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NICE recommends taking ibrutinib off CDF
Photo courtesy of Janssen
The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).
Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).
NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.
This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.
Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF
or similar program.
Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.
New recommendation
NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the
price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.
The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).
The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.
NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.
Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months. 
Photo courtesy of Janssen
The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).
Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).
NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.
This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.
Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF
or similar program.
Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.
New recommendation
NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the
price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.
The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).
The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.
NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.
Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.
Photo courtesy of Janssen
The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).
Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).
NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.
This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.
Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF
or similar program.
Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.
New recommendation
NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the
price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.
The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).
The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.
NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.
Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.
Tazemetostat receives fast track designation for DLBCL
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
Novel CLL drugs could greatly increase costs
New research suggests the increasing use of oral targeted therapies for chronic lymphocytic leukemia (CLL) could raise US treatment costs for the disease by almost 600%.
Investigators modeled the evolving management of CLL from 2011 to 2025 and found that increasing use of the oral targeted therapies ibrutinib and idelalisib could greatly increase costs for both patients and payers.
The team detailed these findings in the Journal of Clinical Oncology.
“The rising cost of cancer care is a serious concern,” said study author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital in Boston.
“The average cost of annual cancer treatment, which was below $10,000 per patient before 2000, has now increased to more than $100,000. Such increasing trends can limit access to new therapies, potentially undermining their clinical effectiveness. These new drugs are highly effective, but their high costs motivated us to project their changing economic burden and affordability.”
Dr Chhatwal and his colleagues noted that ibrutinib and idelalisib each cost around $130,000 per year, and treatment with these drugs may be continued indefinitely.
So the team set out to determine the potential financial impact of the drugs on payers’ budgets, as well as on Medicare-enrolled patients, who represent the majority of CLL patients in the US.
The investigators developed a model to simulate the evolving management of CLL from 2011 to 2025.
In one scenario, chemoimmunotherapy was the standard of care before 2014, while oral targeted therapies were used for patients with del(17p) and relapsed CLL from 2014 onward and for first-line treatment of CLL from 2016 onward.
The team also modeled a scenario in which chemoimmunotherapy was the standard of care throughout the entire time period and compared the costs between these scenarios.
The model projects that:
- Per-patient lifetime costs for CLL treatment will increase from $147,000 to $604,000 from 2016 onward
- The total out-of-pocket costs for Medicare patients will increase from $9200 to $57,000 for patients initiating treatment from 2016 onward
- The total annual cost of CLL management in the US will rise from $0.74 billion in 2011 to $5.13 billion in 2025, an increase of 590%.
“Such substantial increases in the cost are mainly driven by high drug prices, prolonged treatment duration, and the increase in the number of patients living with CLL,” said study author Qiushi Chen, PhD, of Massachusetts General Hospital.
The investigators also noted that the standard measure used to determine the cost-effectiveness of a medical intervention is whether it costs less than $100,000 for each additional year of life gained. The projected cost-effectiveness ratio of oral targeted therapy in CLL is $189,000 for each year gained.
“At the current average wholesale prices, oral targeted therapies for CLL are not cost-effective, and prices would need to drop by 50% to 70% to become cost-effective,” Dr Chhatwal said.
“We are not recommending that clinicians choose less effective CLL management strategies that do not include oral targeted therapies,” said study author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Instead, we propose that the prices of these drugs need to be reduced to make the treatment cost-effective and more affordable, something we hope may happen with all cancer drugs. We also believe more research is needed to explore whether we can discontinue targeted treatment of patients who have responded well without risking worsening of their health.”
New research suggests the increasing use of oral targeted therapies for chronic lymphocytic leukemia (CLL) could raise US treatment costs for the disease by almost 600%.
Investigators modeled the evolving management of CLL from 2011 to 2025 and found that increasing use of the oral targeted therapies ibrutinib and idelalisib could greatly increase costs for both patients and payers.
The team detailed these findings in the Journal of Clinical Oncology.
“The rising cost of cancer care is a serious concern,” said study author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital in Boston.
