven more by end-of-life care practices and organization rather than differences in cohort identification.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to the BCL-2 inhibitor venetoclax when given with rituximab to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Venetoclax already had breakthrough designation from the FDA as single-agent treatment for patients with relapsed or refractory CLL and 17p deletion.

The drug was granted priority review for this indication as well.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The latest breakthrough designation for venetoclax is supported by a phase 2 study of the drug in combination with rituximab in patients with relapsed/refractory CLL. Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 325).

Another phase 2 trial presented at that meeting (abstract LBA-6) showed that single-agent venetoclax is effective against CLL as well.

The drug has also proven active against other hematologic malignancies, including acute myeloid lekemia and multiple myeloma.

However, venetoclax has been shown to pose a risk of tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to the BCL-2 inhibitor venetoclax when given with rituximab to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Venetoclax already had breakthrough designation from the FDA as single-agent treatment for patients with relapsed or refractory CLL and 17p deletion.

The drug was granted priority review for this indication as well.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The latest breakthrough designation for venetoclax is supported by a phase 2 study of the drug in combination with rituximab in patients with relapsed/refractory CLL. Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 325).

Another phase 2 trial presented at that meeting (abstract LBA-6) showed that single-agent venetoclax is effective against CLL as well.

The drug has also proven active against other hematologic malignancies, including acute myeloid lekemia and multiple myeloma.

However, venetoclax has been shown to pose a risk of tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to the BCL-2 inhibitor venetoclax when given with rituximab to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Venetoclax already had breakthrough designation from the FDA as single-agent treatment for patients with relapsed or refractory CLL and 17p deletion.

The drug was granted priority review for this indication as well.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The latest breakthrough designation for venetoclax is supported by a phase 2 study of the drug in combination with rituximab in patients with relapsed/refractory CLL. Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 325).

Another phase 2 trial presented at that meeting (abstract LBA-6) showed that single-agent venetoclax is effective against CLL as well.

The drug has also proven active against other hematologic malignancies, including acute myeloid lekemia and multiple myeloma.

However, venetoclax has been shown to pose a risk of tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Ben Shields, PhD, (left)

and Matt McCormack, PhD

Photo courtesy of the

Walter and Eliza Hall

Institute of Medical Research

Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).

Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.

Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.

“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”

Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.

However, Hhex was not required for normal myelopoiesis.

“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.

“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”

Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.

They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.

“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.

“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”

Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.

“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.

“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”

Ben Shields, PhD, (left)

and Matt McCormack, PhD

Photo courtesy of the

Walter and Eliza Hall

Institute of Medical Research

Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).

Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.

Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.

“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”

Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.

However, Hhex was not required for normal myelopoiesis.

“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.

“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”

Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.

They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.

“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.

“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”

Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.

“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.

“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”

Ben Shields, PhD, (left)

and Matt McCormack, PhD

Photo courtesy of the

Walter and Eliza Hall

Institute of Medical Research

Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).

Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.

Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.

“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”

Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.

However, Hhex was not required for normal myelopoiesis.

“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.

“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”

Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.

They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.

“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.

“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”

Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.

“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.

“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”