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#Patients looking for #clinicaltrials
I just hung up with a friend I haven’t seen in decades. Her father has advanced cancer, and while she does not have formal medical training, a passerby wouldn’t know it. Her questions are spot on, her resources are peer reviewed and validated, and her questions I’d more likely expect from trainees in a formal oncology training program than from the director of an elementary level tutoring service.
Her father is fortunately doing well, but she’s searching for the next plan for when the standard drugs ultimately fail. We know they will fail. She’s connected to patient advocacy groups, emailing physicians across the country, and looking into clinical trials with their exhaustive lists of exclusion criteria. She sees the logistic difficulties with trials far from home. She’s hit the key issues we face every day in clinical research, and she’s never stepped foot in a medical school lecture hall.
Amazingly her story is not unique. When cancer hits close to home is when these problems become very clear. This same story could easily have been retold as the narrative of former Vice President Joe Biden and his care for his son. Both my friend and Mr. Biden, in fact, asked me the same question: How do we get the cutting-edge science from major research centers out to the rest of the country?
The Cancer Moonshot initiative has done much to promote collaboration, but one major success has been in the Count Me In initiative, a partnership between the Biden Cancer Initiative, Emerson Collective, the Broad Institute, and the Dana-Farber Cancer Institute. Their goal is to gain access to thousands of patients, collect data on treatment and outcomes, and collect biological specimens. They are not alone, the MSK-IMPACT initiative – led by David B. Solit, MD, at my institution – aims to sequence rare cancers. Both programs have heavily leveraged social media to access and engage patients.
There are of course concerns. Coming from hundreds or thousands of different sites will mean the data will likely be heterogeneous in formatting and quality. How do we ensure the security of patient data? Can we rely on patients and family members to report accurately and without bias? We know there are challenges and upside to crowdsourced patient recruitment.
David Ginsburg, MD, Karl Desch, MD, and colleagues enrolled more than 1,000 students from the University of Michigan to participate in a study on blood clotting factors. This led to many important findings on the genetic basis for coagulopathies, but also was instructive in uncovering a worrisome aspect of online patient registration. The group recorded the time taken for registrants to read the consent form – including whether the participant clicked a hyperlink that was embedded. Nearly a quarter of participants accepted the terms of the 2,833-word document in less than 10 seconds, and less than 3% clicked the hyperlink (Ann Intern Med. 2011 Sep 6;155[5]:316-22).
Are these patients, who we are asking for their partnership and trust, really understanding to what they are agreeing?
Surely there is tremendous altruism on the part of these patients. Their hopes of helping the future of cancer care does have a real track record. Crowdsourcing efforts that were less far reaching in scope made substantial impact in discovering the genetic basis for polycythemia vera. The patients, contacted largely through printed newspaper ads, have helped millions of others. What will happen when we add in the power of social media will be exciting to see – and there is something else that comes with great power, but since I can’t seem to remember what that is, I’ll just search online.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is an assistant attending physician on the leukemia service and is a clinical researcher in the Ross Levine Lab. Follow him on Twitter @TheDoctorIsVin.
I just hung up with a friend I haven’t seen in decades. Her father has advanced cancer, and while she does not have formal medical training, a passerby wouldn’t know it. Her questions are spot on, her resources are peer reviewed and validated, and her questions I’d more likely expect from trainees in a formal oncology training program than from the director of an elementary level tutoring service.
Her father is fortunately doing well, but she’s searching for the next plan for when the standard drugs ultimately fail. We know they will fail. She’s connected to patient advocacy groups, emailing physicians across the country, and looking into clinical trials with their exhaustive lists of exclusion criteria. She sees the logistic difficulties with trials far from home. She’s hit the key issues we face every day in clinical research, and she’s never stepped foot in a medical school lecture hall.
Amazingly her story is not unique. When cancer hits close to home is when these problems become very clear. This same story could easily have been retold as the narrative of former Vice President Joe Biden and his care for his son. Both my friend and Mr. Biden, in fact, asked me the same question: How do we get the cutting-edge science from major research centers out to the rest of the country?
The Cancer Moonshot initiative has done much to promote collaboration, but one major success has been in the Count Me In initiative, a partnership between the Biden Cancer Initiative, Emerson Collective, the Broad Institute, and the Dana-Farber Cancer Institute. Their goal is to gain access to thousands of patients, collect data on treatment and outcomes, and collect biological specimens. They are not alone, the MSK-IMPACT initiative – led by David B. Solit, MD, at my institution – aims to sequence rare cancers. Both programs have heavily leveraged social media to access and engage patients.
