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Aggressive infant leukemia has few mutations
Photo by Vera Kratochvil
Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.
The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.
“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”
Dr Wilson and his colleagues reported their findings in Nature Genetics.
The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.
The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.
“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”
Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.
Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.
“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.
The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10−5).
Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.
“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.
“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.
“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.” 
Photo by Vera Kratochvil
Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.
The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.
“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”
Dr Wilson and his colleagues reported their findings in Nature Genetics.
The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.
The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.
“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”
Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.
Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.
“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.
The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10−5).
Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.
“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.
“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.
“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”
Photo by Vera Kratochvil
Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.
The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.
“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”
Dr Wilson and his colleagues reported their findings in Nature Genetics.
The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.
The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.
“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”
Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.
Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.
“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.
The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10−5).
Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.
“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.
“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.
“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”
FDA approves first biosimilar product
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.
A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.
Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.
Zarxio can be prescribed for:
- patients with cancer receiving myelosuppressive chemotherapy
- patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
- patients with cancer undergoing bone marrow transplant
- patients undergoing autologous peripheral blood progenitor cell collection and therapy
- patients with severe chronic neutropenia.
Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.
“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.
“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”
Zarxio data
The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.
The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.
In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.
The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.
The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.
About biosimilar approval
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.
This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.
A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.
There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.
Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.
For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.
While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.
For more details on Zarxio, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.
A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.
Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.
Zarxio can be prescribed for:
- patients with cancer receiving myelosuppressive chemotherapy
- patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
- patients with cancer undergoing bone marrow transplant
- patients undergoing autologous peripheral blood progenitor cell collection and therapy
- patients with severe chronic neutropenia.
Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.
“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.
“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”
Zarxio data
The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.
The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.
In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.
The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.
The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.
About biosimilar approval
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.
This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.
A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.
There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.
Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.
For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.
While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.
For more details on Zarxio, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.
A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.
Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.
Zarxio can be prescribed for:
- patients with cancer receiving myelosuppressive chemotherapy
- patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
- patients with cancer undergoing bone marrow transplant
- patients undergoing autologous peripheral blood progenitor cell collection and therapy
- patients with severe chronic neutropenia.
Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.
“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.
“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”
Zarxio data
The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.
The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.
In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.
The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.
The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.
About biosimilar approval
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.
This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.
A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.
There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.
Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.
For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.
While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.
For more details on Zarxio, see the full prescribing information.
NICE recommends apixaban for VTE
Image by Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
A NICE committee concluded that apixaban is clinically and cost-effective for this indication.
The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources.
Image by Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
A NICE committee concluded that apixaban is clinically and cost-effective for this indication.
The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources.
Image by Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
A NICE committee concluded that apixaban is clinically and cost-effective for this indication.
The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources.
FDA approves new antifungal drug
The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.
Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.
“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Clinical trials
The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.
Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.
In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole
The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.
All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.
The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
QIDP status
Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.
As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.
As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.
Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.
Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.
“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Clinical trials
The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.
Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.
In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole
The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.
All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.
The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
QIDP status
Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.
As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.
As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.
Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.
Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.
“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Clinical trials
The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.
Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.
In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole
The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.
All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.
The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
QIDP status
Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.
As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.
As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.
Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.
‘Biodegradable’ CAR may aid transplant in AML
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”
Photo courtesy of
BMT Tandem Meetings
SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.
The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.
In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.
The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.
Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.
“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”
With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.
The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.
The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.
At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.
Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.
Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.
“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.
“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”
So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.
In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.
The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.
Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).
Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.
The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.
“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.
“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”
MGUS diagnosis linked to survival in MM
Patients with multiple myeloma (MM) appear to have better survival if they are first diagnosed with monoclonal gammopathy of undetermined significance (MGUS), according to a study published in JAMA Oncology.
The researchers think this may be because patients with MGUS are evaluated more often for signs of progression to MM. They may therefore be diagnosed with MM and started on therapy at an earlier stage than patients who have not been diagnosed with MGUS.
However, the study did not verify that MM patients initially diagnosed with MGUS were followed more closely than their peers.
So, as authors of a related editorial pointed out, it is difficult to confirm a causal relationship between closer follow-up and better prognosis.
Sigurdur Y. Kristinsson, MD, PhD, of the University of Iceland in Reykjavik, and his colleagues conducted this study, evaluating the impact of prior knowledge of MGUS diagnosis and coexisting illnesses on MM survival.
The study included all patients diagnosed with MM in Sweden (n=14,798) from 1976 to 2005. In all, 394 patients (2.7%) had previously been diagnosed with MGUS.
Patients with prior knowledge of MGUS had better overall survival than patients with MM who didn’t know when they had MGUS—a median survival of 2.8 years and 2.1 years, respectively (hazard ratio=0.86, P<0.01).