“The average cost of annual cancer treatment, which was below $10,000 per patient before 2000, has now increased to more than $100,000. Such increasing trends can limit access to new therapies, potentially undermining their clinical effectiveness. These new drugs are highly effective, but their high costs motivated us to project their changing economic burden and affordability.”
Dr Chhatwal and his colleagues noted that ibrutinib and idelalisib each cost around $130,000 per year, and treatment with these drugs may be continued indefinitely.
So the team set out to determine the potential financial impact of the drugs on payers’ budgets, as well as on Medicare-enrolled patients, who represent the majority of CLL patients in the US.
The investigators developed a model to simulate the evolving management of CLL from 2011 to 2025.
In one scenario, chemoimmunotherapy was the standard of care before 2014, while oral targeted therapies were used for patients with del(17p) and relapsed CLL from 2014 onward and for first-line treatment of CLL from 2016 onward.
The team also modeled a scenario in which chemoimmunotherapy was the standard of care throughout the entire time period and compared the costs between these scenarios.
The model projects that:
- Per-patient lifetime costs for CLL treatment will increase from $147,000 to $604,000 from 2016 onward
- The total out-of-pocket costs for Medicare patients will increase from $9200 to $57,000 for patients initiating treatment from 2016 onward
- The total annual cost of CLL management in the US will rise from $0.74 billion in 2011 to $5.13 billion in 2025, an increase of 590%.
“Such substantial increases in the cost are mainly driven by high drug prices, prolonged treatment duration, and the increase in the number of patients living with CLL,” said study author Qiushi Chen, PhD, of Massachusetts General Hospital.
The investigators also noted that the standard measure used to determine the cost-effectiveness of a medical intervention is whether it costs less than $100,000 for each additional year of life gained. The projected cost-effectiveness ratio of oral targeted therapy in CLL is $189,000 for each year gained.
“At the current average wholesale prices, oral targeted therapies for CLL are not cost-effective, and prices would need to drop by 50% to 70% to become cost-effective,” Dr Chhatwal said.
“We are not recommending that clinicians choose less effective CLL management strategies that do not include oral targeted therapies,” said study author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Instead, we propose that the prices of these drugs need to be reduced to make the treatment cost-effective and more affordable, something we hope may happen with all cancer drugs. We also believe more research is needed to explore whether we can discontinue targeted treatment of patients who have responded well without risking worsening of their health.”
New research suggests the increasing use of oral targeted therapies for chronic lymphocytic leukemia (CLL) could raise US treatment costs for the disease by almost 600%.
Investigators modeled the evolving management of CLL from 2011 to 2025 and found that increasing use of the oral targeted therapies ibrutinib and idelalisib could greatly increase costs for both patients and payers.
The team detailed these findings in the Journal of Clinical Oncology.
“The rising cost of cancer care is a serious concern,” said study author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital in Boston.
“The average cost of annual cancer treatment, which was below $10,000 per patient before 2000, has now increased to more than $100,000. Such increasing trends can limit access to new therapies, potentially undermining their clinical effectiveness. These new drugs are highly effective, but their high costs motivated us to project their changing economic burden and affordability.”
Dr Chhatwal and his colleagues noted that ibrutinib and idelalisib each cost around $130,000 per year, and treatment with these drugs may be continued indefinitely.
So the team set out to determine the potential financial impact of the drugs on payers’ budgets, as well as on Medicare-enrolled patients, who represent the majority of CLL patients in the US.
The investigators developed a model to simulate the evolving management of CLL from 2011 to 2025.
In one scenario, chemoimmunotherapy was the standard of care before 2014, while oral targeted therapies were used for patients with del(17p) and relapsed CLL from 2014 onward and for first-line treatment of CLL from 2016 onward.
The team also modeled a scenario in which chemoimmunotherapy was the standard of care throughout the entire time period and compared the costs between these scenarios.
The model projects that:
- Per-patient lifetime costs for CLL treatment will increase from $147,000 to $604,000 from 2016 onward
- The total out-of-pocket costs for Medicare patients will increase from $9200 to $57,000 for patients initiating treatment from 2016 onward
- The total annual cost of CLL management in the US will rise from $0.74 billion in 2011 to $5.13 billion in 2025, an increase of 590%.
