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How a cancer diagnosis affects income
receiving treatment
Photo by Rhoda Baer
A new study indicates that when American adults are diagnosed with
cancer, they experience significant decreases in the probability of
working, in the number of hours they work, and correspondingly, in their
incomes.
Additionally, these effects appear to be more pronounced among men than women.
Anna Zajacova, PhD, of the University of Wyoming in Laramie, and her colleagues reported these findings in Cancer.
The researchers analyzed data from the Panel Study of Income Dynamics, a nationally representative, prospective, population-based, observational study with individual and family level economic information. The data spanned the period from 1999 to 2009.
The team used models to estimate the impact of cancer on employment, hours worked, individual income, and total family income.
The results showed that, after a cancer diagnosis, the probability of a patient being employed dropped by almost 10 percentage points, and hours worked declined by up to 200 hours, or about 5 weeks of full-time work, in the first year.
Annual labor market earnings dropped almost 40% within 2 years of diagnosis, and they remained lower than before diagnosis. Total family income declined by 20%, although it recovered within 4 years of cancer diagnosis.
These effects were primarily driven by losses among male cancer survivors. For women diagnosed with cancer, the losses were largely not statistically significant.
“Fifteen million American adults are cancer survivors, and American families need economic support while they are dealing with the rigors of cancer treatment,” Dr Zajacova said.
“Our paper suggests that families where an adult—especially a working-age male—is diagnosed with cancer suffer short-term and long-term declines in their economic well-being. We need to improve workplace and insurance safety nets so families can focus on dealing with the cancer treatment rather than deal with the financial and employment fallout.” 
receiving treatment
Photo by Rhoda Baer
A new study indicates that when American adults are diagnosed with
cancer, they experience significant decreases in the probability of
working, in the number of hours they work, and correspondingly, in their
incomes.
Additionally, these effects appear to be more pronounced among men than women.
Anna Zajacova, PhD, of the University of Wyoming in Laramie, and her colleagues reported these findings in Cancer.
The researchers analyzed data from the Panel Study of Income Dynamics, a nationally representative, prospective, population-based, observational study with individual and family level economic information. The data spanned the period from 1999 to 2009.
The team used models to estimate the impact of cancer on employment, hours worked, individual income, and total family income.
The results showed that, after a cancer diagnosis, the probability of a patient being employed dropped by almost 10 percentage points, and hours worked declined by up to 200 hours, or about 5 weeks of full-time work, in the first year.
Annual labor market earnings dropped almost 40% within 2 years of diagnosis, and they remained lower than before diagnosis. Total family income declined by 20%, although it recovered within 4 years of cancer diagnosis.
These effects were primarily driven by losses among male cancer survivors. For women diagnosed with cancer, the losses were largely not statistically significant.
“Fifteen million American adults are cancer survivors, and American families need economic support while they are dealing with the rigors of cancer treatment,” Dr Zajacova said.
“Our paper suggests that families where an adult—especially a working-age male—is diagnosed with cancer suffer short-term and long-term declines in their economic well-being. We need to improve workplace and insurance safety nets so families can focus on dealing with the cancer treatment rather than deal with the financial and employment fallout.”
receiving treatment
Photo by Rhoda Baer
A new study indicates that when American adults are diagnosed with
cancer, they experience significant decreases in the probability of
working, in the number of hours they work, and correspondingly, in their
incomes.
Additionally, these effects appear to be more pronounced among men than women.
Anna Zajacova, PhD, of the University of Wyoming in Laramie, and her colleagues reported these findings in Cancer.
The researchers analyzed data from the Panel Study of Income Dynamics, a nationally representative, prospective, population-based, observational study with individual and family level economic information. The data spanned the period from 1999 to 2009.
The team used models to estimate the impact of cancer on employment, hours worked, individual income, and total family income.
The results showed that, after a cancer diagnosis, the probability of a patient being employed dropped by almost 10 percentage points, and hours worked declined by up to 200 hours, or about 5 weeks of full-time work, in the first year.
Annual labor market earnings dropped almost 40% within 2 years of diagnosis, and they remained lower than before diagnosis. Total family income declined by 20%, although it recovered within 4 years of cancer diagnosis.
These effects were primarily driven by losses among male cancer survivors. For women diagnosed with cancer, the losses were largely not statistically significant.