There are of course concerns. Coming from hundreds or thousands of different sites will mean the data will likely be heterogeneous in formatting and quality. How do we ensure the security of patient data? Can we rely on patients and family members to report accurately and without bias? We know there are challenges and upside to crowdsourced patient recruitment.
David Ginsburg, MD, Karl Desch, MD, and colleagues enrolled more than 1,000 students from the University of Michigan to participate in a study on blood clotting factors. This led to many important findings on the genetic basis for coagulopathies, but also was instructive in uncovering a worrisome aspect of online patient registration. The group recorded the time taken for registrants to read the consent form – including whether the participant clicked a hyperlink that was embedded. Nearly a quarter of participants accepted the terms of the 2,833-word document in less than 10 seconds, and less than 3% clicked the hyperlink (Ann Intern Med. 2011 Sep 6;155[5]:316-22).
Are these patients, who we are asking for their partnership and trust, really understanding to what they are agreeing?
Surely there is tremendous altruism on the part of these patients. Their hopes of helping the future of cancer care does have a real track record. Crowdsourcing efforts that were less far reaching in scope made substantial impact in discovering the genetic basis for polycythemia vera. The patients, contacted largely through printed newspaper ads, have helped millions of others. What will happen when we add in the power of social media will be exciting to see – and there is something else that comes with great power, but since I can’t seem to remember what that is, I’ll just search online.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is an assistant attending physician on the leukemia service and is a clinical researcher in the Ross Levine Lab. Follow him on Twitter @TheDoctorIsVin.
I just hung up with a friend I haven’t seen in decades. Her father has advanced cancer, and while she does not have formal medical training, a passerby wouldn’t know it. Her questions are spot on, her resources are peer reviewed and validated, and her questions I’d more likely expect from trainees in a formal oncology training program than from the director of an elementary level tutoring service.
Her father is fortunately doing well, but she’s searching for the next plan for when the standard drugs ultimately fail. We know they will fail. She’s connected to patient advocacy groups, emailing physicians across the country, and looking into clinical trials with their exhaustive lists of exclusion criteria. She sees the logistic difficulties with trials far from home. She’s hit the key issues we face every day in clinical research, and she’s never stepped foot in a medical school lecture hall.
Amazingly her story is not unique. When cancer hits close to home is when these problems become very clear. This same story could easily have been retold as the narrative of former Vice President Joe Biden and his care for his son. Both my friend and Mr. Biden, in fact, asked me the same question: How do we get the cutting-edge science from major research centers out to the rest of the country?
The Cancer Moonshot initiative has done much to promote collaboration, but one major success has been in the Count Me In initiative, a partnership between the Biden Cancer Initiative, Emerson Collective, the Broad Institute, and the Dana-Farber Cancer Institute. Their goal is to gain access to thousands of patients, collect data on treatment and outcomes, and collect biological specimens. They are not alone, the MSK-IMPACT initiative – led by David B. Solit, MD, at my institution – aims to sequence rare cancers. Both programs have heavily leveraged social media to access and engage patients.
There are of course concerns. Coming from hundreds or thousands of different sites will mean the data will likely be heterogeneous in formatting and quality. How do we ensure the security of patient data? Can we rely on patients and family members to report accurately and without bias? We know there are challenges and upside to crowdsourced patient recruitment.
David Ginsburg, MD, Karl Desch, MD, and colleagues enrolled more than 1,000 students from the University of Michigan to participate in a study on blood clotting factors. This led to many important findings on the genetic basis for coagulopathies, but also was instructive in uncovering a worrisome aspect of online patient registration. The group recorded the time taken for registrants to read the consent form – including whether the participant clicked a hyperlink that was embedded. Nearly a quarter of participants accepted the terms of the 2,833-word document in less than 10 seconds, and less than 3% clicked the hyperlink (Ann Intern Med. 2011 Sep 6;155[5]:316-22).
Are these patients, who we are asking for their partnership and trust, really understanding to what they are agreeing?
Surely there is tremendous altruism on the part of these patients. Their hopes of helping the future of cancer care does have a real track record. Crowdsourcing efforts that were less far reaching in scope made substantial impact in discovering the genetic basis for polycythemia vera. The patients, contacted largely through printed newspaper ads, have helped millions of others. What will happen when we add in the power of social media will be exciting to see – and there is something else that comes with great power, but since I can’t seem to remember what that is, I’ll just search online.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is an assistant attending physician on the leukemia service and is a clinical researcher in the Ross Levine Lab. Follow him on Twitter @TheDoctorIsVin.
Under his IDH2: Epigenetic drivers of clonal hematopoiesis
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
Antibodies Part 3: In whose corner is genome editing’s best cut-man sitting?
