AML

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

SAN DIEGO — Allogeneic stem cell transplant is associated with a significant survival benefit in patients with NPM1-mutated acute myeloid leukemia (AML) who are in their first complete remission and have measurable residual disease (MRD) after two courses of induction therapy, according to an analysis of UK National Cancer Research Institute study data.

This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.

The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.

Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.

Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.” 

Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.

The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features. 

The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors. 

Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point. 

In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19. 

Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).

However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not. 

In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.

Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).

The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Allogeneic stem cell transplant is associated with a significant survival benefit in patients with NPM1-mutated acute myeloid leukemia (AML) who are in their first complete remission and have measurable residual disease (MRD) after two courses of induction therapy, according to an analysis of UK National Cancer Research Institute study data.

This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.

The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.

Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.

Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.” 

Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.

The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features. 

The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors. 

Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point. 

In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19. 

Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).

However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not. 

In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.

Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).

The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Allogeneic stem cell transplant is associated with a significant survival benefit in patients with NPM1-mutated acute myeloid leukemia (AML) who are in their first complete remission and have measurable residual disease (MRD) after two courses of induction therapy, according to an analysis of UK National Cancer Research Institute study data.

This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.

The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.

Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.

Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.” 

Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.

The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features. 

The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors. 

Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point. 

In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19. 

Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).

However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not. 

In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.

Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).

The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A polygenic score can link outcomes in Black pediatric patients with acute myeloid leukemia (AML) to genetic traits that arise more frequently in this population, new data reveal. 

The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.

In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide. 

The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine. 

The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.

This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH. 

The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday. 

Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity. 

In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML. 

The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine. 

Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.

Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%). 

Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24). 

However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away. 

Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).

“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.

In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.

No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable.. 
 

A version of this article appeared on Medscape.com.

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

New research strengthens the body of evidence demonstrating an increased risk of blood cancer from exposure to low doses of radiation from CT scans. The results suggest that, for every 10,000 children examined with an average low dose of 8 mGy, 1-2 will likely develop a hematologic malignancy related to radiation exposure over the next 12 years.

The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.

This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.

These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.

Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.

The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.

A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.

Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.

The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.

Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.

“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”

The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research strengthens the body of evidence demonstrating an increased risk of blood cancer from exposure to low doses of radiation from CT scans. The results suggest that, for every 10,000 children examined with an average low dose of 8 mGy, 1-2 will likely develop a hematologic malignancy related to radiation exposure over the next 12 years.

The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.

This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.

These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.

Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.

The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.

A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.

Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.

The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.

Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.

“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”

The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research strengthens the body of evidence demonstrating an increased risk of blood cancer from exposure to low doses of radiation from CT scans. The results suggest that, for every 10,000 children examined with an average low dose of 8 mGy, 1-2 will likely develop a hematologic malignancy related to radiation exposure over the next 12 years.

The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.

This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.

These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.

Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.

The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.

A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.

Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.

The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.

Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.

“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”

The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

For patients with acute myeloid leukemia (AML), especially those who are older or have relapsed/refractory disease, standard chemotherapy treatments often fail to change their poor clinical trajectories. These days, however, a new era of targeted therapy is improving prognoses somewhat – and raising hopes that even bigger advancements are on the horizon.

“We went almost 3 decades with nothing, then all of a sudden we’ve had nine approvals in 5 or 6 years,” said Harvard Medical School, Boston, leukemia specialist Amir Fathi, MD, in an interview. “We’ve had a lot of advancement and a number of good options emerge.”

However, Dr. Fathi and other hematologists cautioned that the treatment landscape is becoming more complex to navigate. And they noted that prognoses for many older patients with AML remain grim. The expensive new treatments may only extend their lifespans by a matter of months, although some are surviving for years.

As the specialists explained, there are a variety of reasons why AML is especially difficult to treat.