“Such substantial increases in the cost are mainly driven by high drug prices, prolonged treatment duration, and the increase in the number of patients living with CLL,” said study author Qiushi Chen, PhD, of Massachusetts General Hospital.
The investigators also noted that the standard measure used to determine the cost-effectiveness of a medical intervention is whether it costs less than $100,000 for each additional year of life gained. The projected cost-effectiveness ratio of oral targeted therapy in CLL is $189,000 for each year gained.
“At the current average wholesale prices, oral targeted therapies for CLL are not cost-effective, and prices would need to drop by 50% to 70% to become cost-effective,” Dr Chhatwal said.
“We are not recommending that clinicians choose less effective CLL management strategies that do not include oral targeted therapies,” said study author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Instead, we propose that the prices of these drugs need to be reduced to make the treatment cost-effective and more affordable, something we hope may happen with all cancer drugs. We also believe more research is needed to explore whether we can discontinue targeted treatment of patients who have responded well without risking worsening of their health.”
How EBV drives lymphomagenesis
Image by Ed Uthman
Results of research published in eLIFE appear to explain how Epstein-Barr virus (EBV) controls a pair of genes to drive lymphomagenesis.
Researchers set out to determine how EBV controls MYC, which is known to drive lymphoma development when activated, and BCL2L11, a gene that normally triggers apoptosis to prevent lymphoma but can be silenced by EBV.
The team discovered that EBV controls MYC and BCL2L11 by hijacking enhancer regions of DNA, which are situated far away from the genes.
These enhancers act as “control centers” and are able to contact and control genes from long distances by the looping out of the intervening stretches of DNA.
The researchers found that EBV activates MYC by increasing contacts between a specific set of enhancers and the gene.
The team said an Epstein-Barr nuclear antigen, EBNA2, activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream enhancer-promoter interactions and decrease downstream interactions.
They noted that EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers, and BRG1 is required for enhancer-promoter interactions in EBV-infected cells.
The researchers also discovered new enhancers that control BCL2L11. In this case, though, EBV stops these control centers from contacting the gene.
Specifically, the team found a hematopoietic enhancer hub that is inactivated by the Epstein-Barr nuclear antigens EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2.
Therefore, the researchers set out to determine if an EZH1/2 inhibitor, UNC1999, could reverse this effect. They found that UNC1999 did reverse enhancer inactivation, upregulated BCL2L11, and induced apoptosis in EBV-positive Burkitt lymphoma cells.
“This is a key step towards uncovering how this common virus, which affects thousands of people every year, causes blood cancer,” said study author Michelle West, PhD, of the University of Sussex in Brighton, UK.
“It is now important to carry out further studies to determine how the Epstein-Barr virus controls other genes that are associated with lymphoma. This will tell us more about how the virus drives lymphoma development and will help to identify new ways of targeting Epstein-Barr virus-infected cancer cells with specific drugs.”
Image by Ed Uthman
Results of research published in eLIFE appear to explain how Epstein-Barr virus (EBV) controls a pair of genes to drive lymphomagenesis.
Researchers set out to determine how EBV controls MYC, which is known to drive lymphoma development when activated, and BCL2L11, a gene that normally triggers apoptosis to prevent lymphoma but can be silenced by EBV.
The team discovered that EBV controls MYC and BCL2L11 by hijacking enhancer regions of DNA, which are situated far away from the genes.
These enhancers act as “control centers” and are able to contact and control genes from long distances by the looping out of the intervening stretches of DNA.
The researchers found that EBV activates MYC by increasing contacts between a specific set of enhancers and the gene.
The team said an Epstein-Barr nuclear antigen, EBNA2, activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream enhancer-promoter interactions and decrease downstream interactions.
They noted that EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers, and BRG1 is required for enhancer-promoter interactions in EBV-infected cells.
The researchers also discovered new enhancers that control BCL2L11. In this case, though, EBV stops these control centers from contacting the gene.
Specifically, the team found a hematopoietic enhancer hub that is inactivated by the Epstein-Barr nuclear antigens EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2.
