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Risk-directed Approaches to AML Therapy

Panelists: Elias Jabbour, MD, MD Anderson Cancer Center; Martin S. Tallman, MD, Memorial Sloan Kettering Cancer Center; Richard M. Stone, MD, Dana-Farber Cancer Institute; Harry Erba, MD, PhD, University of Alabama; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published Online: Tuesday, Jan 10, 2017



Transcript:

Elias Jabbour, MD:
Hello, and thank you for joining this OncLive Peer Exchange® titled “Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia.” Use of next-generation sequencing technology has generated a plethora of novel insights into the genetics of AML, providing important information about dysregulated signaling involved in leukemic transformation and leading to new therapeutic targets. After a dearth of new therapies available for acute myeloid leukemia (AML) over the last few decades, we are transitioning into a new era, with several promising strategies in late-stage development. This expert panel discussion will focus on the latest advances in treatment for patients with AML and will provide practical information on how to use the newest therapies.

I am Elias Jabbour. I’m an associate professor in the Leukemia Department at MD Anderson Cancer Center in Houston, Texas. Participating today on our distinguished panel are Dr. Harry Erba, professor of internal medicine and director of the Hematologic Malignancy Program at the University of Alabama in Birmingham, Alabama; Dr. Mark Levis, program leader of Hematologic Malignancies and Bone Marrow Transplant at the Sidney Kimmel Comprehensive Cancer Center and a professor of oncology at Johns Hopkins University in Baltimore, Maryland; Dr. Richard Stone, professor of medicine at the Harvard Medical School, associate physician of medicine at Brigham and Women’s Hospital, and chief of staff and director of the Adult Leukemia Program at the Dana-Farber Cancer Institute in Boston, Massachusetts; and Dr. Martin Tallman, chief of leukemia service in the Department of Medicine at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College in New York, New York. Thank you so much for joining us. Let’s start.

So, today we’ll have 2 segments essentially, starting with the state-of-the-art in management of AML, and then we move to the second part, where we’re discussing the new clinical trials, the new drugs that are promising and hopefully will be approved in AML. I want to start with Dr. Tallman. Today, somebody comes to our clinic with AML, let’s say a young adult. AML, what are the diagnostic procedures that can decide therapy, and what is the standard of care for these patients?

Martin S. Tallman, MD: I think in my younger patients, there has been a significant change, including among older patients, in terms of trying to identify prognostic factors that can predict how a patient will do with intensive chemotherapy or less intensive therapy. For younger patients, most of them can be treated with intensive chemotherapy, and we try to risk-stratify those patients. We always obtain cytogenetics and molecular genetics; immunophenotyping is standard therapy. But for patients who are under age 55 to 60, most of whom can tolerate intensive chemotherapy, a standard-of-care today would be—if a patient’s not participating on a clinical trial—to receive intensive induction chemotherapy with an anthracycline, either daunorubicin or idarubicin for 3 days, and 7 days of continuous-infusion cytarabine (Ara-C).

There have been several recent studies that have suggested that among younger patients—in fact, patients up to age 65—higher-than-formally used doses of daunorubicin may be beneficial. So, up to age 65, I think it has become standard-of-care to administer 90 mg of daunorubicin per day for 3 days and continuous-infusion cytarabine.

Elias Jabbour, MD: There was a study last year about a lower dose of anthracyclines to, instead of the 90 mg, go back to 60 mg or 12 mg/m2 of idarubicin. Do you have any thought on that?

Martin S. Tallman, MD: I think that it’s clear everyone should receive at least 60 mg. I think 45 mg, which is actually the original approved dose, is probably inadequate. I think there hasn’t been adequate proof that 90 mg is definitely greater than 60 mg, but it certainly is safe and tolerable. So, up to age 65, I think there’s sufficient data to justify a 90-mg dose.

Elias Jabbour, MD: And how about high-dose Ara-C induction?

Martin S. Tallman, MD: High dose Ara-C induction has been studied. There has been no clear benefit. And I think as long as patients get high-dose cytarabine and consolidation, there’s no clear role for routine use of high-dose cytarabine during induction.

Elias Jabbour, MD: So, what is the minimum to be done before starting therapy? Today, in our practice, there are a lot of labs. They can sell you tons of gene testing. For a physician in a community, what do they need to do—the minimum—in order to decide on therapy, whether you go for transplant or chemotherapy or clinical trials?

Martin S. Tallman, MD: Well, I think immunophenotyping should be done on all patients. I think cytogenetics should be done. I think molecular genetics should be done. And of the molecular genetics, there are all kinds of panels now that one can send: 30-gene panels, 400-gene panels. But I think in terms of what is actionable or targetable, there are several. And I think all patients, of course, just had the FLT3 mutation, ITD, and TKD done. They should have IDH done. I think they should have a CEBP-alpha done, and they should have the c-Kit done. I think those are the major ones. And PM1 should be done, of course.