“AML is one of the fastest growing human cancers, with tumor cell doubling times measured in mere hours in some patients. Therefore patients can present critically ill with white blood cell counts in the [hundreds of thousands of white blood cells per microliter instead of the normal range of 4,000-11,000]," said leukemia specialist Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y. “Because blood cells are found in every organ of the body, the sheer volume of rapidly growing cancer cells can overwhelm multiple organ systems in a very short amount of time. These rapid growing cells and the fact that the median age of diagnosis with AML is 67-70 years old makes this a clinically challenging cancer to treat. Chemotherapy strong enough to kill cancer cells run the risk of also harming the patient as well.”

Also, older patients often have comorbidities, and they face risks of infection from both the disease and its treatments, said AML specialist Nicole R. Grieselhuber, MD, PhD, of the Ohio State University, Columbus, in an interview.

Enter targeted therapy, which “has allowed individuals who previously were not candidates for cytotoxic chemotherapy because of their age or possible toxicities to receive effective therapy for AML,” Dr. Wang said. “Therapy directed at specific biological features of AML cells such as mutations (FLT3, IDH1, IDH2) or surface proteins (CD33) can augment the efficacy of conventional chemotherapy or in some cases (i.e., FLT3 inhibitors) be more effective than chemotherapy in controlling AML.”

Targeted therapy drugs “are expected to more selectively kill cancer cells and spare normal counterparts,” she added.

The FDA has approved nine targeted therapy drugs for AML in the last few years.

Retinoic acid and arsenic trioxide therapy for acute promyelocytic leukemia “has transformed this AML subtype into one of the most curable AML diseases,” Dr. Wang said. A 2017 long-term analysis of the drug combination found that complete remission was reached in 96% of 54 high-risk patients and 133 low-risk patients; the 5-year survival rate was 88%. (Some patients also received gemtuzumab ozogamicin, a CD33 antibody-drug conjugate.)

According to Dr. Wang, three FLT3 inhibitors have been approved for AML with the FLT3 mutation: midostaurin and quizartinib in the frontline setting in conjunction with intensive chemotherapy and gilteritinib for relapsed/refractory FLT3-mutant AML.

A 2017 study linked midostaurin plus chemotherapy to longer survival (hazard ratio for death = 0.78; P = .009), versus placebo plus chemotherapy, in patients aged 18-59. This year, a phase 3 randomized trial of quizartinib versus placebo linked the drug to longer survival median overall (31.9 months versus 15.1 months; P = .032) In a 2019 trial, patients who took gilteritinib had longer median overall survival (9.3 months versus 5.6 months; HR for death = 0.64; P < .001).

The success of these treatments “has led FLT3 mutant AML to be reclassified from a poor risk AML subtype to intermediate risk AML,” Dr. Wang said.

A 2022 report about FLT3 inhibitors cautioned, however, that “several drug resistance mechanisms have been identified” and added that “the benefit of FLT3 inhibitor maintenance therapy, either post chemotherapy or post transplant, remains controversial, although several studies are ongoing.”

Gemtuzumab ozogamicin is a monoclonal antibody connected to a chemotherapy drug, according to the American Cancer Society. “The addition of gemtuzumab ozogamicin to intensive chemotherapy has enhanced outcomes of favorable and intermediate risk disease,” Dr. Wang said.

Ivosidenib, olutasidenib, and enasidenib target the IDH1 or IDH2 genes in ADL. “These drugs seem to work by helping the leukemia cells mature (differentiate) into more normal cells,” according to the American Cancer Society. “Because of this, they are sometimes referred to as differentiation agents.”

In older adults, a combination treatment with venetoclax, a BCL-2 inhibitor, and a hypomethylating agent has become standard, Ohio State’s Dr. Grieselhuber said. The treatment is FDA approved.

There are caveats to targeted therapy in AML. The treatments can be enormously expensive, “and even patients with insurance are often shocked by the copay,” Dr. Grieselhuber said. It helps to work with pharmacists, social workers, or nurse navigators to help patients afford the treatments, she said.