We are in the midst of a revolution in genome editing. Science now exists in “AC,” or after CRISPR. Able to speedily and efficiently make genomic cuts with surgical precision, CRISPR/Cas9 is used almost ubiquitously now in the scientific community to study and alter DNA across fields ranging from medicine to agriculture to zoology. The possibilities of the biological and therapeutic implications are seemingly endless, as are the important ethical implications of their impact. Likely because of the latter, CRISPR technology has made its way from publications like Science and Nature into the lay public domains of Newsweek and NBC News.
In fact, CRISPR technology made its way into one of my favorite podcasts, WNYC’s “Radio Lab” in June 20151. The episode was entitled “Antibodies Part 1,” perhaps assuming that other technologies would also be discussed later although that has never happened. Actually, in an update early this year, the podcast jokingly addressed never moving on to “Part 2,” then followed with an update on how far CRISPR technology has progressed. Putting aside the technological advances and the early clinical applications, as well as the immense ethical considerations, CRISPR technology faces a new controversy, not one from a white coat but rather from a black robe.
In her CommonHealth blog2, Carey Goldberg of WBUR Boston Public Radio compared the case with the bout between undefeated Muhammad Ali and undefeated Joe Frazier at New York’s Madison Square Garden. Both men had legitimate claims to the title of World Heavyweight Champion. What transpired is now known as the “Fight of the Century.”
The analogy is apt. Boxing is about speed and control. Ali dominated the first three rounds with his jab, a punch that is both offensive with its attack and defensive in keeping one’s opponent at a distance. Dr. Doudna and her collaborator Emmanuelle Charpentier, PhD, published their work first (Science. 2012 Aug 17;337[6096]:816-21)3. UC Berkeley filed their patent first in May 2012.
Boxing is about timing and opportunity. Under the barrage of Ali’s jabs, Frazier found an inside position and caught Ali with a left hook. Dr. Zhang’s work followed closely after but had previously applied the technology in murine and human cells (Science. 2013 Feb 15; 339[6121]:819-23)4. The Broad Institute used this key difference to apply for its own patents under expedited review, which were granted in April 2014.
Boxing is about a punch and a counterpunch. Though fatigued, Ali continued to connect with combination punches. Frazier’s left hook pummeled Ali’s jaw. UC Berkeley filed an interference motion to invalidate the Broad Institute patent claim on the basis that the extension to eukaryotic cells was “obvious” based on the published work by Dr. Doudna’s group. In February, USPTO ruled that the Broad patent application may proceed, citing “patentably distinct subject matter.” Initial reports had indicated that Berkeley may appeal the decision, but no official filings have been made public.
Like the Fight of the Century, this case may go the distance and be decided by the judges. In a unanimous decision, Joe Frazier won the first of three epic bouts. The final scorecard is not known in the patent disputes; on March 28, the European Patent Office announced it will grant the patent application on behalf of Dr. Doudna and Dr. Charpentier.
Much like a prizefight, Wall Street has also been taking bets on who will prevail, with CRISPR-based biotech backing both sides mirroring the mid-bout odds, just as Ali dominated early with the jab, until Frazier evened the match with a left hook to the jaw. Ali fell to his knee on the canvas in the 11th round; will the European Patent Office decision prove to be a slip or a decisive knockdown? With so much at stake, the only assurance is that, as with the Ali-Frazier bout, there is likely more fighting to be done.
References:
1. Radio Lab
2. CommonHealth blog
3. Jinek M, et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012 Aug 17;337(6096):816-21.
4. Le Cong et al., Multiplex genome engineering using CRISPR/Cas Systems. Science. 2013 Feb 15;339(6121):819-23. Multiplex genome engineering using CRISPR/Cas Systems.
Science. 2017 Feb 15: Round one of CRISPR patent legal battle goes to the Broad Institute.
StreetInsider.com: CRISPR Therapeutics (CRSP) says EPO to grant CRISPR/Cas gene editing patent.
vinya@mskcc.org
On Twitter @thedoctorisvin
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
We are in the midst of a revolution in genome editing. Science now exists in “AC,” or after CRISPR. Able to speedily and efficiently make genomic cuts with surgical precision, CRISPR/Cas9 is used almost ubiquitously now in the scientific community to study and alter DNA across fields ranging from medicine to agriculture to zoology. The possibilities of the biological and therapeutic implications are seemingly endless, as are the important ethical implications of their impact. Likely because of the latter, CRISPR technology has made its way from publications like Science and Nature into the lay public domains of Newsweek and NBC News.