“Fifteen million American adults are cancer survivors, and American families need economic support while they are dealing with the rigors of cancer treatment,” Dr Zajacova said.
“Our paper suggests that families where an adult—especially a working-age male—is diagnosed with cancer suffer short-term and long-term declines in their economic well-being. We need to improve workplace and insurance safety nets so families can focus on dealing with the cancer treatment rather than deal with the financial and employment fallout.”
Group identifies potential target for AML
marrow cells generated by AE
Image courtesy of
The Rockefeller University
Preclinical research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the histone demethylase JMJD1C.
Investigators found that JMJD1C interacts with RUNX1–RUNX1T1 (formerly AML1-ETO and abbreviated here as AE), a transcription factor generated by the t(8;21) translocation in AML.
However, the team also found that JMJD1C is required for proliferation in many AML cell lines, not just those with AE.
Robert G. Roeder, PhD, of The Rockefeller University in New York, New York, and his colleagues detailed these findings in Genes and Development.
The investigators began this study by searching for proteins that interact with AE, and they identified JMJD1C. To investigate the relationship between JMJD1C and AE, the team explored the broader effects of removing JMJD1C.
“We found that numerous genes were downregulated upon loss of JMJD1C, and the set overlaps significantly with the genes that are normally activated by AE,” said study author Mo Chen, PhD, a researcher in Dr Roeder’s lab.
The investigators also found that AML cells are addicted to the presence of JMJD1C, and, without it, they cannot survive. The team observed an increase in apoptosis when JMJD1C was depleted from Kasumi-1 and SKNO-1 cell lines.
With subsequent experiments, the investigators confirmed that JMJD1C interacts with AE and demonstrated that JMJD1C is required for AE to exert its cancer-promoting effects. But they also found that JMJD1C plays an even broader role in AML.
“We were very surprised to find that JMJD1C is required for the proliferation of other acute myeloid leukemia cell lines, which do not have AE,” Dr Chen said.
The team found that depleting JMJD1C compromised the growth of the following cell lines: Kasumi-1 (AML1-ETO; AML M2), MOLM-13 (MLL-AF9, FLT3ITD; AML M5a), THP-1 (MLL-AF9, NRASmut; AML M5), HNT-34 (BCR-ABL1; AML M4), MV4-11 (MLL-AF4; AML M5), CMK (JAK3A527V; AML M7+ Down’s Syndrome), HEL (AML M6), NOMO-1 (MLL-AF9; AML M5a), NB4 (PML-RARα; AML M3), and HL-60 (MYC amplification; AML M2).
The only cell line that was not affected by depletion of JMJD1C was KG-1 (NRASmut; AML).
To build upon this discovery, the investigators looked for transcription factors aside from AE that might be responsible for JMJD1C addiction. The team found at least 2—LYL1 and HEB—that can recruit JMJD1C to target genes in diseased cells that lack AE, fueling leukemia growth.
The investigators said these results suggest JMJD1C may play a general role in promoting the growth of myeloid leukemias.
“We are excited because this type of general phenomena is an ideal target for drug development,” Dr Roeder said. “Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia.”
marrow cells generated by AE
Image courtesy of
The Rockefeller University
Preclinical research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the histone demethylase JMJD1C.
Investigators found that JMJD1C interacts with RUNX1–RUNX1T1 (formerly AML1-ETO and abbreviated here as AE), a transcription factor generated by the t(8;21) translocation in AML.
However, the team also found that JMJD1C is required for proliferation in many AML cell lines, not just those with AE.
Robert G. Roeder, PhD, of The Rockefeller University in New York, New York, and his colleagues detailed these findings in Genes and Development.
The investigators began this study by searching for proteins that interact with AE, and they identified JMJD1C. To investigate the relationship between JMJD1C and AE, the team explored the broader effects of removing JMJD1C.
“We found that numerous genes were downregulated upon loss of JMJD1C, and the set overlaps significantly with the genes that are normally activated by AE,” said study author Mo Chen, PhD, a researcher in Dr Roeder’s lab.
The investigators also found that AML cells are addicted to the presence of JMJD1C, and, without it, they cannot survive. The team observed an increase in apoptosis when JMJD1C was depleted from Kasumi-1 and SKNO-1 cell lines.
With subsequent experiments, the investigators confirmed that JMJD1C interacts with AE and demonstrated that JMJD1C is required for AE to exert its cancer-promoting effects. But they also found that JMJD1C plays an even broader role in AML.