Side effects vary by therapy and can include QT elongation and differentiation syndrome.

Most challenging of all, many AML patients still face shortened lifespans even if new treatments are available for them.

“Typically for older patients with AML, the lifespan of patients with therapy was 5-7 months and without therapy was 2-3 months,” Dr. Wang said. “Now, with regimens specifically designed for elderly and/or unfit subjects, many individuals are now routinely living more than a year: 14-18 months to 3-4 years.”

But “the vast majority of AML patients will still die of their disease with overall 5-year outcomes still less than 30% in all age categories,” she said. In addition, “fewer than 50% of AML patients are eligible for treatment with FDA-approved targeted therapies, as their disease biology does not express the mutation or protein needed for efficacy.”

Still, she said, “this represents a vast improvement.” And, she added, “in younger individuals, the combination of chemotherapy followed by allogeneic transplant has now permitted more of these individuals to be cured of their disease.” Dr. Grieselhuber noted that transplants are now considered appropriate even for patients in their 60s or early 70s, and they can be combined with targeted therapy.

Dr. Grieselhuber urged colleagues to keep in mind that quality-of-life preferences will play a role in some patient choices. For example, a elderly patient may reject burdensome infusion therapy and choose a pill instead, even if it has less efficacy. “There’s really no one-size-fits-all,” she said.

And, she added, it can be difficult to make choices about treatment because of the lack of randomized, head-to-head data regarding new therapies.

What’s on the horizon? Dr. Wang highlighted a novel class of targeted therapies called menin inhibitors for patients with NPM1-mutated AML, which she said accounts for one-third of patients with the disease. A treatment targeting disease in the 5%-10% patients with the KMT2A gene is also in the works, she said.

For now, Dr. Wang said it’s essential for clinicians “to perform timely comprehensive molecular and genomic tests on all AML patients at diagnosis and relapse to determine which individuals would benefit from targeted therapy versus cytotoxic chemotherapy. And participation in clinical trials at every stage of AML therapy can help accelerate clinical development of new agents for this disease.”

Dr. Fathi discloses relationships with Daiichi Sankyo, Pfizer, Rigel, Autolus, Amgen, Servier, Takeda, Orum, Menarini, Remix, AbbVie, Astellas, BMS, Ibsen, Gilead, Genentech, and AstraZeneca. Dr. Wang discloses ties with AbbVie, Astellas, BMS, CTI Biopharma, Daiichi Sankyo, Gilead, GSK, Johnson & Johnson, Kite, Kura, Novartis, Pfizer, Rigel, Sellas, and Sumitomo Pharma. Dr. Grieselhuber has no disclosures.

For patients with acute myeloid leukemia (AML), especially those who are older or have relapsed/refractory disease, standard chemotherapy treatments often fail to change their poor clinical trajectories. These days, however, a new era of targeted therapy is improving prognoses somewhat – and raising hopes that even bigger advancements are on the horizon.

“We went almost 3 decades with nothing, then all of a sudden we’ve had nine approvals in 5 or 6 years,” said Harvard Medical School, Boston, leukemia specialist Amir Fathi, MD, in an interview. “We’ve had a lot of advancement and a number of good options emerge.”

However, Dr. Fathi and other hematologists cautioned that the treatment landscape is becoming more complex to navigate. And they noted that prognoses for many older patients with AML remain grim. The expensive new treatments may only extend their lifespans by a matter of months, although some are surviving for years.

As the specialists explained, there are a variety of reasons why AML is especially difficult to treat.

“AML is one of the fastest growing human cancers, with tumor cell doubling times measured in mere hours in some patients. Therefore patients can present critically ill with white blood cell counts in the [hundreds of thousands of white blood cells per microliter instead of the normal range of 4,000-11,000]," said leukemia specialist Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y. “Because blood cells are found in every organ of the body, the sheer volume of rapidly growing cancer cells can overwhelm multiple organ systems in a very short amount of time. These rapid growing cells and the fact that the median age of diagnosis with AML is 67-70 years old makes this a clinically challenging cancer to treat. Chemotherapy strong enough to kill cancer cells run the risk of also harming the patient as well.”