Elias Jabbour, MD: That’s great. I want to go to Richard. Most of our patients, they are 60 years or older. AML does increase with age. Unfortunately, for these patients, they have comorbidities. How do you define “unfit” patients and what are “elderly”’ people? You can have somebody who is 65 who is fit; you can have somebody who’s 55 already, with a performance status of 4. So, how do you define “unfit” and what do you suggest for them?

Richard M. Stone, MD: Well, that’s a really great question and one that’s been asked for the last umpteen years about AML. The median age of AML is 68 or 70, so you’re absolutely right that most of our patients are older. And we try to get away from the word “elderly.” It’s a bit pejorative, so we like to use “older,” especially as some of the panelists are getting to that age group right now. Anyway, the definition of “unfit” is really a huge bugaboo, and I try to get away from it. I try to think about, as Marty was saying, 2 major factors: fitness, biologically; first, comorbidities of the patient and then the likelihood of response to chemotherapy based on disease-related factors.

So, when I do see a patient who’s over age 65, I say, “Are they fit? Could they withstand the chemotherapy within a reasonable likelihood? Are they going to have a huge mortality rate?” And to make a long story short, for performance status, if they are 3 or worse, they’re going to do miserably with chemotherapy. As far as the disease biology, I’m sure we’ll talk a lot more about that. But for p53 mutations, complex cytogenetics, those people aren’t going to do well with 3+7. And so, I’d be more apt to treat even perhaps a fit patient with a less intensive therapy, although there’s a lot of discussion about whether that’s really a good idea or not.

Elias Jabbour, MD: So, what is less intensive chemotherapy today?

Richard M. Stone, MD: Today, the less intensive chemotherapy in the United States, even though it’s not approved, is a hypomethylating agent, either cytidine or decitabine. In other countries, low-dose Ara-C is still used a lot, especially if that country does not have an approval for a hypomethylator available.

Elias Jabbour, MD: Before we move to the new therapies because, obviously, as you mentioned, it’s needed for these patients, how do you assess efficacy? Complete remission or improvement of the count or living longer? And you know, I want to ask you first for the elderly patient and then I want to go back to Dr. Tallman to talk about those who are young, who are fit.

Richard M. Stone, MD: Well, for the older patient, if they’re getting intensive therapy—and many will do so—we still use standard histologic complete remission criteria. We probably should think about moving to a more nuanced definition of remission; that is, by using molecular or immunophenotypic studies to assess for minimal residual disease. For an older adult to whom I’m giving nonintensive chemotherapy, I tend to view, for good or ill, my treatment strategy as being the same as it is for mild dysplasia: keep giving the drugs until progression or severe toxicity.

Transcript Edited for Clarity

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Transcript:

Elias Jabbour, MD:
Hello, and thank you for joining this OncLive Peer Exchange® titled “Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia.” Use of next-generation sequencing technology has generated a plethora of novel insights into the genetics of AML, providing important information about dysregulated signaling involved in leukemic transformation and leading to new therapeutic targets. After a dearth of new therapies available for acute myeloid leukemia (AML) over the last few decades, we are transitioning into a new era, with several promising strategies in late-stage development. This expert panel discussion will focus on the latest advances in treatment for patients with AML and will provide practical information on how to use the newest therapies.

I am Elias Jabbour. I’m an associate professor in the Leukemia Department at MD Anderson Cancer Center in Houston, Texas. Participating today on our distinguished panel are Dr. Harry Erba, professor of internal medicine and director of the Hematologic Malignancy Program at the University of Alabama in Birmingham, Alabama; Dr. Mark Levis, program leader of Hematologic Malignancies and Bone Marrow Transplant at the Sidney Kimmel Comprehensive Cancer Center and a professor of oncology at Johns Hopkins University in Baltimore, Maryland; Dr. Richard Stone, professor of medicine at the Harvard Medical School, associate physician of medicine at Brigham and Women’s Hospital, and chief of staff and director of the Adult Leukemia Program at the Dana-Farber Cancer Institute in Boston, Massachusetts; and Dr. Martin Tallman, chief of leukemia service in the Department of Medicine at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College in New York, New York. Thank you so much for joining us. Let’s start.

So, today we’ll have 2 segments essentially, starting with the state-of-the-art in management of AML, and then we move to the second part, where we’re discussing the new clinical trials, the new drugs that are promising and hopefully will be approved in AML. I want to start with Dr. Tallman. Today, somebody comes to our clinic with AML, let’s say a young adult. AML, what are the diagnostic procedures that can decide therapy, and what is the standard of care for these patients?

Martin S. Tallman, MD: I think in my younger patients, there has been a significant change, including among older patients, in terms of trying to identify prognostic factors that can predict how a patient will do with intensive chemotherapy or less intensive therapy. For younger patients, most of them can be treated with intensive chemotherapy, and we try to risk-stratify those patients. We always obtain cytogenetics and molecular genetics; immunophenotyping is standard therapy. But for patients who are under age 55 to 60, most of whom can tolerate intensive chemotherapy, a standard-of-care today would be—if a patient’s not participating on a clinical trial—to receive intensive induction chemotherapy with an anthracycline, either daunorubicin or idarubicin for 3 days, and 7 days of continuous-infusion cytarabine (Ara-C).