In fact, CRISPR technology made its way into one of my favorite podcasts, WNYC’s “Radio Lab” in June 20151. The episode was entitled “Antibodies Part 1,” perhaps assuming that other technologies would also be discussed later although that has never happened. Actually, in an update early this year, the podcast jokingly addressed never moving on to “Part 2,” then followed with an update on how far CRISPR technology has progressed. Putting aside the technological advances and the early clinical applications, as well as the immense ethical considerations, CRISPR technology faces a new controversy, not one from a white coat but rather from a black robe.
In her CommonHealth blog2, Carey Goldberg of WBUR Boston Public Radio compared the case with the bout between undefeated Muhammad Ali and undefeated Joe Frazier at New York’s Madison Square Garden. Both men had legitimate claims to the title of World Heavyweight Champion. What transpired is now known as the “Fight of the Century.”
The analogy is apt. Boxing is about speed and control. Ali dominated the first three rounds with his jab, a punch that is both offensive with its attack and defensive in keeping one’s opponent at a distance. Dr. Doudna and her collaborator Emmanuelle Charpentier, PhD, published their work first (Science. 2012 Aug 17;337[6096]:816-21)3. UC Berkeley filed their patent first in May 2012.
Boxing is about timing and opportunity. Under the barrage of Ali’s jabs, Frazier found an inside position and caught Ali with a left hook. Dr. Zhang’s work followed closely after but had previously applied the technology in murine and human cells (Science. 2013 Feb 15; 339[6121]:819-23)4. The Broad Institute used this key difference to apply for its own patents under expedited review, which were granted in April 2014.
Boxing is about a punch and a counterpunch. Though fatigued, Ali continued to connect with combination punches. Frazier’s left hook pummeled Ali’s jaw. UC Berkeley filed an interference motion to invalidate the Broad Institute patent claim on the basis that the extension to eukaryotic cells was “obvious” based on the published work by Dr. Doudna’s group. In February, USPTO ruled that the Broad patent application may proceed, citing “patentably distinct subject matter.” Initial reports had indicated that Berkeley may appeal the decision, but no official filings have been made public.
Like the Fight of the Century, this case may go the distance and be decided by the judges. In a unanimous decision, Joe Frazier won the first of three epic bouts. The final scorecard is not known in the patent disputes; on March 28, the European Patent Office announced it will grant the patent application on behalf of Dr. Doudna and Dr. Charpentier.
Much like a prizefight, Wall Street has also been taking bets on who will prevail, with CRISPR-based biotech backing both sides mirroring the mid-bout odds, just as Ali dominated early with the jab, until Frazier evened the match with a left hook to the jaw. Ali fell to his knee on the canvas in the 11th round; will the European Patent Office decision prove to be a slip or a decisive knockdown? With so much at stake, the only assurance is that, as with the Ali-Frazier bout, there is likely more fighting to be done.
References:
1. Radio Lab
2. CommonHealth blog
3. Jinek M, et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012 Aug 17;337(6096):816-21.
4. Le Cong et al., Multiplex genome engineering using CRISPR/Cas Systems. Science. 2013 Feb 15;339(6121):819-23. Multiplex genome engineering using CRISPR/Cas Systems.
Science. 2017 Feb 15: Round one of CRISPR patent legal battle goes to the Broad Institute.
StreetInsider.com: CRISPR Therapeutics (CRSP) says EPO to grant CRISPR/Cas gene editing patent.
vinya@mskcc.org
On Twitter @thedoctorisvin
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
We are in the midst of a revolution in genome editing. Science now exists in “AC,” or after CRISPR. Able to speedily and efficiently make genomic cuts with surgical precision, CRISPR/Cas9 is used almost ubiquitously now in the scientific community to study and alter DNA across fields ranging from medicine to agriculture to zoology. The possibilities of the biological and therapeutic implications are seemingly endless, as are the important ethical implications of their impact. Likely because of the latter, CRISPR technology has made its way from publications like Science and Nature into the lay public domains of Newsweek and NBC News.
In fact, CRISPR technology made its way into one of my favorite podcasts, WNYC’s “Radio Lab” in June 20151. The episode was entitled “Antibodies Part 1,” perhaps assuming that other technologies would also be discussed later although that has never happened. Actually, in an update early this year, the podcast jokingly addressed never moving on to “Part 2,” then followed with an update on how far CRISPR technology has progressed. Putting aside the technological advances and the early clinical applications, as well as the immense ethical considerations, CRISPR technology faces a new controversy, not one from a white coat but rather from a black robe.
In her CommonHealth blog2, Carey Goldberg of WBUR Boston Public Radio compared the case with the bout between undefeated Muhammad Ali and undefeated Joe Frazier at New York’s Madison Square Garden. Both men had legitimate claims to the title of World Heavyweight Champion. What transpired is now known as the “Fight of the Century.”