Also, older patients often have comorbidities, and they face risks of infection from both the disease and its treatments, said AML specialist Nicole R. Grieselhuber, MD, PhD, of the Ohio State University, Columbus, in an interview.

Enter targeted therapy, which “has allowed individuals who previously were not candidates for cytotoxic chemotherapy because of their age or possible toxicities to receive effective therapy for AML,” Dr. Wang said. “Therapy directed at specific biological features of AML cells such as mutations (FLT3, IDH1, IDH2) or surface proteins (CD33) can augment the efficacy of conventional chemotherapy or in some cases (i.e., FLT3 inhibitors) be more effective than chemotherapy in controlling AML.”

Targeted therapy drugs “are expected to more selectively kill cancer cells and spare normal counterparts,” she added.

The FDA has approved nine targeted therapy drugs for AML in the last few years.

Retinoic acid and arsenic trioxide therapy for acute promyelocytic leukemia “has transformed this AML subtype into one of the most curable AML diseases,” Dr. Wang said. A 2017 long-term analysis of the drug combination found that complete remission was reached in 96% of 54 high-risk patients and 133 low-risk patients; the 5-year survival rate was 88%. (Some patients also received gemtuzumab ozogamicin, a CD33 antibody-drug conjugate.)

According to Dr. Wang, three FLT3 inhibitors have been approved for AML with the FLT3 mutation: midostaurin and quizartinib in the frontline setting in conjunction with intensive chemotherapy and gilteritinib for relapsed/refractory FLT3-mutant AML.

A 2017 study linked midostaurin plus chemotherapy to longer survival (hazard ratio for death = 0.78; P = .009), versus placebo plus chemotherapy, in patients aged 18-59. This year, a phase 3 randomized trial of quizartinib versus placebo linked the drug to longer survival median overall (31.9 months versus 15.1 months; P = .032) In a 2019 trial, patients who took gilteritinib had longer median overall survival (9.3 months versus 5.6 months; HR for death = 0.64; P < .001).

The success of these treatments “has led FLT3 mutant AML to be reclassified from a poor risk AML subtype to intermediate risk AML,” Dr. Wang said.

A 2022 report about FLT3 inhibitors cautioned, however, that “several drug resistance mechanisms have been identified” and added that “the benefit of FLT3 inhibitor maintenance therapy, either post chemotherapy or post transplant, remains controversial, although several studies are ongoing.”

Gemtuzumab ozogamicin is a monoclonal antibody connected to a chemotherapy drug, according to the American Cancer Society. “The addition of gemtuzumab ozogamicin to intensive chemotherapy has enhanced outcomes of favorable and intermediate risk disease,” Dr. Wang said.

Ivosidenib, olutasidenib, and enasidenib target the IDH1 or IDH2 genes in ADL. “These drugs seem to work by helping the leukemia cells mature (differentiate) into more normal cells,” according to the American Cancer Society. “Because of this, they are sometimes referred to as differentiation agents.”

In older adults, a combination treatment with venetoclax, a BCL-2 inhibitor, and a hypomethylating agent has become standard, Ohio State’s Dr. Grieselhuber said. The treatment is FDA approved.

There are caveats to targeted therapy in AML. The treatments can be enormously expensive, “and even patients with insurance are often shocked by the copay,” Dr. Grieselhuber said. It helps to work with pharmacists, social workers, or nurse navigators to help patients afford the treatments, she said.

Side effects vary by therapy and can include QT elongation and differentiation syndrome.

Most challenging of all, many AML patients still face shortened lifespans even if new treatments are available for them.

