Leukemia, Myelodysplasia, Transplantation

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

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.