The analogy is apt. Boxing is about speed and control. Ali dominated the first three rounds with his jab, a punch that is both offensive with its attack and defensive in keeping one’s opponent at a distance. Dr. Doudna and her collaborator Emmanuelle Charpentier, PhD, published their work first (Science. 2012 Aug 17;337[6096]:816-21)3. UC Berkeley filed their patent first in May 2012.
Boxing is about timing and opportunity. Under the barrage of Ali’s jabs, Frazier found an inside position and caught Ali with a left hook. Dr. Zhang’s work followed closely after but had previously applied the technology in murine and human cells (Science. 2013 Feb 15; 339[6121]:819-23)4. The Broad Institute used this key difference to apply for its own patents under expedited review, which were granted in April 2014.
Boxing is about a punch and a counterpunch. Though fatigued, Ali continued to connect with combination punches. Frazier’s left hook pummeled Ali’s jaw. UC Berkeley filed an interference motion to invalidate the Broad Institute patent claim on the basis that the extension to eukaryotic cells was “obvious” based on the published work by Dr. Doudna’s group. In February, USPTO ruled that the Broad patent application may proceed, citing “patentably distinct subject matter.” Initial reports had indicated that Berkeley may appeal the decision, but no official filings have been made public.
Like the Fight of the Century, this case may go the distance and be decided by the judges. In a unanimous decision, Joe Frazier won the first of three epic bouts. The final scorecard is not known in the patent disputes; on March 28, the European Patent Office announced it will grant the patent application on behalf of Dr. Doudna and Dr. Charpentier.
Much like a prizefight, Wall Street has also been taking bets on who will prevail, with CRISPR-based biotech backing both sides mirroring the mid-bout odds, just as Ali dominated early with the jab, until Frazier evened the match with a left hook to the jaw. Ali fell to his knee on the canvas in the 11th round; will the European Patent Office decision prove to be a slip or a decisive knockdown? With so much at stake, the only assurance is that, as with the Ali-Frazier bout, there is likely more fighting to be done.
References:
1. Radio Lab
2. CommonHealth blog
3. Jinek M, et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012 Aug 17;337(6096):816-21.
4. Le Cong et al., Multiplex genome engineering using CRISPR/Cas Systems. Science. 2013 Feb 15;339(6121):819-23. Multiplex genome engineering using CRISPR/Cas Systems.
Science. 2017 Feb 15: Round one of CRISPR patent legal battle goes to the Broad Institute.
StreetInsider.com: CRISPR Therapeutics (CRSP) says EPO to grant CRISPR/Cas gene editing patent.
vinya@mskcc.org
On Twitter @thedoctorisvin
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
FOUND IN TRANSLATION Minimal nomenclature and maximum sensitivity complicate MRD measures
In hematologic malignancies, there is a deep and direct connection between each individual patient, that patient’s symptoms, the visible cells that cause the disease, and the direct measurements and assessments of those cells. The totality of these factors helps to determine the diagnosis and treatment plan. As a butterfly needle often is sufficient for obtaining a diagnostic tumor biopsy, it is not surprising that these same diagnostic techniques are now standardly being used to monitor disease response.
The techniques differ in their limits of detection, however. With sequencing depths able to reliably detect variant allele frequencies of less than 10%, even when patients’ overt leukemia may no longer be detectable, clinicians may be left to ponder what to do with persistent “preleukemic” or “rising clones.”1-3
These patients, now more appropriately stratified for risk of recurrence, are in desperate need of better care algorithms. Standard MRD assessment by flow cytometric analysis is able to detect less than 1 x 10-4 cells. While it can be applied to most patients, its sensitivity will likely be surpassed by new and emerging genomic assays. Real time quantitative polymerase chain reaction (RT-qPCR) and next generation sequencing (NGS) require a leukemia-specific abnormality but have the potential for far greater sensitivity with deeper sequencing techniques.
Long-term follow up data in acute promyelocytic leukemia (APL) provides the illustrative example where morphologic remission is not durable in the setting of a persistent PML-RARa transcript and therapeutic goals for PCR negativity irrespective of morphology are standard. Pathologic fusion proteins are ideal for marker-driven therapy, but are found in only about 50% of patients, mainly those with APL and Philadelphia chromosome-positive leukemias.
With driver mutations identified in the majority of patients, we can be hopeful that NGS negativity may be a useful clinical endpoint. In work presented at ASH 2016 by Bartlomiej M Getta, MBBS, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues, patients with concordant MRD positivity by flow cytometry and NGS had inferior outcomes, even after allogeneic transplant, compared to patients with MRD positivity on one assay but not both.5 Nonetheless, caution should be taken in early adoption of NGS as a independent marker of MRD status for two main reasons: 1) False positives and lack of standardization make current interpretation difficult. 2) The presence of “preleukemic” clones remains enigmatic – and no matter the nomenclature used, can a DNMT3A or IDH-mutant clone really be deemed “clonal hematopoiesis of indeterminate potential” when a patient has already had clonal transformation?