Therefore, the researchers set out to determine if an EZH1/2 inhibitor, UNC1999, could reverse this effect. They found that UNC1999 did reverse enhancer inactivation, upregulated BCL2L11, and induced apoptosis in EBV-positive Burkitt lymphoma cells.
“This is a key step towards uncovering how this common virus, which affects thousands of people every year, causes blood cancer,” said study author Michelle West, PhD, of the University of Sussex in Brighton, UK.
“It is now important to carry out further studies to determine how the Epstein-Barr virus controls other genes that are associated with lymphoma. This will tell us more about how the virus drives lymphoma development and will help to identify new ways of targeting Epstein-Barr virus-infected cancer cells with specific drugs.”
Image by Ed Uthman
Results of research published in eLIFE appear to explain how Epstein-Barr virus (EBV) controls a pair of genes to drive lymphomagenesis.
Researchers set out to determine how EBV controls MYC, which is known to drive lymphoma development when activated, and BCL2L11, a gene that normally triggers apoptosis to prevent lymphoma but can be silenced by EBV.
The team discovered that EBV controls MYC and BCL2L11 by hijacking enhancer regions of DNA, which are situated far away from the genes.
These enhancers act as “control centers” and are able to contact and control genes from long distances by the looping out of the intervening stretches of DNA.
The researchers found that EBV activates MYC by increasing contacts between a specific set of enhancers and the gene.
The team said an Epstein-Barr nuclear antigen, EBNA2, activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream enhancer-promoter interactions and decrease downstream interactions.
They noted that EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers, and BRG1 is required for enhancer-promoter interactions in EBV-infected cells.
The researchers also discovered new enhancers that control BCL2L11. In this case, though, EBV stops these control centers from contacting the gene.
Specifically, the team found a hematopoietic enhancer hub that is inactivated by the Epstein-Barr nuclear antigens EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2.
Therefore, the researchers set out to determine if an EZH1/2 inhibitor, UNC1999, could reverse this effect. They found that UNC1999 did reverse enhancer inactivation, upregulated BCL2L11, and induced apoptosis in EBV-positive Burkitt lymphoma cells.
“This is a key step towards uncovering how this common virus, which affects thousands of people every year, causes blood cancer,” said study author Michelle West, PhD, of the University of Sussex in Brighton, UK.
“It is now important to carry out further studies to determine how the Epstein-Barr virus controls other genes that are associated with lymphoma. This will tell us more about how the virus drives lymphoma development and will help to identify new ways of targeting Epstein-Barr virus-infected cancer cells with specific drugs.”
Drug dubbed ‘breakthrough’ for CTCL subtypes
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (Adcetris) as a treatment for 2 subtypes of cutaneous T-cell lymphoma (CTCL).
The drug now has this designation for the treatment of patients with CD30-expressing mycosis fungoides (MF) and patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL) who require systemic therapy and have received 1 prior systemic therapy.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Brentuximab vedotin in CTCL
Brentuximab vedotin is an antibody-drug conjugate directed to CD30, which is expressed on skin lesions in approximately 50% of patients with CTCL. The drug is being developed by Seattle Genetics and Takeda Pharmaceutical Company Limited.
Brentuximab vedotin has orphan drug designation from the FDA for the treatment of MF. The drug also received orphan drug designation from the European Commission for CTCL, including subtypes pcALCL and MF.
Brentuximab vedotin has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase 3 ALCANZA trial.
This trial was designed to compare single-agent brentuximab vedotin to investigator’s choice of standard therapies—methotrexate or bexarotene—in patients with CD30-expressing CTCL, including those with pcALCL or MF.
The trial has enrolled 131 patients at 50 sites globally. Patients with pcALCL must have received at least 1 prior systemic or radiation therapy, and patients with MF must have received at least 1 prior systemic therapy.
The study’s primary endpoint is objective response lasting at least 4 months (ORR4), as assessed by Global Response Score, in the brentuximab vedotin arm compared to the control arm. Key secondary endpoints are complete response rate, progression-free survival, and reduction in the burden of symptoms during treatment.