There have been several recent studies that have suggested that among younger patients—in fact, patients up to age 65—higher-than-formally used doses of daunorubicin may be beneficial. So, up to age 65, I think it has become standard-of-care to administer 90 mg of daunorubicin per day for 3 days and continuous-infusion cytarabine.

Elias Jabbour, MD: There was a study last year about a lower dose of anthracyclines to, instead of the 90 mg, go back to 60 mg or 12 mg/m2 of idarubicin. Do you have any thought on that?

Martin S. Tallman, MD: I think that it’s clear everyone should receive at least 60 mg. I think 45 mg, which is actually the original approved dose, is probably inadequate. I think there hasn’t been adequate proof that 90 mg is definitely greater than 60 mg, but it certainly is safe and tolerable. So, up to age 65, I think there’s sufficient data to justify a 90-mg dose.

Elias Jabbour, MD: And how about high-dose Ara-C induction?

Martin S. Tallman, MD: High dose Ara-C induction has been studied. There has been no clear benefit. And I think as long as patients get high-dose cytarabine and consolidation, there’s no clear role for routine use of high-dose cytarabine during induction.

Elias Jabbour, MD: So, what is the minimum to be done before starting therapy? Today, in our practice, there are a lot of labs. They can sell you tons of gene testing. For a physician in a community, what do they need to do—the minimum—in order to decide on therapy, whether you go for transplant or chemotherapy or clinical trials?

Martin S. Tallman, MD: Well, I think immunophenotyping should be done on all patients. I think cytogenetics should be done. I think molecular genetics should be done. And of the molecular genetics, there are all kinds of panels now that one can send: 30-gene panels, 400-gene panels. But I think in terms of what is actionable or targetable, there are several. And I think all patients, of course, just had the FLT3 mutation, ITD, and TKD done. They should have IDH done. I think they should have a CEBP-alpha done, and they should have the c-Kit done. I think those are the major ones. And PM1 should be done, of course.

Elias Jabbour, MD: That’s great. I want to go to Richard. Most of our patients, they are 60 years or older. AML does increase with age. Unfortunately, for these patients, they have comorbidities. How do you define “unfit” patients and what are “elderly”’ people? You can have somebody who is 65 who is fit; you can have somebody who’s 55 already, with a performance status of 4. So, how do you define “unfit” and what do you suggest for them?

Richard M. Stone, MD: Well, that’s a really great question and one that’s been asked for the last umpteen years about AML. The median age of AML is 68 or 70, so you’re absolutely right that most of our patients are older. And we try to get away from the word “elderly.” It’s a bit pejorative, so we like to use “older,” especially as some of the panelists are getting to that age group right now. Anyway, the definition of “unfit” is really a huge bugaboo, and I try to get away from it. I try to think about, as Marty was saying, 2 major factors: fitness, biologically; first, comorbidities of the patient and then the likelihood of response to chemotherapy based on disease-related factors.

So, when I do see a patient who’s over age 65, I say, “Are they fit? Could they withstand the chemotherapy within a reasonable likelihood? Are they going to have a huge mortality rate?” And to make a long story short, for performance status, if they are 3 or worse, they’re going to do miserably with chemotherapy. As far as the disease biology, I’m sure we’ll talk a lot more about that. But for p53 mutations, complex cytogenetics, those people aren’t going to do well with 3+7. And so, I’d be more apt to treat even perhaps a fit patient with a less intensive therapy, although there’s a lot of discussion about whether that’s really a good idea or not.

Elias Jabbour, MD: So, what is less intensive chemotherapy today?

Richard M. Stone, MD: Today, the less intensive chemotherapy in the United States, even though it’s not approved, is a hypomethylating agent, either cytidine or decitabine. In other countries, low-dose Ara-C is still used a lot, especially if that country does not have an approval for a hypomethylator available.

Elias Jabbour, MD: Before we move to the new therapies because, obviously, as you mentioned, it’s needed for these patients, how do you assess efficacy? Complete remission or improvement of the count or living longer? And you know, I want to ask you first for the elderly patient and then I want to go back to Dr. Tallman to talk about those who are young, who are fit.

Richard M. Stone, MD: Well, for the older patient, if they’re getting intensive therapy—and many will do so—we still use standard histologic complete remission criteria. We probably should think about moving to a more nuanced definition of remission; that is, by using molecular or immunophenotypic studies to assess for minimal residual disease. For an older adult to whom I’m giving nonintensive chemotherapy, I tend to view, for good or ill, my treatment strategy as being the same as it is for mild dysplasia: keep giving the drugs until progression or severe toxicity.

Transcript Edited for Clarity
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