“Typically for older patients with AML, the lifespan of patients with therapy was 5-7 months and without therapy was 2-3 months,” Dr. Wang said. “Now, with regimens specifically designed for elderly and/or unfit subjects, many individuals are now routinely living more than a year: 14-18 months to 3-4 years.”

But “the vast majority of AML patients will still die of their disease with overall 5-year outcomes still less than 30% in all age categories,” she said. In addition, “fewer than 50% of AML patients are eligible for treatment with FDA-approved targeted therapies, as their disease biology does not express the mutation or protein needed for efficacy.”

Still, she said, “this represents a vast improvement.” And, she added, “in younger individuals, the combination of chemotherapy followed by allogeneic transplant has now permitted more of these individuals to be cured of their disease.” Dr. Grieselhuber noted that transplants are now considered appropriate even for patients in their 60s or early 70s, and they can be combined with targeted therapy.

Dr. Grieselhuber urged colleagues to keep in mind that quality-of-life preferences will play a role in some patient choices. For example, a elderly patient may reject burdensome infusion therapy and choose a pill instead, even if it has less efficacy. “There’s really no one-size-fits-all,” she said.

And, she added, it can be difficult to make choices about treatment because of the lack of randomized, head-to-head data regarding new therapies.

What’s on the horizon? Dr. Wang highlighted a novel class of targeted therapies called menin inhibitors for patients with NPM1-mutated AML, which she said accounts for one-third of patients with the disease. A treatment targeting disease in the 5%-10% patients with the KMT2A gene is also in the works, she said.

For now, Dr. Wang said it’s essential for clinicians “to perform timely comprehensive molecular and genomic tests on all AML patients at diagnosis and relapse to determine which individuals would benefit from targeted therapy versus cytotoxic chemotherapy. And participation in clinical trials at every stage of AML therapy can help accelerate clinical development of new agents for this disease.”

Dr. Fathi discloses relationships with Daiichi Sankyo, Pfizer, Rigel, Autolus, Amgen, Servier, Takeda, Orum, Menarini, Remix, AbbVie, Astellas, BMS, Ibsen, Gilead, Genentech, and AstraZeneca. Dr. Wang discloses ties with AbbVie, Astellas, BMS, CTI Biopharma, Daiichi Sankyo, Gilead, GSK, Johnson & Johnson, Kite, Kura, Novartis, Pfizer, Rigel, Sellas, and Sumitomo Pharma. Dr. Grieselhuber has no disclosures.

For patients with acute myeloid leukemia (AML), especially those who are older or have relapsed/refractory disease, standard chemotherapy treatments often fail to change their poor clinical trajectories. These days, however, a new era of targeted therapy is improving prognoses somewhat – and raising hopes that even bigger advancements are on the horizon.

“We went almost 3 decades with nothing, then all of a sudden we’ve had nine approvals in 5 or 6 years,” said Harvard Medical School, Boston, leukemia specialist Amir Fathi, MD, in an interview. “We’ve had a lot of advancement and a number of good options emerge.”

However, Dr. Fathi and other hematologists cautioned that the treatment landscape is becoming more complex to navigate. And they noted that prognoses for many older patients with AML remain grim. The expensive new treatments may only extend their lifespans by a matter of months, although some are surviving for years.

As the specialists explained, there are a variety of reasons why AML is especially difficult to treat.

“AML is one of the fastest growing human cancers, with tumor cell doubling times measured in mere hours in some patients. Therefore patients can present critically ill with white blood cell counts in the [hundreds of thousands of white blood cells per microliter instead of the normal range of 4,000-11,000]," said leukemia specialist Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y. “Because blood cells are found in every organ of the body, the sheer volume of rapidly growing cancer cells can overwhelm multiple organ systems in a very short amount of time. These rapid growing cells and the fact that the median age of diagnosis with AML is 67-70 years old makes this a clinically challenging cancer to treat. Chemotherapy strong enough to kill cancer cells run the risk of also harming the patient as well.”

