Leukemia, Myelodysplasia, Transplantation

Mitochondria (red and green)

surrounding fused cells

Credit: IRB Barcelona

Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.

Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.

The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.

TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.

To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.

“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.

“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”

Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.

“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”

The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.

According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.

Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.

“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”

Mitochondria (red and green)

surrounding fused cells

Credit: IRB Barcelona

Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.

Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.

The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.

TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.

To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.

“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.

“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”

Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.

“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”

The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.

According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.

Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.

“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”

Mitochondria (red and green)

surrounding fused cells

Credit: IRB Barcelona

Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.

Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.

The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.

TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.

To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.

“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.

“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”

Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.

“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”

The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.

According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.

Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.

“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”

Slide showing LSCs

Credit: Robert Paulson

Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).

NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).

In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.

The researchers detailed these results in Cancer Research.

“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.

Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.

To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.

The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.

On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.

Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.

“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.

Slide showing LSCs

Credit: Robert Paulson

Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).

NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).

In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.

The researchers detailed these results in Cancer Research.

“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.

Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.

To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.

The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.

On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.

Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.

“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.

Slide showing LSCs

Credit: Robert Paulson

Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).

NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).

In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.

The researchers detailed these results in Cancer Research.

“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.

Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.

To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.

The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.

On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.

Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.

“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.

Hematopoietic stem cells
in the bone marrow

A new study helps explain how blood production declines with age and why older individuals are not suitable donors for hematopoietic stem cell (HSC) transplant.

The research also reveals a potential approach for mitigating

the negative effects of aging on the blood, which can lead to anemia,

bone marrow failure, and myeloid malignancies.

The study, conducted in mice, suggests HSCs falter with age because they lose the ability to replicate their DNA accurately and efficiently during cell division.

Emmanuelle Passegué, PhD, of the University of California San Francisco, and her colleagues reported this discovery in Nature.

The researchers analyzed old HSCs in mice and found a scarcity of protein components needed to form the mini-chromosome maintenance helicase. This molecular machine unwinds double-stranded DNA so the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division.

The HSCs were stressed by the loss of this machine’s activity. As a result, they had an increased risk for DNA damage and death when forced to divide.

On the other hand, the cells tended to survive unless they were confronted with a “strong replication challenge” like transplantation.

The researchers also discovered that even after the stress associated with DNA replication, old HSCs retained molecular tags on histones, a feature often associated with DNA damage.

However, these old survivors could repair induced DNA damage as efficiently as young stem cells.

“Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated,” Dr Passegué said.

Of course, not all was well in the old, surviving HSCs. The molecular tags accumulated on genes needed to make ribosomes.

Dr Passegué said she will further explore the consequences of reduced protein production as part of her ongoing research. She hopes it might be possible to prevent declining stem cell populations by developing a drug to prevent the loss of the helicase components needed to unwind and replicate DNA, thereby avoiding immune system failure.

Hematopoietic stem cells
in the bone marrow

A new study helps explain how blood production declines with age and why older individuals are not suitable donors for hematopoietic stem cell (HSC) transplant.

The research also reveals a potential approach for mitigating

the negative effects of aging on the blood, which can lead to anemia,

bone marrow failure, and myeloid malignancies.

The study, conducted in mice, suggests HSCs falter with age because they lose the ability to replicate their DNA accurately and efficiently during cell division.

Emmanuelle Passegué, PhD, of the University of California San Francisco, and her colleagues reported this discovery in Nature.

The researchers analyzed old HSCs in mice and found a scarcity of protein components needed to form the mini-chromosome maintenance helicase. This molecular machine unwinds double-stranded DNA so the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division.

The HSCs were stressed by the loss of this machine’s activity. As a result, they had an increased risk for DNA damage and death when forced to divide.

On the other hand, the cells tended to survive unless they were confronted with a “strong replication challenge” like transplantation.

The researchers also discovered that even after the stress associated with DNA replication, old HSCs retained molecular tags on histones, a feature often associated with DNA damage.

However, these old survivors could repair induced DNA damage as efficiently as young stem cells.

“Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated,” Dr Passegué said.

Of course, not all was well in the old, surviving HSCs. The molecular tags accumulated on genes needed to make ribosomes.

Dr Passegué said she will further explore the consequences of reduced protein production as part of her ongoing research. She hopes it might be possible to prevent declining stem cell populations by developing a drug to prevent the loss of the helicase components needed to unwind and replicate DNA, thereby avoiding immune system failure.

Hematopoietic stem cells
in the bone marrow

A new study helps explain how blood production declines with age and why older individuals are not suitable donors for hematopoietic stem cell (HSC) transplant.

The research also reveals a potential approach for mitigating

the negative effects of aging on the blood, which can lead to anemia,

bone marrow failure, and myeloid malignancies.

The study, conducted in mice, suggests HSCs falter with age because they lose the ability to replicate their DNA accurately and efficiently during cell division.

Emmanuelle Passegué, PhD, of the University of California San Francisco, and her colleagues reported this discovery in Nature.

The researchers analyzed old HSCs in mice and found a scarcity of protein components needed to form the mini-chromosome maintenance helicase. This molecular machine unwinds double-stranded DNA so the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division.