Conversely, not all patients reported in the work by Klco2 and Getta ultimately relapse. Thus, while it would be preferred to clear all mutant clones, as a therapeutic goal this likely would subject many patients to unnecessary toxicity. One half of the patients reported by Getta were disease free at a year with concordant flow and NGS positive MRD while patients with NGS positivity alone had outcomes equivalent to those of MRD-negative patients, highlighting that certain persistent clones in NGS-only, MRD-positive patients might be amenable to immunotherapy, either with checkpoint inhibitors or allogeneic transplant. Insight into which clones remain quiescent and which are more sinister will require more investigation, but there does seem to be an additive role to NGS-positivity, whereby all MRD is not created equal and the precision and clinical utility of MRD status will likely take on nuanced nomenclature.
References
1. Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Science Translational Medicine 4, 149ra118, doi: 10.1126/scitranslmed.3004315 (2012).
2. Klco, J. M. et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314:811-22. doi: 10.1001/jama.2015.9643.
3. Wong, T. N. et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 2016;127:893-7. doi: 10.1182/blood-2015-10-677021 (2016).
4. Lane, A. A. et al. Results from Ongoing Phase II Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD), Abstract 215, ASH 2016.
5. Getta, B. M. et al. Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant, Abstract 834, ASH 2016.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, New York, where he is a clinical instructor, on the staff of the leukemia service, and a clinical researcher in The Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
In hematologic malignancies, there is a deep and direct connection between each individual patient, that patient’s symptoms, the visible cells that cause the disease, and the direct measurements and assessments of those cells. The totality of these factors helps to determine the diagnosis and treatment plan. As a butterfly needle often is sufficient for obtaining a diagnostic tumor biopsy, it is not surprising that these same diagnostic techniques are now standardly being used to monitor disease response.
The techniques differ in their limits of detection, however. With sequencing depths able to reliably detect variant allele frequencies of less than 10%, even when patients’ overt leukemia may no longer be detectable, clinicians may be left to ponder what to do with persistent “preleukemic” or “rising clones.”1-3
These patients, now more appropriately stratified for risk of recurrence, are in desperate need of better care algorithms. Standard MRD assessment by flow cytometric analysis is able to detect less than 1 x 10-4 cells. While it can be applied to most patients, its sensitivity will likely be surpassed by new and emerging genomic assays. Real time quantitative polymerase chain reaction (RT-qPCR) and next generation sequencing (NGS) require a leukemia-specific abnormality but have the potential for far greater sensitivity with deeper sequencing techniques.
Long-term follow up data in acute promyelocytic leukemia (APL) provides the illustrative example where morphologic remission is not durable in the setting of a persistent PML-RARa transcript and therapeutic goals for PCR negativity irrespective of morphology are standard. Pathologic fusion proteins are ideal for marker-driven therapy, but are found in only about 50% of patients, mainly those with APL and Philadelphia chromosome-positive leukemias.
With driver mutations identified in the majority of patients, we can be hopeful that NGS negativity may be a useful clinical endpoint. In work presented at ASH 2016 by Bartlomiej M Getta, MBBS, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues, patients with concordant MRD positivity by flow cytometry and NGS had inferior outcomes, even after allogeneic transplant, compared to patients with MRD positivity on one assay but not both.5 Nonetheless, caution should be taken in early adoption of NGS as a independent marker of MRD status for two main reasons: 1) False positives and lack of standardization make current interpretation difficult. 2) The presence of “preleukemic” clones remains enigmatic – and no matter the nomenclature used, can a DNMT3A or IDH-mutant clone really be deemed “clonal hematopoiesis of indeterminate potential” when a patient has already had clonal transformation?
Conversely, not all patients reported in the work by Klco2 and Getta ultimately relapse. Thus, while it would be preferred to clear all mutant clones, as a therapeutic goal this likely would subject many patients to unnecessary toxicity. One half of the patients reported by Getta were disease free at a year with concordant flow and NGS positive MRD while patients with NGS positivity alone had outcomes equivalent to those of MRD-negative patients, highlighting that certain persistent clones in NGS-only, MRD-positive patients might be amenable to immunotherapy, either with checkpoint inhibitors or allogeneic transplant. Insight into which clones remain quiescent and which are more sinister will require more investigation, but there does seem to be an additive role to NGS-positivity, whereby all MRD is not created equal and the precision and clinical utility of MRD status will likely take on nuanced nomenclature.