“We were very surprised to find that JMJD1C is required for the proliferation of other acute myeloid leukemia cell lines, which do not have AE,” Dr Chen said.
The team found that depleting JMJD1C compromised the growth of the following cell lines: Kasumi-1 (AML1-ETO; AML M2), MOLM-13 (MLL-AF9, FLT3ITD; AML M5a), THP-1 (MLL-AF9, NRASmut; AML M5), HNT-34 (BCR-ABL1; AML M4), MV4-11 (MLL-AF4; AML M5), CMK (JAK3A527V; AML M7+ Down’s Syndrome), HEL (AML M6), NOMO-1 (MLL-AF9; AML M5a), NB4 (PML-RARα; AML M3), and HL-60 (MYC amplification; AML M2).
The only cell line that was not affected by depletion of JMJD1C was KG-1 (NRASmut; AML).
To build upon this discovery, the investigators looked for transcription factors aside from AE that might be responsible for JMJD1C addiction. The team found at least 2—LYL1 and HEB—that can recruit JMJD1C to target genes in diseased cells that lack AE, fueling leukemia growth.
The investigators said these results suggest JMJD1C may play a general role in promoting the growth of myeloid leukemias.
“We are excited because this type of general phenomena is an ideal target for drug development,” Dr Roeder said. “Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia.”
marrow cells generated by AE
Image courtesy of
The Rockefeller University
Preclinical research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the histone demethylase JMJD1C.
Investigators found that JMJD1C interacts with RUNX1–RUNX1T1 (formerly AML1-ETO and abbreviated here as AE), a transcription factor generated by the t(8;21) translocation in AML.
However, the team also found that JMJD1C is required for proliferation in many AML cell lines, not just those with AE.
Robert G. Roeder, PhD, of The Rockefeller University in New York, New York, and his colleagues detailed these findings in Genes and Development.
The investigators began this study by searching for proteins that interact with AE, and they identified JMJD1C. To investigate the relationship between JMJD1C and AE, the team explored the broader effects of removing JMJD1C.
“We found that numerous genes were downregulated upon loss of JMJD1C, and the set overlaps significantly with the genes that are normally activated by AE,” said study author Mo Chen, PhD, a researcher in Dr Roeder’s lab.
The investigators also found that AML cells are addicted to the presence of JMJD1C, and, without it, they cannot survive. The team observed an increase in apoptosis when JMJD1C was depleted from Kasumi-1 and SKNO-1 cell lines.
With subsequent experiments, the investigators confirmed that JMJD1C interacts with AE and demonstrated that JMJD1C is required for AE to exert its cancer-promoting effects. But they also found that JMJD1C plays an even broader role in AML.
“We were very surprised to find that JMJD1C is required for the proliferation of other acute myeloid leukemia cell lines, which do not have AE,” Dr Chen said.
The team found that depleting JMJD1C compromised the growth of the following cell lines: Kasumi-1 (AML1-ETO; AML M2), MOLM-13 (MLL-AF9, FLT3ITD; AML M5a), THP-1 (MLL-AF9, NRASmut; AML M5), HNT-34 (BCR-ABL1; AML M4), MV4-11 (MLL-AF4; AML M5), CMK (JAK3A527V; AML M7+ Down’s Syndrome), HEL (AML M6), NOMO-1 (MLL-AF9; AML M5a), NB4 (PML-RARα; AML M3), and HL-60 (MYC amplification; AML M2).
The only cell line that was not affected by depletion of JMJD1C was KG-1 (NRASmut; AML).
To build upon this discovery, the investigators looked for transcription factors aside from AE that might be responsible for JMJD1C addiction. The team found at least 2—LYL1 and HEB—that can recruit JMJD1C to target genes in diseased cells that lack AE, fueling leukemia growth.
The investigators said these results suggest JMJD1C may play a general role in promoting the growth of myeloid leukemias.
“We are excited because this type of general phenomena is an ideal target for drug development,” Dr Roeder said. “Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia.”
NCCN unveils 'Evidence Blocks' to facilitate treatment discussions
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Emerging evidence is resolving questions in CML management
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Novel compound could treat leukemia
A small-molecule compound that has previously shown activity against Ewing sarcoma and prostate cancer may fight leukemia as well, according to preclinical research published in Oncotarget.