Also, older patients often have comorbidities, and they face risks of infection from both the disease and its treatments, said AML specialist Nicole R. Grieselhuber, MD, PhD, of the Ohio State University, Columbus, in an interview.

Enter targeted therapy, which “has allowed individuals who previously were not candidates for cytotoxic chemotherapy because of their age or possible toxicities to receive effective therapy for AML,” Dr. Wang said. “Therapy directed at specific biological features of AML cells such as mutations (FLT3, IDH1, IDH2) or surface proteins (CD33) can augment the efficacy of conventional chemotherapy or in some cases (i.e., FLT3 inhibitors) be more effective than chemotherapy in controlling AML.”

Targeted therapy drugs “are expected to more selectively kill cancer cells and spare normal counterparts,” she added.

The FDA has approved nine targeted therapy drugs for AML in the last few years.

Retinoic acid and arsenic trioxide therapy for acute promyelocytic leukemia “has transformed this AML subtype into one of the most curable AML diseases,” Dr. Wang said. A 2017 long-term analysis of the drug combination found that complete remission was reached in 96% of 54 high-risk patients and 133 low-risk patients; the 5-year survival rate was 88%. (Some patients also received gemtuzumab ozogamicin, a CD33 antibody-drug conjugate.)

According to Dr. Wang, three FLT3 inhibitors have been approved for AML with the FLT3 mutation: midostaurin and quizartinib in the frontline setting in conjunction with intensive chemotherapy and gilteritinib for relapsed/refractory FLT3-mutant AML.

A 2017 study linked midostaurin plus chemotherapy to longer survival (hazard ratio for death = 0.78; P = .009), versus placebo plus chemotherapy, in patients aged 18-59. This year, a phase 3 randomized trial of quizartinib versus placebo linked the drug to longer survival median overall (31.9 months versus 15.1 months; P = .032) In a 2019 trial, patients who took gilteritinib had longer median overall survival (9.3 months versus 5.6 months; HR for death = 0.64; P < .001).

The success of these treatments “has led FLT3 mutant AML to be reclassified from a poor risk AML subtype to intermediate risk AML,” Dr. Wang said.

A 2022 report about FLT3 inhibitors cautioned, however, that “several drug resistance mechanisms have been identified” and added that “the benefit of FLT3 inhibitor maintenance therapy, either post chemotherapy or post transplant, remains controversial, although several studies are ongoing.”

Gemtuzumab ozogamicin is a monoclonal antibody connected to a chemotherapy drug, according to the American Cancer Society. “The addition of gemtuzumab ozogamicin to intensive chemotherapy has enhanced outcomes of favorable and intermediate risk disease,” Dr. Wang said.

Ivosidenib, olutasidenib, and enasidenib target the IDH1 or IDH2 genes in ADL. “These drugs seem to work by helping the leukemia cells mature (differentiate) into more normal cells,” according to the American Cancer Society. “Because of this, they are sometimes referred to as differentiation agents.”

In older adults, a combination treatment with venetoclax, a BCL-2 inhibitor, and a hypomethylating agent has become standard, Ohio State’s Dr. Grieselhuber said. The treatment is FDA approved.

There are caveats to targeted therapy in AML. The treatments can be enormously expensive, “and even patients with insurance are often shocked by the copay,” Dr. Grieselhuber said. It helps to work with pharmacists, social workers, or nurse navigators to help patients afford the treatments, she said.

Side effects vary by therapy and can include QT elongation and differentiation syndrome.

Most challenging of all, many AML patients still face shortened lifespans even if new treatments are available for them.

“Typically for older patients with AML, the lifespan of patients with therapy was 5-7 months and without therapy was 2-3 months,” Dr. Wang said. “Now, with regimens specifically designed for elderly and/or unfit subjects, many individuals are now routinely living more than a year: 14-18 months to 3-4 years.”