References
1. Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Science Translational Medicine 4, 149ra118, doi: 10.1126/scitranslmed.3004315 (2012).
2. Klco, J. M. et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314:811-22. doi: 10.1001/jama.2015.9643.
3. Wong, T. N. et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 2016;127:893-7. doi: 10.1182/blood-2015-10-677021 (2016).
4. Lane, A. A. et al. Results from Ongoing Phase II Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD), Abstract 215, ASH 2016.
5. Getta, B. M. et al. Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant, Abstract 834, ASH 2016.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, New York, where he is a clinical instructor, on the staff of the leukemia service, and a clinical researcher in The Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
In hematologic malignancies, there is a deep and direct connection between each individual patient, that patient’s symptoms, the visible cells that cause the disease, and the direct measurements and assessments of those cells. The totality of these factors helps to determine the diagnosis and treatment plan. As a butterfly needle often is sufficient for obtaining a diagnostic tumor biopsy, it is not surprising that these same diagnostic techniques are now standardly being used to monitor disease response.
The techniques differ in their limits of detection, however. With sequencing depths able to reliably detect variant allele frequencies of less than 10%, even when patients’ overt leukemia may no longer be detectable, clinicians may be left to ponder what to do with persistent “preleukemic” or “rising clones.”1-3
These patients, now more appropriately stratified for risk of recurrence, are in desperate need of better care algorithms. Standard MRD assessment by flow cytometric analysis is able to detect less than 1 x 10-4 cells. While it can be applied to most patients, its sensitivity will likely be surpassed by new and emerging genomic assays. Real time quantitative polymerase chain reaction (RT-qPCR) and next generation sequencing (NGS) require a leukemia-specific abnormality but have the potential for far greater sensitivity with deeper sequencing techniques.
Long-term follow up data in acute promyelocytic leukemia (APL) provides the illustrative example where morphologic remission is not durable in the setting of a persistent PML-RARa transcript and therapeutic goals for PCR negativity irrespective of morphology are standard. Pathologic fusion proteins are ideal for marker-driven therapy, but are found in only about 50% of patients, mainly those with APL and Philadelphia chromosome-positive leukemias.
With driver mutations identified in the majority of patients, we can be hopeful that NGS negativity may be a useful clinical endpoint. In work presented at ASH 2016 by Bartlomiej M Getta, MBBS, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues, patients with concordant MRD positivity by flow cytometry and NGS had inferior outcomes, even after allogeneic transplant, compared to patients with MRD positivity on one assay but not both.5 Nonetheless, caution should be taken in early adoption of NGS as a independent marker of MRD status for two main reasons: 1) False positives and lack of standardization make current interpretation difficult. 2) The presence of “preleukemic” clones remains enigmatic – and no matter the nomenclature used, can a DNMT3A or IDH-mutant clone really be deemed “clonal hematopoiesis of indeterminate potential” when a patient has already had clonal transformation?
Conversely, not all patients reported in the work by Klco2 and Getta ultimately relapse. Thus, while it would be preferred to clear all mutant clones, as a therapeutic goal this likely would subject many patients to unnecessary toxicity. One half of the patients reported by Getta were disease free at a year with concordant flow and NGS positive MRD while patients with NGS positivity alone had outcomes equivalent to those of MRD-negative patients, highlighting that certain persistent clones in NGS-only, MRD-positive patients might be amenable to immunotherapy, either with checkpoint inhibitors or allogeneic transplant. Insight into which clones remain quiescent and which are more sinister will require more investigation, but there does seem to be an additive role to NGS-positivity, whereby all MRD is not created equal and the precision and clinical utility of MRD status will likely take on nuanced nomenclature.
References
1. Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Science Translational Medicine 4, 149ra118, doi: 10.1126/scitranslmed.3004315 (2012).
2. Klco, J. M. et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314:811-22. doi: 10.1001/jama.2015.9643.
3. Wong, T. N. et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 2016;127:893-7. doi: 10.1182/blood-2015-10-677021 (2016).
4. Lane, A. A. et al. Results from Ongoing Phase II Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD), Abstract 215, ASH 2016.
5. Getta, B. M. et al. Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant, Abstract 834, ASH 2016.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, New York, where he is a clinical instructor, on the staff of the leukemia service, and a clinical researcher in The Ross Levine Lab. Contact Dr. Viny at vinya@mskcc.org.
The complex genetic landscape of AML
A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.
The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.