The compound, YK-4-279, inhibits the oncogenic activity of the fusion protein EWS-FLI1.
“EWS-FLI1 is already known to drive a rare but deadly bone cancer called Ewing sarcoma,” said study author Aykut Üren, MD, of Georgetown University Medical Center in Washington, DC.
“It also appears to drive cancer cell growth in some prostate cancers.”
ETS family fusion proteins are found in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well.
So Dr Üren and his colleagues decided to create a mouse model of EWS-FLI1-induced leukemia and assess the activity of YK-4-279 in this model.
Mice with EWS-FLI1-induced leukemia presented with severe hepatomegaly, splenomegaly, and anemia, followed by rapid death.
The investigators treated these mice with injections of YK-4-279 five days a week for 2 weeks or vehicle intraperitoneal injections on the same schedule.
The team said treatment with YK-4-279 significantly reduced white blood cell counts, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly.
They noted that mice experienced reductions in the weight of their spleens and livers without experiencing reductions in total body weight.
In addition, mice that received YK-4-279 had significantly better overall survival than control mice. The median survival times were 60.5 days and 21 days, respectively.
The investigators also noted that treated mice did not exhibit overt toxicity in the liver, spleen, or bone marrow.
“The fact that treated mice did not get sick from the YK-4-279 gives us an early indication that it might be safe to use in humans, but that is a question that can’t be answered until we conduct clinical trials,” Dr Üren said.
Nevertheless, he and his colleagues believe these results support the continued preclinical development of YK-4-279 for Ewing sarcoma, prostate cancers, and leukemias with highly homologous translocation products or with a clear ETS-driven gene signature.
A small-molecule compound that has previously shown activity against Ewing sarcoma and prostate cancer may fight leukemia as well, according to preclinical research published in Oncotarget.
The compound, YK-4-279, inhibits the oncogenic activity of the fusion protein EWS-FLI1.
“EWS-FLI1 is already known to drive a rare but deadly bone cancer called Ewing sarcoma,” said study author Aykut Üren, MD, of Georgetown University Medical Center in Washington, DC.
“It also appears to drive cancer cell growth in some prostate cancers.”
ETS family fusion proteins are found in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well.
So Dr Üren and his colleagues decided to create a mouse model of EWS-FLI1-induced leukemia and assess the activity of YK-4-279 in this model.
Mice with EWS-FLI1-induced leukemia presented with severe hepatomegaly, splenomegaly, and anemia, followed by rapid death.
The investigators treated these mice with injections of YK-4-279 five days a week for 2 weeks or vehicle intraperitoneal injections on the same schedule.
The team said treatment with YK-4-279 significantly reduced white blood cell counts, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly.
They noted that mice experienced reductions in the weight of their spleens and livers without experiencing reductions in total body weight.
In addition, mice that received YK-4-279 had significantly better overall survival than control mice. The median survival times were 60.5 days and 21 days, respectively.
The investigators also noted that treated mice did not exhibit overt toxicity in the liver, spleen, or bone marrow.
“The fact that treated mice did not get sick from the YK-4-279 gives us an early indication that it might be safe to use in humans, but that is a question that can’t be answered until we conduct clinical trials,” Dr Üren said.
Nevertheless, he and his colleagues believe these results support the continued preclinical development of YK-4-279 for Ewing sarcoma, prostate cancers, and leukemias with highly homologous translocation products or with a clear ETS-driven gene signature.
A small-molecule compound that has previously shown activity against Ewing sarcoma and prostate cancer may fight leukemia as well, according to preclinical research published in Oncotarget.
The compound, YK-4-279, inhibits the oncogenic activity of the fusion protein EWS-FLI1.
“EWS-FLI1 is already known to drive a rare but deadly bone cancer called Ewing sarcoma,” said study author Aykut Üren, MD, of Georgetown University Medical Center in Washington, DC.
“It also appears to drive cancer cell growth in some prostate cancers.”
ETS family fusion proteins are found in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well.
So Dr Üren and his colleagues decided to create a mouse model of EWS-FLI1-induced leukemia and assess the activity of YK-4-279 in this model.
Mice with EWS-FLI1-induced leukemia presented with severe hepatomegaly, splenomegaly, and anemia, followed by rapid death.
The investigators treated these mice with injections of YK-4-279 five days a week for 2 weeks or vehicle intraperitoneal injections on the same schedule.