Topline results of the trial were announced in August. The data showed a significant improvement in the ORR4 for the brentuximab vedotin arm compared to the control arm. The ORR4 was 56.3% and 12.5%, respectively (P<0.0001).
The key secondary endpoints were all statistically significant in favor of the brentuximab vedotin arm. And investigators said the safety profile of brentuximab vedotin was generally consistent with the existing prescribing information.
An abstract detailing results of the ALCANZA trial was accepted for oral presentation at the upcoming ASH Annual Meeting (abstract 182).
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (Adcetris) as a treatment for 2 subtypes of cutaneous T-cell lymphoma (CTCL).
The drug now has this designation for the treatment of patients with CD30-expressing mycosis fungoides (MF) and patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL) who require systemic therapy and have received 1 prior systemic therapy.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Brentuximab vedotin in CTCL
Brentuximab vedotin is an antibody-drug conjugate directed to CD30, which is expressed on skin lesions in approximately 50% of patients with CTCL. The drug is being developed by Seattle Genetics and Takeda Pharmaceutical Company Limited.
Brentuximab vedotin has orphan drug designation from the FDA for the treatment of MF. The drug also received orphan drug designation from the European Commission for CTCL, including subtypes pcALCL and MF.
Brentuximab vedotin has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase 3 ALCANZA trial.
This trial was designed to compare single-agent brentuximab vedotin to investigator’s choice of standard therapies—methotrexate or bexarotene—in patients with CD30-expressing CTCL, including those with pcALCL or MF.
The trial has enrolled 131 patients at 50 sites globally. Patients with pcALCL must have received at least 1 prior systemic or radiation therapy, and patients with MF must have received at least 1 prior systemic therapy.
The study’s primary endpoint is objective response lasting at least 4 months (ORR4), as assessed by Global Response Score, in the brentuximab vedotin arm compared to the control arm. Key secondary endpoints are complete response rate, progression-free survival, and reduction in the burden of symptoms during treatment.
Topline results of the trial were announced in August. The data showed a significant improvement in the ORR4 for the brentuximab vedotin arm compared to the control arm. The ORR4 was 56.3% and 12.5%, respectively (P<0.0001).
The key secondary endpoints were all statistically significant in favor of the brentuximab vedotin arm. And investigators said the safety profile of brentuximab vedotin was generally consistent with the existing prescribing information.
An abstract detailing results of the ALCANZA trial was accepted for oral presentation at the upcoming ASH Annual Meeting (abstract 182).
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (Adcetris) as a treatment for 2 subtypes of cutaneous T-cell lymphoma (CTCL).
The drug now has this designation for the treatment of patients with CD30-expressing mycosis fungoides (MF) and patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL) who require systemic therapy and have received 1 prior systemic therapy.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Brentuximab vedotin in CTCL
Brentuximab vedotin is an antibody-drug conjugate directed to CD30, which is expressed on skin lesions in approximately 50% of patients with CTCL. The drug is being developed by Seattle Genetics and Takeda Pharmaceutical Company Limited.
Brentuximab vedotin has orphan drug designation from the FDA for the treatment of MF. The drug also received orphan drug designation from the European Commission for CTCL, including subtypes pcALCL and MF.
Brentuximab vedotin has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase 3 ALCANZA trial.
This trial was designed to compare single-agent brentuximab vedotin to investigator’s choice of standard therapies—methotrexate or bexarotene—in patients with CD30-expressing CTCL, including those with pcALCL or MF.
The trial has enrolled 131 patients at 50 sites globally. Patients with pcALCL must have received at least 1 prior systemic or radiation therapy, and patients with MF must have received at least 1 prior systemic therapy.
The study’s primary endpoint is objective response lasting at least 4 months (ORR4), as assessed by Global Response Score, in the brentuximab vedotin arm compared to the control arm. Key secondary endpoints are complete response rate, progression-free survival, and reduction in the burden of symptoms during treatment.
Topline results of the trial were announced in August. The data showed a significant improvement in the ORR4 for the brentuximab vedotin arm compared to the control arm. The ORR4 was 56.3% and 12.5%, respectively (P<0.0001).