But “the vast majority of AML patients will still die of their disease with overall 5-year outcomes still less than 30% in all age categories,” she said. In addition, “fewer than 50% of AML patients are eligible for treatment with FDA-approved targeted therapies, as their disease biology does not express the mutation or protein needed for efficacy.”

Still, she said, “this represents a vast improvement.” And, she added, “in younger individuals, the combination of chemotherapy followed by allogeneic transplant has now permitted more of these individuals to be cured of their disease.” Dr. Grieselhuber noted that transplants are now considered appropriate even for patients in their 60s or early 70s, and they can be combined with targeted therapy.

Dr. Grieselhuber urged colleagues to keep in mind that quality-of-life preferences will play a role in some patient choices. For example, a elderly patient may reject burdensome infusion therapy and choose a pill instead, even if it has less efficacy. “There’s really no one-size-fits-all,” she said.

And, she added, it can be difficult to make choices about treatment because of the lack of randomized, head-to-head data regarding new therapies.

What’s on the horizon? Dr. Wang highlighted a novel class of targeted therapies called menin inhibitors for patients with NPM1-mutated AML, which she said accounts for one-third of patients with the disease. A treatment targeting disease in the 5%-10% patients with the KMT2A gene is also in the works, she said.

For now, Dr. Wang said it’s essential for clinicians “to perform timely comprehensive molecular and genomic tests on all AML patients at diagnosis and relapse to determine which individuals would benefit from targeted therapy versus cytotoxic chemotherapy. And participation in clinical trials at every stage of AML therapy can help accelerate clinical development of new agents for this disease.”

Dr. Fathi discloses relationships with Daiichi Sankyo, Pfizer, Rigel, Autolus, Amgen, Servier, Takeda, Orum, Menarini, Remix, AbbVie, Astellas, BMS, Ibsen, Gilead, Genentech, and AstraZeneca. Dr. Wang discloses ties with AbbVie, Astellas, BMS, CTI Biopharma, Daiichi Sankyo, Gilead, GSK, Johnson & Johnson, Kite, Kura, Novartis, Pfizer, Rigel, Sellas, and Sumitomo Pharma. Dr. Grieselhuber has no disclosures.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

Should patients with acute myeloid leukemia (AML) for whom induction therapy fails to induce complete remission proceed to allogeneic hematopoietic stem cell transplant anyway? Or do these patients fare better when they receive an intensive salvage induction regimen to bring them into remission before transplant?

This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.

Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.

“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”

According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.

If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.

The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.

In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.

Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.

At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.

Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.

The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.

These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.

A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.

Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
 

Counterpoint: Aim for complete remission

Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.

The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.

“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.

Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.

A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.

Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.

Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.

It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.

One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.

However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.

“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.

The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Should patients with acute myeloid leukemia (AML) for whom induction therapy fails to induce complete remission proceed to allogeneic hematopoietic stem cell transplant anyway? Or do these patients fare better when they receive an intensive salvage induction regimen to bring them into remission before transplant?

This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.

Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.

“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”

According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.

If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.

The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.

In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.

Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.

At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.

Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.

The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.

These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.

A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.

Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
 

Counterpoint: Aim for complete remission

Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.

The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.

“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.

Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.

A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.

Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.

Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.

It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.

One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.

However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.

“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.

The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Should patients with acute myeloid leukemia (AML) for whom induction therapy fails to induce complete remission proceed to allogeneic hematopoietic stem cell transplant anyway? Or do these patients fare better when they receive an intensive salvage induction regimen to bring them into remission before transplant?

This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.

Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.

“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”

According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.

If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.

The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.

In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.

Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.

At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.

Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.

The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.

These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.

A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.

Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
 

Counterpoint: Aim for complete remission

Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.

The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.

“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.

Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.

A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.

Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.

Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.

It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.

One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.

However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.

“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.

The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.

A version of this article appeared on Medscape.com.