The team said treatment with YK-4-279 significantly reduced white blood cell counts, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly.
They noted that mice experienced reductions in the weight of their spleens and livers without experiencing reductions in total body weight.
In addition, mice that received YK-4-279 had significantly better overall survival than control mice. The median survival times were 60.5 days and 21 days, respectively.
The investigators also noted that treated mice did not exhibit overt toxicity in the liver, spleen, or bone marrow.
“The fact that treated mice did not get sick from the YK-4-279 gives us an early indication that it might be safe to use in humans, but that is a question that can’t be answered until we conduct clinical trials,” Dr Üren said.
Nevertheless, he and his colleagues believe these results support the continued preclinical development of YK-4-279 for Ewing sarcoma, prostate cancers, and leukemias with highly homologous translocation products or with a clear ETS-driven gene signature.
Antibody can turn AML cells against each other
Image by Joshua Stokes
Scientists say they have discovered an antibody that can transform leukemic cells into immune cells that target their former “siblings.”
This agonist antibody, which is highly specific for the thrombopoietin receptor, can turn acute myeloid leukemia (AML) cells into dendritic cells.
With extended exposure to the antibody, these dendritic cells can then transform into natural killer (NK)-like cells that target AML cells.
The scientists described these discoveries in PNAS.
“It’s a totally new approach to cancer, and we’re working to test it in human patients as soon as possible,” said study author Richard A. Lerner, MD, of The Scripps Research Institute in La Jolla, California.
Unexpected transformation
Dr Lerner’s lab has pioneered techniques to generate and screen large libraries of antibodies to find therapeutic antibodies that bind to a desired target or activate a desired receptor on cells.
During the course of this work, the team discovered a phenomenon they call “receptor pleiotropism,” in which agonist antibodies against known receptors cause cell fates that are extremely different from those induced by the natural agonist to the receptor.
Why this happens is unclear, but the discovery led the scientists to wonder if they could use the method to convert leukemia cells into non-cancerous cells.
To find out, they tested 20 of their recently discovered receptor-activating antibodies against AML cells from patients. This revealed the transformative properties of the agonist antibody that is highly specific for the thrombopoietin receptor.
When this antibody was applied to healthy, immature bone marrow cells, it caused them to mature into megakaryocytes. However, when the antibody was applied to AML cells, they were converted into dendritic cells.
With longer exposures to the antibody and certain other in vitro conditions, the induced dendritic cells morphed into cells that closely resemble NK cells.
“That antibody could have turned those acute myeloid leukemia cells into a lot of other cell types, but, somehow, we were lucky enough to get NK cells,” Dr Lerner said.
The team examined these induced NK cells with electron microscopy and observed that many of the cells had extended tendrils through the outer membranes of neighboring AML cells. In in vitro tests, a modest number of these NK cells wiped out about 15% of the surrounding AML cell population in 24 hours.
The scientists also noted that the induced NK cells’ cancer-killing effects appeared to be purely “fratricidal.” Unrelated breast cancer cells did not die off in large numbers in the presence of the NK cells.
Fratricidin therapy
Why the induced NK cells appear to target only closely related cells isn’t yet clear. However, the finding suggests there may be antibodies—and even small-molecule compounds—that would turn other cancerous cell types into fratricidal NK cells by activating other receptors expressed on those cells.
Such fratricidal therapies, which Dr Lerner calls “fratricidins,” would have several potential advantages. First, especially if they are antibodies, they could be clinically useful with little or no further modification.
Second, their high specificity for their target receptors, and the resulting NK cells’ specificity for related cancer cells, should reduce the likelihood of adverse effects.
Finally, the peculiar dynamics of fratricidin therapy, in which every cancerous cell is potentially convertible to a cancer-killing NK cell, suggests that—if the strategy works—it might not just reduce the targeted cancer-cell population in a patient but eliminate it altogether.
“We’re in discussions with pharmaceutical companies to take this straight into humans after the appropriate preclinical toxicity studies,” Dr Lerner said.
This research was supported by the JPB Foundation and Zebra Biologics.
Image by Joshua Stokes
Scientists say they have discovered an antibody that can transform leukemic cells into immune cells that target their former “siblings.”
This agonist antibody, which is highly specific for the thrombopoietin receptor, can turn acute myeloid leukemia (AML) cells into dendritic cells.
With extended exposure to the antibody, these dendritic cells can then transform into natural killer (NK)-like cells that target AML cells.
