AML

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

mbock@frontlinemedcom.com

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

mbock@frontlinemedcom.com

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

mbock@frontlinemedcom.com

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.