The key secondary endpoints were all statistically significant in favor of the brentuximab vedotin arm. And investigators said the safety profile of brentuximab vedotin was generally consistent with the existing prescribing information.
An abstract detailing results of the ALCANZA trial was accepted for oral presentation at the upcoming ASH Annual Meeting (abstract 182).
CHMP recommends expanding use of drug in CLL
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra®).
The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).
The CHMP’s recommendation will be reviewed by the European Commission.
A final decision is expected in the coming months.
Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.
The European Commission has already approved ofatumumab for the following indications:
- As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
- For use in combination with chlorambucil or bendamustine in CLL patients who
have not received prior therapy and are not eligible for
fludarabine-based therapy.
COMPLEMENT 2 trial
The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.
The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.
The primary endpoint was progression-free survival, as assessed by an independent review committee.
The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).
Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra®).
The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).
The CHMP’s recommendation will be reviewed by the European Commission.
A final decision is expected in the coming months.
Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.
The European Commission has already approved ofatumumab for the following indications:
- As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
- For use in combination with chlorambucil or bendamustine in CLL patients who
have not received prior therapy and are not eligible for
fludarabine-based therapy.
COMPLEMENT 2 trial
The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.
The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.
The primary endpoint was progression-free survival, as assessed by an independent review committee.
The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).
Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra®).
The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).
The CHMP’s recommendation will be reviewed by the European Commission.
A final decision is expected in the coming months.
Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.
The European Commission has already approved ofatumumab for the following indications:
- As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
- For use in combination with chlorambucil or bendamustine in CLL patients who
have not received prior therapy and are not eligible for
fludarabine-based therapy.
COMPLEMENT 2 trial
The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.
The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.
The primary endpoint was progression-free survival, as assessed by an independent review committee.
The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).
Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.
Blood test can predict outcomes in DLBCL, team says
Photo by Juan D. Alfonso
A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.
Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.
This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.
Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.
They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.
The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.
In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.
The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.
Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.
Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.
Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.
Photo by Juan D. Alfonso
A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.
Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.
This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.
Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.
They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.
The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.
In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.
The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.
Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.
Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.
Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.
Photo by Juan D. Alfonso
A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.
Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.
This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.
Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.
They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.
The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.
In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.
The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.
Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.
Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.
Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.
Combine flow and HTS for sensitive MRD detection in CLL, speaker says
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”
NORD publishes physician guide to CTCL
mycosis fungoides
The National Organization for Rare Disorders (NORD) has published a guide for physicians treating patients with cutaneous T-cell lymphoma (CTCL).
The guide contains information about disease classification, signs and symptoms of CTCL, methods of diagnosing the disease, standard therapies, and investigational therapies for CTCL.
The guide also includes a list of resources for physicians and patients.
“The NORD Physician Guide to Cutaneous T-Cell Lymphoma (CTCL)” is available for free on the NORD Physician Guides website.
The guide was made possible by an educational grant from Therakos, now a part of Mallinckrodt Pharmaceuticals.
The guide was developed in collaboration with Oleg E. Akilov, MD, PhD, of the University of Pittsburgh School of Medicine in Pennsylvania.
“Eczema and even some cases of psoriasis may look very similar to mycosis fungoides, the most common type of cutaneous T-cell lymphomas,” Dr Akilov noted.
“It is important to be aware of these similarities and to be ready to think about cutaneous lymphoma when a patient with ‘common dermatosis’ does not respond to regular treatments.”
About NORD guides
NORD established its physician guide series as part of a broader strategic initiative to promote earlier diagnosis and state-of-the-art care for people with rare diseases. Each online guide is written or reviewed by a medical professional with expertise on the topic.
Other recent guides in the series include:
- The NORD Physician Guide to Mitochondrial Myopathies
- The NORD Physician Guide to Paroxysmal Nocturnal Hemoglobinuria (PNH)
- The NORD Physician Guide to Atypical Hemolytic Uremic Syndrome (aHUS)
- The NORD Physician Guide to Nontuberculous Mycobacterial Lung Disease.
“People who have rare diseases often go for many years without a diagnosis,” said Marsha Lanes, a genetic counselor in NORD’s Educational Initiatives Department.