The HSCs were stressed by the loss of this machine’s activity. As a result, they had an increased risk for DNA damage and death when forced to divide.

On the other hand, the cells tended to survive unless they were confronted with a “strong replication challenge” like transplantation.

The researchers also discovered that even after the stress associated with DNA replication, old HSCs retained molecular tags on histones, a feature often associated with DNA damage.

However, these old survivors could repair induced DNA damage as efficiently as young stem cells.

“Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated,” Dr Passegué said.

Of course, not all was well in the old, surviving HSCs. The molecular tags accumulated on genes needed to make ribosomes.

Dr Passegué said she will further explore the consequences of reduced protein production as part of her ongoing research. She hopes it might be possible to prevent declining stem cell populations by developing a drug to prevent the loss of the helicase components needed to unwind and replicate DNA, thereby avoiding immune system failure.

Test tubes

Researchers have discovered a potential therapeutic target for T-cell acute lymphoblastic leukemia (T-ALL), according to a paper published in Cell.

The team first identified long, non-coding strands of RNA (lncRNA) that were active in T cells from patients with T-ALL but not in the healthy T cells of subjects without the disease.

Further analysis revealed that inhibiting 1 of these lncRNAs, LUNAR1 (leukemia-induced non-coding activator RNA-1), stalled T-ALL growth in vitro and in vivo.

The study offers preliminary evidence that drugs targeting LUNAR1 could treat T-ALL, and LUNAR1 could aid in diagnosing the disease, said Iannis Aifantis, PhD, of NYU Langone Medical Center in New York.

“Our study shows that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia and plays a key role in how this cancer develops,” he noted, adding that overproduction of LUNAR1 was recorded in almost all (90%) of the leukemia patients analyzed.

To make these discoveries, Dr Aifantis and his colleagues performed ultra-high-depth RNA sequencing of human T-ALL cell lines and primary leukemia samples.

They used the resulting data to generate the most comprehensive T-ALL transcriptome assembly to date and then isolated putative lncRNA genes. This revealed 6023 lncRNAs that are active in T-ALL, 60% of which had not been identified before.

The researchers zeroed in on LUNAR1 by pinpointing the lncRNAs that were active in the NOTCH1 pathway, which is active in at least half of T-ALL patients. LUNAR1 stood out right away, the team said, as the most highly expressed lncRNA.

The researchers also found that LUNAR1 does not produce cancerous proteins on its own. However, its production proved essential to the cell-to-cell signaling action of another protein, IGF-1R (insulin-like growth factor 1 receptor), which is tied to many cancers, including leukemia.

Additional experiments showed that the gene coding for LUNAR1 is near the gene for IGF-1R and located toward the end of the chromosome. When activated, LUNAR1’s position allows it to chemically loop back and, in turn, bind to and activate IGF-1R.

According to Dr Aifantis, this research shows that T-ALL could simply be described as a condition of “too much errant signaling.” He noted that, in normal T cells, lncRNAs such as LUNAR1 are not transcribed, NOTCH1 is inactive, and there is no looping back of LUNAR1 to activate IGF-1R.

To confirm their findings, the researchers also transplanted human leukemia T cells into mice and inhibited LUNAR1 in some of the animals. Tumor growth stalled only in those mice in which LUNAR1 was inactivated.

The researchers said their next step is to develop a more effective inhibitor of LUNAR1, preferably something that would precisely target 1 or more of its 200-plus component nucleotides.

Test tubes

Researchers have discovered a potential therapeutic target for T-cell acute lymphoblastic leukemia (T-ALL), according to a paper published in Cell.

The team first identified long, non-coding strands of RNA (lncRNA) that were active in T cells from patients with T-ALL but not in the healthy T cells of subjects without the disease.

Further analysis revealed that inhibiting 1 of these lncRNAs, LUNAR1 (leukemia-induced non-coding activator RNA-1), stalled T-ALL growth in vitro and in vivo.

The study offers preliminary evidence that drugs targeting LUNAR1 could treat T-ALL, and LUNAR1 could aid in diagnosing the disease, said Iannis Aifantis, PhD, of NYU Langone Medical Center in New York.

“Our study shows that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia and plays a key role in how this cancer develops,” he noted, adding that overproduction of LUNAR1 was recorded in almost all (90%) of the leukemia patients analyzed.

To make these discoveries, Dr Aifantis and his colleagues performed ultra-high-depth RNA sequencing of human T-ALL cell lines and primary leukemia samples.

They used the resulting data to generate the most comprehensive T-ALL transcriptome assembly to date and then isolated putative lncRNA genes. This revealed 6023 lncRNAs that are active in T-ALL, 60% of which had not been identified before.

The researchers zeroed in on LUNAR1 by pinpointing the lncRNAs that were active in the NOTCH1 pathway, which is active in at least half of T-ALL patients. LUNAR1 stood out right away, the team said, as the most highly expressed lncRNA.