When speaking with relapsed patients, I often say that, while we are very good at cutting down trees in AML, we still have not done very well with getting rid of the roots. Admittedly, this metaphor grossly oversimplifies cancer stem cell biology, but it gets at the real importance of the work by Dr. Papaemmanuil and her colleagues. The interactions of gene mutations such as NPM1 and DNMT3A are not uncommon and their co-mutation in isolation has an intermediate prognosis. The clonal acquisition of a codon 12/13 mutation in NRAS seems to result in a more favorable prognosis – lending to the likelihood that the tumor is simply more chemosensitive. In contrast, the acquisition of FLT3-ITD by the NPM1/DNMT3A co-mutant clone results in a very poor prognosis likely due to chemoresistance.
The real power of this study’s findings is the potential for building a toolbox of agents to push against the innate clonal selection and force the “tree” to grow in a direction that is detrimental to its survival. One could consider using FLT3 inhibitors in the wild-type setting of a genetic background primed towards FLT3-ITD evolution to prevent this resistant outgrowth. Of course, such an approach needs to be studied first in a laboratory setting, but similar therapeutic strategies have been applied to BRAF in melanoma. Peter Nowell urged “controlling the evolutionary process in tumors before it reaches the late stage,” and this new ordinal understanding of AML may help to do just that.
vinya@mskcc.org
On Twitter @thedoctorisvin
A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.
The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.
When speaking with relapsed patients, I often say that, while we are very good at cutting down trees in AML, we still have not done very well with getting rid of the roots. Admittedly, this metaphor grossly oversimplifies cancer stem cell biology, but it gets at the real importance of the work by Dr. Papaemmanuil and her colleagues. The interactions of gene mutations such as NPM1 and DNMT3A are not uncommon and their co-mutation in isolation has an intermediate prognosis. The clonal acquisition of a codon 12/13 mutation in NRAS seems to result in a more favorable prognosis – lending to the likelihood that the tumor is simply more chemosensitive. In contrast, the acquisition of FLT3-ITD by the NPM1/DNMT3A co-mutant clone results in a very poor prognosis likely due to chemoresistance.
The real power of this study’s findings is the potential for building a toolbox of agents to push against the innate clonal selection and force the “tree” to grow in a direction that is detrimental to its survival. One could consider using FLT3 inhibitors in the wild-type setting of a genetic background primed towards FLT3-ITD evolution to prevent this resistant outgrowth. Of course, such an approach needs to be studied first in a laboratory setting, but similar therapeutic strategies have been applied to BRAF in melanoma. Peter Nowell urged “controlling the evolutionary process in tumors before it reaches the late stage,” and this new ordinal understanding of AML may help to do just that.
vinya@mskcc.org
On Twitter @thedoctorisvin
A unifying genetic basis has been sought to explain the complex and heterogeneous nature of myeloid neoplasms since before Janet Rowley’s quinacrine banding discovered the Philadelphia chromosome (Nature. 1973;243[5405]:290-3). In the decades following that discovery, groundbreaking work has uncovered new chromosomal abnormalities, new gene fusions, new recurrent mutations – often with prognostic implications, but rarely with therapeutic ones.
The recent work by Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues reaffirms the genetic heterogeneity of AML based on molecular profiling of patients from three large European trials. Yet the most insightful aspect of this reclassification is not just the detail of the genetic resolution but the realization that, even within a gene such as NRAS, the genetic background for acquisition of a codon 12/13 mutation is mutually exclusive with clones where NRAS codon 61 occurs.
When speaking with relapsed patients, I often say that, while we are very good at cutting down trees in AML, we still have not done very well with getting rid of the roots. Admittedly, this metaphor grossly oversimplifies cancer stem cell biology, but it gets at the real importance of the work by Dr. Papaemmanuil and her colleagues. The interactions of gene mutations such as NPM1 and DNMT3A are not uncommon and their co-mutation in isolation has an intermediate prognosis. The clonal acquisition of a codon 12/13 mutation in NRAS seems to result in a more favorable prognosis – lending to the likelihood that the tumor is simply more chemosensitive. In contrast, the acquisition of FLT3-ITD by the NPM1/DNMT3A co-mutant clone results in a very poor prognosis likely due to chemoresistance.
The real power of this study’s findings is the potential for building a toolbox of agents to push against the innate clonal selection and force the “tree” to grow in a direction that is detrimental to its survival. One could consider using FLT3 inhibitors in the wild-type setting of a genetic background primed towards FLT3-ITD evolution to prevent this resistant outgrowth. Of course, such an approach needs to be studied first in a laboratory setting, but similar therapeutic strategies have been applied to BRAF in melanoma. Peter Nowell urged “controlling the evolutionary process in tumors before it reaches the late stage,” and this new ordinal understanding of AML may help to do just that.
vinya@mskcc.org
On Twitter @thedoctorisvin