But patients with prior knowledge of their MGUS status had more coexisting illnesses, including systemic and organ-bound autoimmune diseases (P=0.02 for both), autoimmune diseases without auto-antibodies (P<0.001), infections (P<0.001), ischemic heart disease (P<0.001), heart failure (P=0.03), cerebrovascular diseases (P=0.04), and renal diseases (P<0.001).
Low M-protein concentration at MGUS diagnosis was associated with poorer survival among MM patients with prior knowledge of MGUS. Patients who had M-protein concentrations less than 0.5 g/dL had significantly worse survival than patients with concentrations of 0.5 to 3.0 g/dL (hazard ratio=1.86, P=0.01).
The researchers said the worse survival observed in these patients may be a result of less frequent clinical follow-up.
“Our results reflect the importance of lifelong follow-up for individuals diagnosed as having MGUS, independent of risk score, and highlight the need for better risk models based on the biology of the disease,” the researchers wrote.
“Patients should receive balanced information stressing not only the overall very low risk of progression to malignant neoplasm but also the symptoms that could signal such development and the need to consult their physician.”
Authors of a related editorial—Robert A. Kyle, MD, and S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota—expressed a somewhat different viewpoint.
“It cannot be determined whether MM patients with a known MGUS in the Icelandic study were followed more closely than those in whom a MGUS was not recognized, and, hence, it is difficult to attribute a causal relationship between follow-up and better prognosis,” they wrote.
“We also need studies to address the question of the possible merits of screening for the presence of MGUS in a normal, older population. The cost, inconvenience, and anxiety produced by the awareness of potential progression of a recognized MGUS, as well as the low absolute risk of progression (0.5% to 1%), probably override the possible potential benefit of screening for MGUS.”
Patients with multiple myeloma (MM) appear to have better survival if they are first diagnosed with monoclonal gammopathy of undetermined significance (MGUS), according to a study published in JAMA Oncology.
The researchers think this may be because patients with MGUS are evaluated more often for signs of progression to MM. They may therefore be diagnosed with MM and started on therapy at an earlier stage than patients who have not been diagnosed with MGUS.
However, the study did not verify that MM patients initially diagnosed with MGUS were followed more closely than their peers.
So, as authors of a related editorial pointed out, it is difficult to confirm a causal relationship between closer follow-up and better prognosis.
Sigurdur Y. Kristinsson, MD, PhD, of the University of Iceland in Reykjavik, and his colleagues conducted this study, evaluating the impact of prior knowledge of MGUS diagnosis and coexisting illnesses on MM survival.
The study included all patients diagnosed with MM in Sweden (n=14,798) from 1976 to 2005. In all, 394 patients (2.7%) had previously been diagnosed with MGUS.
Patients with prior knowledge of MGUS had better overall survival than patients with MM who didn’t know when they had MGUS—a median survival of 2.8 years and 2.1 years, respectively (hazard ratio=0.86, P<0.01).
But patients with prior knowledge of their MGUS status had more coexisting illnesses, including systemic and organ-bound autoimmune diseases (P=0.02 for both), autoimmune diseases without auto-antibodies (P<0.001), infections (P<0.001), ischemic heart disease (P<0.001), heart failure (P=0.03), cerebrovascular diseases (P=0.04), and renal diseases (P<0.001).
Low M-protein concentration at MGUS diagnosis was associated with poorer survival among MM patients with prior knowledge of MGUS. Patients who had M-protein concentrations less than 0.5 g/dL had significantly worse survival than patients with concentrations of 0.5 to 3.0 g/dL (hazard ratio=1.86, P=0.01).
The researchers said the worse survival observed in these patients may be a result of less frequent clinical follow-up.
“Our results reflect the importance of lifelong follow-up for individuals diagnosed as having MGUS, independent of risk score, and highlight the need for better risk models based on the biology of the disease,” the researchers wrote.
“Patients should receive balanced information stressing not only the overall very low risk of progression to malignant neoplasm but also the symptoms that could signal such development and the need to consult their physician.”
Authors of a related editorial—Robert A. Kyle, MD, and S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota—expressed a somewhat different viewpoint.
“It cannot be determined whether MM patients with a known MGUS in the Icelandic study were followed more closely than those in whom a MGUS was not recognized, and, hence, it is difficult to attribute a causal relationship between follow-up and better prognosis,” they wrote.
“We also need studies to address the question of the possible merits of screening for the presence of MGUS in a normal, older population. The cost, inconvenience, and anxiety produced by the awareness of potential progression of a recognized MGUS, as well as the low absolute risk of progression (0.5% to 1%), probably override the possible potential benefit of screening for MGUS.”
Patients with multiple myeloma (MM) appear to have better survival if they are first diagnosed with monoclonal gammopathy of undetermined significance (MGUS), according to a study published in JAMA Oncology.