“The purpose of NORD’s free online physician guides is to reduce the time to diagnosis and encourage optimal treatment for patients with little-known and little-understood rare diseases.”
mycosis fungoides
The National Organization for Rare Disorders (NORD) has published a guide for physicians treating patients with cutaneous T-cell lymphoma (CTCL).
The guide contains information about disease classification, signs and symptoms of CTCL, methods of diagnosing the disease, standard therapies, and investigational therapies for CTCL.
The guide also includes a list of resources for physicians and patients.
“The NORD Physician Guide to Cutaneous T-Cell Lymphoma (CTCL)” is available for free on the NORD Physician Guides website.
The guide was made possible by an educational grant from Therakos, now a part of Mallinckrodt Pharmaceuticals.
The guide was developed in collaboration with Oleg E. Akilov, MD, PhD, of the University of Pittsburgh School of Medicine in Pennsylvania.
“Eczema and even some cases of psoriasis may look very similar to mycosis fungoides, the most common type of cutaneous T-cell lymphomas,” Dr Akilov noted.
“It is important to be aware of these similarities and to be ready to think about cutaneous lymphoma when a patient with ‘common dermatosis’ does not respond to regular treatments.”
About NORD guides
NORD established its physician guide series as part of a broader strategic initiative to promote earlier diagnosis and state-of-the-art care for people with rare diseases. Each online guide is written or reviewed by a medical professional with expertise on the topic.
Other recent guides in the series include:
- The NORD Physician Guide to Mitochondrial Myopathies
- The NORD Physician Guide to Paroxysmal Nocturnal Hemoglobinuria (PNH)
- The NORD Physician Guide to Atypical Hemolytic Uremic Syndrome (aHUS)
- The NORD Physician Guide to Nontuberculous Mycobacterial Lung Disease.
“People who have rare diseases often go for many years without a diagnosis,” said Marsha Lanes, a genetic counselor in NORD’s Educational Initiatives Department.
“The purpose of NORD’s free online physician guides is to reduce the time to diagnosis and encourage optimal treatment for patients with little-known and little-understood rare diseases.”
mycosis fungoides
The National Organization for Rare Disorders (NORD) has published a guide for physicians treating patients with cutaneous T-cell lymphoma (CTCL).
The guide contains information about disease classification, signs and symptoms of CTCL, methods of diagnosing the disease, standard therapies, and investigational therapies for CTCL.
The guide also includes a list of resources for physicians and patients.
“The NORD Physician Guide to Cutaneous T-Cell Lymphoma (CTCL)” is available for free on the NORD Physician Guides website.
The guide was made possible by an educational grant from Therakos, now a part of Mallinckrodt Pharmaceuticals.
The guide was developed in collaboration with Oleg E. Akilov, MD, PhD, of the University of Pittsburgh School of Medicine in Pennsylvania.
“Eczema and even some cases of psoriasis may look very similar to mycosis fungoides, the most common type of cutaneous T-cell lymphomas,” Dr Akilov noted.
“It is important to be aware of these similarities and to be ready to think about cutaneous lymphoma when a patient with ‘common dermatosis’ does not respond to regular treatments.”
About NORD guides
NORD established its physician guide series as part of a broader strategic initiative to promote earlier diagnosis and state-of-the-art care for people with rare diseases. Each online guide is written or reviewed by a medical professional with expertise on the topic.
Other recent guides in the series include:
- The NORD Physician Guide to Mitochondrial Myopathies
- The NORD Physician Guide to Paroxysmal Nocturnal Hemoglobinuria (PNH)
- The NORD Physician Guide to Atypical Hemolytic Uremic Syndrome (aHUS)
- The NORD Physician Guide to Nontuberculous Mycobacterial Lung Disease.
“People who have rare diseases often go for many years without a diagnosis,” said Marsha Lanes, a genetic counselor in NORD’s Educational Initiatives Department.
“The purpose of NORD’s free online physician guides is to reduce the time to diagnosis and encourage optimal treatment for patients with little-known and little-understood rare diseases.”
Genetic screening for CLL premature, speaker says
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.