Leukemia, Myelodysplasia, Transplantation

General Medical Sciences

New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.

Researchers found they could divide patients into risk groups according to their methylation levels.

Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.

“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.

She and her colleagues described this research in Nature Communications.

The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.

Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.

In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.

In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.

“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.

“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”

The researchers also found that methylation levels might predict spontaneous remission as well.

Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.

“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.

“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.”

General Medical Sciences

New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.

Researchers found they could divide patients into risk groups according to their methylation levels.

Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.

“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.

She and her colleagues described this research in Nature Communications.

The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.

Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.

In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.

In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.

“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.

“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”

The researchers also found that methylation levels might predict spontaneous remission as well.

Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.

“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.

“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.”

General Medical Sciences

New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.

Researchers found they could divide patients into risk groups according to their methylation levels.

Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.

“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.

She and her colleagues described this research in Nature Communications.

The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.

Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.

In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.

In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.

“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.

“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”

The researchers also found that methylation levels might predict spontaneous remission as well.

Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.

“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.

“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Lab mouse

Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).

By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.

In fact, the team observed AML regression with no harmful impact on the function of normal cells.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.

“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”

With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.

First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.

Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.

Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”

The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.

In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.

For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.

The team observed “marked” AML regression and prolonged survival in these mice compared to controls.

While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.

“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”

Lab mouse

Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).

By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.

In fact, the team observed AML regression with no harmful impact on the function of normal cells.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.

“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”

With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.

First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.

Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.

Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”

The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.

In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.

For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.

The team observed “marked” AML regression and prolonged survival in these mice compared to controls.

While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.

“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”

Lab mouse

Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).

By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.

In fact, the team observed AML regression with no harmful impact on the function of normal cells.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.

“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”

With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.

First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.

Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.

Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”

The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.

In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.

For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.

The team observed “marked” AML regression and prolonged survival in these mice compared to controls.

While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.

“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”

Photo courtesy of Janssen

New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).

It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.

But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.

Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.

The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.

These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.

With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.

Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.

The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.

The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.

“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.

“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”

Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.

The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.

Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”

The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.

“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.

Photo courtesy of Janssen

New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).

It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.

But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.

Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.

The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.

These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.

With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.

Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.

The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.

The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.

“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.

“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”

Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.

The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.

Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”

The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.

“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.

Photo courtesy of Janssen

New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).

It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.

But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.

Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.

The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.

These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.

With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.

Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.

The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.

The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.

“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.

“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”

Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.

The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.

Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”

The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.

“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

 

ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.

Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“In an unprecedentedly large AML cohort we show that assessment of residual gene mutations in CR by next-generation sequencing is applicable to the great majority of newly diagnosed adults with AML,” Dr. Grob said.

By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.

They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.

More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.

To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.

The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.

They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.

About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).

Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.

However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).

Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).

When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).

NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).

In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).

When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.

The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.

SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.

 

ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.

Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“In an unprecedentedly large AML cohort we show that assessment of residual gene mutations in CR by next-generation sequencing is applicable to the great majority of newly diagnosed adults with AML,” Dr. Grob said.

By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.

They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.

More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.

To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.

The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.

They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.

About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).

Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.

However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).

Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).

When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).

NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).

In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).

When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.

The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.

SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.

 

ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.

Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“In an unprecedentedly large AML cohort we show that assessment of residual gene mutations in CR by next-generation sequencing is applicable to the great majority of newly diagnosed adults with AML,” Dr. Grob said.

By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.

They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.

More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.

To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.

The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.

They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.

About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).

Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.

However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).

Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).

When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).

NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).

In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).

When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.

The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.

SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.

HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).

The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).

Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.

The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.

With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.

No adverse events related to CX-01 were reported.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.

HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).

The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).

Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.

The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.

With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.

No adverse events related to CX-01 were reported.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.

HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).

The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).

Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.

The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.

With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.

No adverse events related to CX-01 were reported.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

 

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

“Our mature data after a median follow-up of 6.5 years confirms a significant prolongation by the addition of sorafenib to standard chemotherapy in terms of event-free survival. We saw a significant [relapse-free survival] prolongation with sorafenib, with a hazard ratio of 0.64, which means that five to six patients need to be treated with sorafenib in order to prevent one relapse,” he said at the annual meeting of the American Society of Hematology.

Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.

In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.

Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m² on days 3-5) plus cytarabine (100 mg/m² on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m² twice daily on days 1, 3, and 5).

Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.

The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).

The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.

At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.

A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.

Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).

Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.

Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.

Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.

OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).

During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.

“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.

Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.

The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
 

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

 

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

“Our mature data after a median follow-up of 6.5 years confirms a significant prolongation by the addition of sorafenib to standard chemotherapy in terms of event-free survival. We saw a significant [relapse-free survival] prolongation with sorafenib, with a hazard ratio of 0.64, which means that five to six patients need to be treated with sorafenib in order to prevent one relapse,” he said at the annual meeting of the American Society of Hematology.

Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.

In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.

Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m² on days 3-5) plus cytarabine (100 mg/m² on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m² twice daily on days 1, 3, and 5).

Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.

The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).

The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.

At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.

A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.

Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).

Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.

Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.

Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.

OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).

During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.

“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.

Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.

The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
 

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

 

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

“Our mature data after a median follow-up of 6.5 years confirms a significant prolongation by the addition of sorafenib to standard chemotherapy in terms of event-free survival. We saw a significant [relapse-free survival] prolongation with sorafenib, with a hazard ratio of 0.64, which means that five to six patients need to be treated with sorafenib in order to prevent one relapse,” he said at the annual meeting of the American Society of Hematology.

Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.

In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.

Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m² on days 3-5) plus cytarabine (100 mg/m² on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m² twice daily on days 1, 3, and 5).

Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.

The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).

The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.

At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.

A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.

Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).

Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.

Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.

Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.

OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).

During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.

“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.

Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.

The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
 

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.