The researchers think this may be because patients with MGUS are evaluated more often for signs of progression to MM. They may therefore be diagnosed with MM and started on therapy at an earlier stage than patients who have not been diagnosed with MGUS.
However, the study did not verify that MM patients initially diagnosed with MGUS were followed more closely than their peers.
So, as authors of a related editorial pointed out, it is difficult to confirm a causal relationship between closer follow-up and better prognosis.
Sigurdur Y. Kristinsson, MD, PhD, of the University of Iceland in Reykjavik, and his colleagues conducted this study, evaluating the impact of prior knowledge of MGUS diagnosis and coexisting illnesses on MM survival.
The study included all patients diagnosed with MM in Sweden (n=14,798) from 1976 to 2005. In all, 394 patients (2.7%) had previously been diagnosed with MGUS.
Patients with prior knowledge of MGUS had better overall survival than patients with MM who didn’t know when they had MGUS—a median survival of 2.8 years and 2.1 years, respectively (hazard ratio=0.86, P<0.01).
But patients with prior knowledge of their MGUS status had more coexisting illnesses, including systemic and organ-bound autoimmune diseases (P=0.02 for both), autoimmune diseases without auto-antibodies (P<0.001), infections (P<0.001), ischemic heart disease (P<0.001), heart failure (P=0.03), cerebrovascular diseases (P=0.04), and renal diseases (P<0.001).
Low M-protein concentration at MGUS diagnosis was associated with poorer survival among MM patients with prior knowledge of MGUS. Patients who had M-protein concentrations less than 0.5 g/dL had significantly worse survival than patients with concentrations of 0.5 to 3.0 g/dL (hazard ratio=1.86, P=0.01).
The researchers said the worse survival observed in these patients may be a result of less frequent clinical follow-up.
“Our results reflect the importance of lifelong follow-up for individuals diagnosed as having MGUS, independent of risk score, and highlight the need for better risk models based on the biology of the disease,” the researchers wrote.
“Patients should receive balanced information stressing not only the overall very low risk of progression to malignant neoplasm but also the symptoms that could signal such development and the need to consult their physician.”
Authors of a related editorial—Robert A. Kyle, MD, and S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota—expressed a somewhat different viewpoint.
“It cannot be determined whether MM patients with a known MGUS in the Icelandic study were followed more closely than those in whom a MGUS was not recognized, and, hence, it is difficult to attribute a causal relationship between follow-up and better prognosis,” they wrote.
“We also need studies to address the question of the possible merits of screening for the presence of MGUS in a normal, older population. The cost, inconvenience, and anxiety produced by the awareness of potential progression of a recognized MGUS, as well as the low absolute risk of progression (0.5% to 1%), probably override the possible potential benefit of screening for MGUS.”
Studies help explain multidrug resistance in cancer
(right) and Sung Chang Lee
Photo courtesy of
The Scripps Research Institute
Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.
They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.
The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.
The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.
“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.
He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.
A better look at transporters
For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.
Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.
Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.
The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.
Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.
“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”
A closer look at binding
In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.
The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.
Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.
The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.
Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.
(right) and Sung Chang Lee
Photo courtesy of
The Scripps Research Institute
Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.
They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.
The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.
The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.
“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.
He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.
A better look at transporters
For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.
Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.
Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.
The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.
Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.
“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”
A closer look at binding
In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.
The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.
Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.
The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.
Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.
(right) and Sung Chang Lee
Photo courtesy of
The Scripps Research Institute
Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.
They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.
The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.
The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.
“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.
He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.
A better look at transporters
For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.
Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.
Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.
The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.
Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.
“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”
A closer look at binding
In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.
The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.
Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.
The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.
Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.
FDA’s new app provides info on drug shortages
a Nokia smart phone
Photo by Halvard Lundgaard
The US Food and Drug Administration (FDA) has launched the agency’s first mobile application (app) designed to speed public access to information on drug shortages.
The app provides details regarding current drug shortages, resolved shortages, and discontinued drug products.
It works just like the FDA’s drug shortages website. App users can search for a drug by its generic name or active ingredient, or they can browse by therapeutic category.
The app can also be used to report a suspected drug shortage or supply issue to the FDA.
The app is available for free download via iTunes (for Apple devices) and the Google Play store (for Android devices). It can be found by searching “FDA Drug Shortages.”
The FDA developed the app to improve access to information about drug shortages, as part of the agency’s efforts outlined in the Strategic Plan for Preventing and Mitigating Drug Shortages.
“The FDA understands that healthcare professionals and pharmacists need real-time information about drug shortages to make treatment decisions,” said Valerie Jensen, associate director of the Drug Shortage Staff in the FDA’s Center for Drug Evaluation and Research.