The scientists described these discoveries in PNAS.
“It’s a totally new approach to cancer, and we’re working to test it in human patients as soon as possible,” said study author Richard A. Lerner, MD, of The Scripps Research Institute in La Jolla, California.
Unexpected transformation
Dr Lerner’s lab has pioneered techniques to generate and screen large libraries of antibodies to find therapeutic antibodies that bind to a desired target or activate a desired receptor on cells.
During the course of this work, the team discovered a phenomenon they call “receptor pleiotropism,” in which agonist antibodies against known receptors cause cell fates that are extremely different from those induced by the natural agonist to the receptor.
Why this happens is unclear, but the discovery led the scientists to wonder if they could use the method to convert leukemia cells into non-cancerous cells.
To find out, they tested 20 of their recently discovered receptor-activating antibodies against AML cells from patients. This revealed the transformative properties of the agonist antibody that is highly specific for the thrombopoietin receptor.
When this antibody was applied to healthy, immature bone marrow cells, it caused them to mature into megakaryocytes. However, when the antibody was applied to AML cells, they were converted into dendritic cells.
With longer exposures to the antibody and certain other in vitro conditions, the induced dendritic cells morphed into cells that closely resemble NK cells.
“That antibody could have turned those acute myeloid leukemia cells into a lot of other cell types, but, somehow, we were lucky enough to get NK cells,” Dr Lerner said.
The team examined these induced NK cells with electron microscopy and observed that many of the cells had extended tendrils through the outer membranes of neighboring AML cells. In in vitro tests, a modest number of these NK cells wiped out about 15% of the surrounding AML cell population in 24 hours.
The scientists also noted that the induced NK cells’ cancer-killing effects appeared to be purely “fratricidal.” Unrelated breast cancer cells did not die off in large numbers in the presence of the NK cells.
Fratricidin therapy
Why the induced NK cells appear to target only closely related cells isn’t yet clear. However, the finding suggests there may be antibodies—and even small-molecule compounds—that would turn other cancerous cell types into fratricidal NK cells by activating other receptors expressed on those cells.
Such fratricidal therapies, which Dr Lerner calls “fratricidins,” would have several potential advantages. First, especially if they are antibodies, they could be clinically useful with little or no further modification.
Second, their high specificity for their target receptors, and the resulting NK cells’ specificity for related cancer cells, should reduce the likelihood of adverse effects.
Finally, the peculiar dynamics of fratricidin therapy, in which every cancerous cell is potentially convertible to a cancer-killing NK cell, suggests that—if the strategy works—it might not just reduce the targeted cancer-cell population in a patient but eliminate it altogether.
“We’re in discussions with pharmaceutical companies to take this straight into humans after the appropriate preclinical toxicity studies,” Dr Lerner said.
This research was supported by the JPB Foundation and Zebra Biologics.
Image by Joshua Stokes
Scientists say they have discovered an antibody that can transform leukemic cells into immune cells that target their former “siblings.”
This agonist antibody, which is highly specific for the thrombopoietin receptor, can turn acute myeloid leukemia (AML) cells into dendritic cells.
With extended exposure to the antibody, these dendritic cells can then transform into natural killer (NK)-like cells that target AML cells.
The scientists described these discoveries in PNAS.
“It’s a totally new approach to cancer, and we’re working to test it in human patients as soon as possible,” said study author Richard A. Lerner, MD, of The Scripps Research Institute in La Jolla, California.
Unexpected transformation
Dr Lerner’s lab has pioneered techniques to generate and screen large libraries of antibodies to find therapeutic antibodies that bind to a desired target or activate a desired receptor on cells.
During the course of this work, the team discovered a phenomenon they call “receptor pleiotropism,” in which agonist antibodies against known receptors cause cell fates that are extremely different from those induced by the natural agonist to the receptor.
Why this happens is unclear, but the discovery led the scientists to wonder if they could use the method to convert leukemia cells into non-cancerous cells.
To find out, they tested 20 of their recently discovered receptor-activating antibodies against AML cells from patients. This revealed the transformative properties of the agonist antibody that is highly specific for the thrombopoietin receptor.
When this antibody was applied to healthy, immature bone marrow cells, it caused them to mature into megakaryocytes. However, when the antibody was applied to AML cells, they were converted into dendritic cells.