The researchers also found that LUNAR1 does not produce cancerous proteins on its own. However, its production proved essential to the cell-to-cell signaling action of another protein, IGF-1R (insulin-like growth factor 1 receptor), which is tied to many cancers, including leukemia.

Additional experiments showed that the gene coding for LUNAR1 is near the gene for IGF-1R and located toward the end of the chromosome. When activated, LUNAR1’s position allows it to chemically loop back and, in turn, bind to and activate IGF-1R.

According to Dr Aifantis, this research shows that T-ALL could simply be described as a condition of “too much errant signaling.” He noted that, in normal T cells, lncRNAs such as LUNAR1 are not transcribed, NOTCH1 is inactive, and there is no looping back of LUNAR1 to activate IGF-1R.

To confirm their findings, the researchers also transplanted human leukemia T cells into mice and inhibited LUNAR1 in some of the animals. Tumor growth stalled only in those mice in which LUNAR1 was inactivated.

The researchers said their next step is to develop a more effective inhibitor of LUNAR1, preferably something that would precisely target 1 or more of its 200-plus component nucleotides.

Test tubes

Researchers have discovered a potential therapeutic target for T-cell acute lymphoblastic leukemia (T-ALL), according to a paper published in Cell.

The team first identified long, non-coding strands of RNA (lncRNA) that were active in T cells from patients with T-ALL but not in the healthy T cells of subjects without the disease.

Further analysis revealed that inhibiting 1 of these lncRNAs, LUNAR1 (leukemia-induced non-coding activator RNA-1), stalled T-ALL growth in vitro and in vivo.

The study offers preliminary evidence that drugs targeting LUNAR1 could treat T-ALL, and LUNAR1 could aid in diagnosing the disease, said Iannis Aifantis, PhD, of NYU Langone Medical Center in New York.

“Our study shows that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia and plays a key role in how this cancer develops,” he noted, adding that overproduction of LUNAR1 was recorded in almost all (90%) of the leukemia patients analyzed.

To make these discoveries, Dr Aifantis and his colleagues performed ultra-high-depth RNA sequencing of human T-ALL cell lines and primary leukemia samples.

They used the resulting data to generate the most comprehensive T-ALL transcriptome assembly to date and then isolated putative lncRNA genes. This revealed 6023 lncRNAs that are active in T-ALL, 60% of which had not been identified before.

The researchers zeroed in on LUNAR1 by pinpointing the lncRNAs that were active in the NOTCH1 pathway, which is active in at least half of T-ALL patients. LUNAR1 stood out right away, the team said, as the most highly expressed lncRNA.

The researchers also found that LUNAR1 does not produce cancerous proteins on its own. However, its production proved essential to the cell-to-cell signaling action of another protein, IGF-1R (insulin-like growth factor 1 receptor), which is tied to many cancers, including leukemia.

Additional experiments showed that the gene coding for LUNAR1 is near the gene for IGF-1R and located toward the end of the chromosome. When activated, LUNAR1’s position allows it to chemically loop back and, in turn, bind to and activate IGF-1R.

According to Dr Aifantis, this research shows that T-ALL could simply be described as a condition of “too much errant signaling.” He noted that, in normal T cells, lncRNAs such as LUNAR1 are not transcribed, NOTCH1 is inactive, and there is no looping back of LUNAR1 to activate IGF-1R.

To confirm their findings, the researchers also transplanted human leukemia T cells into mice and inhibited LUNAR1 in some of the animals. Tumor growth stalled only in those mice in which LUNAR1 was inactivated.

The researchers said their next step is to develop a more effective inhibitor of LUNAR1, preferably something that would precisely target 1 or more of its 200-plus component nucleotides.

Myelodysplastic syndromes (MDS) are a spectrum of clonal myeloid disorders characterized by ineffective hematopoiesis, cytopenias, qualitative disorders of blood cells, clonal chromosomal abnormalities, and the potential for clonal evolution to acute myeloid leukemia (AML). In this review, we discuss the various pathogenic conditions included in the spectrum of MDS and the associated risk stratification for these conditions. We further discuss the treatment recommendations based on the risk status and the expected prognosis.

To read the full article in PDF:

Click here

Myelodysplastic syndromes (MDS) are a spectrum of clonal myeloid disorders characterized by ineffective hematopoiesis, cytopenias, qualitative disorders of blood cells, clonal chromosomal abnormalities, and the potential for clonal evolution to acute myeloid leukemia (AML). In this review, we discuss the various pathogenic conditions included in the spectrum of MDS and the associated risk stratification for these conditions. We further discuss the treatment recommendations based on the risk status and the expected prognosis.

To read the full article in PDF:

Click here

Myelodysplastic syndromes (MDS) are a spectrum of clonal myeloid disorders characterized by ineffective hematopoiesis, cytopenias, qualitative disorders of blood cells, clonal chromosomal abnormalities, and the potential for clonal evolution to acute myeloid leukemia (AML). In this review, we discuss the various pathogenic conditions included in the spectrum of MDS and the associated risk stratification for these conditions. We further discuss the treatment recommendations based on the risk status and the expected prognosis.

To read the full article in PDF:

Click here

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.