“The new mobile app is an innovative tool that will offer easier and faster access to important drug shortage information.”
a Nokia smart phone
Photo by Halvard Lundgaard
The US Food and Drug Administration (FDA) has launched the agency’s first mobile application (app) designed to speed public access to information on drug shortages.
The app provides details regarding current drug shortages, resolved shortages, and discontinued drug products.
It works just like the FDA’s drug shortages website. App users can search for a drug by its generic name or active ingredient, or they can browse by therapeutic category.
The app can also be used to report a suspected drug shortage or supply issue to the FDA.
The app is available for free download via iTunes (for Apple devices) and the Google Play store (for Android devices). It can be found by searching “FDA Drug Shortages.”
The FDA developed the app to improve access to information about drug shortages, as part of the agency’s efforts outlined in the Strategic Plan for Preventing and Mitigating Drug Shortages.
“The FDA understands that healthcare professionals and pharmacists need real-time information about drug shortages to make treatment decisions,” said Valerie Jensen, associate director of the Drug Shortage Staff in the FDA’s Center for Drug Evaluation and Research.
“The new mobile app is an innovative tool that will offer easier and faster access to important drug shortage information.”
a Nokia smart phone
Photo by Halvard Lundgaard
The US Food and Drug Administration (FDA) has launched the agency’s first mobile application (app) designed to speed public access to information on drug shortages.
The app provides details regarding current drug shortages, resolved shortages, and discontinued drug products.
It works just like the FDA’s drug shortages website. App users can search for a drug by its generic name or active ingredient, or they can browse by therapeutic category.
The app can also be used to report a suspected drug shortage or supply issue to the FDA.
The app is available for free download via iTunes (for Apple devices) and the Google Play store (for Android devices). It can be found by searching “FDA Drug Shortages.”
The FDA developed the app to improve access to information about drug shortages, as part of the agency’s efforts outlined in the Strategic Plan for Preventing and Mitigating Drug Shortages.
“The FDA understands that healthcare professionals and pharmacists need real-time information about drug shortages to make treatment decisions,” said Valerie Jensen, associate director of the Drug Shortage Staff in the FDA’s Center for Drug Evaluation and Research.
“The new mobile app is an innovative tool that will offer easier and faster access to important drug shortage information.”
Regimen prolongs PFS, increases AEs in MCL
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Results of a phase 3 study suggest the VR-CAP regimen is more effective but less safe than R-CHOP in patients with newly diagnosed mantle cell lymphoma (MCL).
Patients who received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) had superior progression-free survival (PFS) when compared to patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
But VR-CAP was also associated with more adverse events (AEs), particularly hematologic toxicities.
Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported results from this trial, known as LYM-3002, in NEJM. The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
LYM-3002 included 487 patients newly diagnosed with MCL who were not eligible for stem cell transplant.
Patients were randomized to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (similar to the R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11).
The median follow-up was 40 months. The VR-CAP regimen significantly improved PFS, the primary endpoint, when compared to R-CHOP.
According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio [HR]=0.63, P<0.001).
Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (HR=0.51, P<0.001).
Patients in the VR-CAP arm also fared better with regard to some secondary endpoints. The complete response rate was higher in the VR-CAP arm than the R-CHOP arm—53% and 42%, respectively (HR=1.29, P=0.007).
And patients in the VR-CAP arm had a longer median treatment-free interval—40.6 months and 20.5 months, respectively (HR=0.50, P<0.001).
However, there was no significant difference in overall survival between the treatment arms. The median overall survival was not reached in the VR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80, P=0.17). The 4-year overall survival rate was 64% and 54%, respectively.
The investigators said VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious AEs were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.
Hematologic toxicity was more common in the VR-CAP arm than the R-CHOP arm. This included thrombocytopenia (72% vs 19%), neutropenia (88% vs 74%), anemia (51% vs 37%), leukopenia (50% vs 38%), lymphocytopenia (31% vs 13%), and febrile neutropenia (17% vs 14%).
Treatment discontinuation due to AEs occurred in 8% of patients in the VR-CAP arm and 6% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.
It was based on these results that bortezomib was approved for use in patients with newly diagnosed MCL in the Europe Union and the US.
Placenta-derived cells may improve recovery after HSCT
Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.
Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.
Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.
Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.
The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.
The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.
The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.
Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).
PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.
Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).
One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.
Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).
On day 23, there were no significant differences in the number of cells between the treatment groups.
Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.
“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.
“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”
Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.
Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.
Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.
Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.
The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.
The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.
The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.
Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).
PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.
Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).
One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.
Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).
On day 23, there were no significant differences in the number of cells between the treatment groups.
Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.
“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.
“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”
Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.
Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.
Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.
Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.
The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.
The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.
The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.
Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).
PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.
Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).
One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.
Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).
On day 23, there were no significant differences in the number of cells between the treatment groups.
Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.
“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.
“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”