With longer exposures to the antibody and certain other in vitro conditions, the induced dendritic cells morphed into cells that closely resemble NK cells.
“That antibody could have turned those acute myeloid leukemia cells into a lot of other cell types, but, somehow, we were lucky enough to get NK cells,” Dr Lerner said.
The team examined these induced NK cells with electron microscopy and observed that many of the cells had extended tendrils through the outer membranes of neighboring AML cells. In in vitro tests, a modest number of these NK cells wiped out about 15% of the surrounding AML cell population in 24 hours.
The scientists also noted that the induced NK cells’ cancer-killing effects appeared to be purely “fratricidal.” Unrelated breast cancer cells did not die off in large numbers in the presence of the NK cells.
Fratricidin therapy
Why the induced NK cells appear to target only closely related cells isn’t yet clear. However, the finding suggests there may be antibodies—and even small-molecule compounds—that would turn other cancerous cell types into fratricidal NK cells by activating other receptors expressed on those cells.
Such fratricidal therapies, which Dr Lerner calls “fratricidins,” would have several potential advantages. First, especially if they are antibodies, they could be clinically useful with little or no further modification.
Second, their high specificity for their target receptors, and the resulting NK cells’ specificity for related cancer cells, should reduce the likelihood of adverse effects.
Finally, the peculiar dynamics of fratricidin therapy, in which every cancerous cell is potentially convertible to a cancer-killing NK cell, suggests that—if the strategy works—it might not just reduce the targeted cancer-cell population in a patient but eliminate it altogether.
“We’re in discussions with pharmaceutical companies to take this straight into humans after the appropriate preclinical toxicity studies,” Dr Lerner said.
This research was supported by the JPB Foundation and Zebra Biologics.
6PGD inhibitors could treat leukemia, other cancers
Photo by Rhoda Baer
Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.
These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.
In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.
Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.
The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.
“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”
Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).
But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.
When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.
Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.
Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.
S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.
Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.
And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.
Photo by Rhoda Baer
Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.
These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.
In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.
Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.
The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.
“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”
Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).
But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.
When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.
Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.
Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.
S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.
Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.
And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.
Photo by Rhoda Baer
Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.
These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.
In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.
Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.
The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.
“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”
Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).
But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.
When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.
Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.
Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.
S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.
Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.
And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.
Drug granted breakthrough designation for ALL
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.
When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.
Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.
The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.
Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.
This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.
Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.
The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.
However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).
In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.
The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).
Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.
Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).
There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.
Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).
*Information in the abstract differs from the presentation.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.
When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.
Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.
The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.
Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.
This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.
Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.
The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.
However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).
In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.
The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).
Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.
Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).
There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.
Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).
*Information in the abstract differs from the presentation.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.
When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.
Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.
The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.
Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.
This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.
Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.
The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.
However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).
In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.
The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).
Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.
Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).
There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.
Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).
*Information in the abstract differs from the presentation.
Study provides clearer picture of JMML
Photo by Petr Kratochvil
Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.
The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.
The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.
Researchers reported these discoveries in Nature Genetics.
“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”
“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”
So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.
Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.
These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.
Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.
For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.
The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.
Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.
“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.
“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”
Photo by Petr Kratochvil
Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.
The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.
The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.
Researchers reported these discoveries in Nature Genetics.
“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”
“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”
So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.
Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.
These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.
Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.
For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.
The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.
Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.
“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.
“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”
Photo by Petr Kratochvil
Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.
The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.
The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.
Researchers reported these discoveries in Nature Genetics.
“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”
“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”
So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.
Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.
These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.
Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.
For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.
The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.
Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.
“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.
“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”
Model recapitulates cancer susceptibility in DBA
Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).
DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.
The team found that RPL11-deficient mice
developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.
Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.
Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.
In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.
“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”
“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”
In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.
“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.
The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.
Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid
progenitors and defective erythroid maturation.
Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia
and intestinal atrophy in adult mice. And these mice died within a few weeks.
Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).
DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.
The team found that RPL11-deficient mice
developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.
Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.
Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.
In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.
“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”
“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”
In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.
“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.
The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.
Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid
progenitors and defective erythroid maturation.
Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia
and intestinal atrophy in adult mice. And these mice died within a few weeks.
Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).
DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.
The team found that RPL11-deficient mice
developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.
Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.
Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.
In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.
“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”
“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”
In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.
“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.
The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.
Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid
progenitors and defective erythroid maturation.
Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia
and intestinal atrophy in adult mice. And these mice died within a few weeks.