Cover Story

Targeted treatments for acute myeloid leukemia yield modest improvements, great hope

Acute myeloid leukemia historically has been one of the more deadly and difficult-to-treat cancers, with a 5-year survival rate below 30%.

Moreover, a one-size-fits-all treatment approach is not applicable to this complex and heterogenous disease, particularly in older adults. These patients — who comprise the majority of the AML population — often present with difficult, chemotherapy resistant or intolerant disease.

“In the past, we treated everyone with the same therapy and found that older people did not tolerate the intensive chemotherapy as well,” Tapan M. Kadia, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “Additionally, the type of AML that is seen in older patients is different than a 20- or 30-year-old with newly diagnosed AML. On the surface, you would call both these patients newly diagnosed AML, but they are very different from each other.”

Tapan M. Kadia, MD
Tapan M. Kadia

However, a greater understanding of the genetic heterogeneity of AML has led to numerous FDA approvals of targeted therapies, which some believe are poised to change the landscape of AML treatment and its prognosis.

“We are entering into a promising new era in the management of AML, brought about by a convergence of molecular discoveries, leukemia stem cell theory and strategies to harness the immune system,” Jonathan M. Gerber, MD, chief of hematology/oncology and medical director of the Cancer Center at UMass Medical School and UMass Memorial Health Care, as well as a HemOnc Today Editorial Board Member, said in an interview. “However, this is just the beginning; and there is much work yet to be done, in order to deliver treatments for AML that are more effective and less toxic.”

HemOnc Today spoke with hematologic oncologists about discoveries related to the biology of AML that have led to new treatments, how new agents fit into the treatment armamentarium, and what research questions and challenging patient populations will be the focus of investigations moving forward.

Beyond ‘7 + 3’

Over the past several decades, the mainstay of AML treatment has been the “7 + 3” induction chemotherapy regimen.

This treatment — still commonly used in younger patients — consists of 7 days of cytarabine, followed by 3 days of either daunorubicin or idarubicin.

“This was what had been used for about 40 to 45 years before the advent of the new drugs,” Naval Daver, MD, associate professor in the leukemia department at MD Anderson Cancer Center, told HemOnc Today. “The prognosis was really divided based on the age of the patient.”

Naval Daver, MD
Naval Daver

Since 1960, the prognosis of patients aged younger than 65 years has steadily improved, primarily due to improved prognostication tools and appropriate use of hematopoietic stem cell transplantation.

Additionally, improvements in supportive medications — such as antifungals, antivirals and antibacterials — and better transplant-related management have contributed to improved outcomes.

“The overall cure rate for younger AML patients has gone from about 15% to about 45% to 50% in the last 4 decades,” Daver said. “There has been progress there, but we’re still at best at about 50% with standard 7 + 3 and stem cell transplant use.”

However, this progress hasn’t been mirrored in the population of patients aged older than 65 years, for whom survival rates remain in the 5% to 10% range.

The goal of avoiding the morbidity and mortality of intensive chemotherapy in older patients prompted clinicians to begin seeking less-aggressive chemotherapy regimens.

“In older patients, the standard of care recently has been hypomethylating agents, such as azacitidine [Vidaza, Celgene] and decitabine,” Kadia said. “These drugs — initially approved for myelodysplastic syndrome but later approved for AML — were well-tolerated in most patients, but the outcomes were not great.”

Now, the landscape is driven by greater insight into the various biological mechanisms of AML, which have been key to targeting the heterogenous factors characteristic of this disease.

Amir T. Fathi, MD
Amir T. Fathi

“It’s been a slow and gradual process, but over the course of the past decade, there has been a series of significant advances in elucidating the molecular underpinnings of AML and the common alterations that seem to trigger the disease or allow it to persist,” Amir T. Fathi, MD, director of the leukemia program at Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, told HemOnc Today. “Among these are FLT3 mutations — which impact about one-third of AML patients — and IDH1 and IDH2 mutations, which impact about 20% of patients.”

These mutations can be targeted with small molecules that inhibit the altered enzymes generated by the mutations, Fathi said, and inhibitors of altered FLT3 and IDH proteins have been successfully developed in preclinical and clinical studies and are increasingly available and efficacious for patients with AML.

“These drugs appear to have a therapeutic impact to the point that a sizable subset of patients treated with FLT3 and IDH1/IDH2 inhibitors seems to have a clinically meaningful response to treatment,” he said. “Due to their demonstrated tolerability, efficacy and success in clinical trials, some of these agents have achieved FDA approval.”

Among the targeted drugs approved by the FDA are midostaurin (Rydapt, Novartis) for newly diagnosed patients with a FLT3 mutation; enasidenib (Idhifa, Celgene), an IDH2 inhibitor for relapsed/refractory AML; gemtuzumab ozogamicin (Mylotarg, Pfizer) for newly diagnosed adults with CD33-positive disease; gilteritinib (Xospata, Astellas) for relapsed/refractory patients with a FLT3 mutation; and the IDH1 inhibitor ivosidenib (Tibsovo, Agios Pharmaceuticals).

The armamentarium also has been expanded to include Vyxeos (Jazz Pharmaceuticals), a liposome injection of daunorubicin and cytarabine for adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes; venetoclax (Venclexta; AbbVie, Genentech) for adults aged 75 years or older with chemotherapy-precluding comorbidities; and glasdegib (Daurismo, Pfizer) for newly diagnosed adults for whom intensive chemotherapy is not an option.

Targeting subcategories of AML based on certain mutations is a part of precision medicine, according to Pamela S. Becker, MD, PhD.
Targeting subcategories of AML based on certain mutations is a part of precision medicine, according to Pamela S. Becker, MD, PhD. “We’re trying to target therapeutic vulnerability in these particular patients, rather than giving the same 7 + 3 to everybody, which is what we did for 40 years,” she said.

Source: Seattle Cancer Care Alliance.

“This whole approach — which involves targeting subcategories of AML based on certain mutations — is considered part of precision medicine,” Pamela S. Becker, MD, PhD, professor of medicine in the division of hematology at University of Washington School of Medicine and attending physician at Seattle Cancer Care Alliance, said in an interview with HemOnc Today. “We’re trying to target therapeutic vulnerability in these particular patients, rather than giving the same 7 + 3 to everybody, which is what we did for 40 years.”

Cytogenetics and other next-generation genetic tests have enabled researchers to identify these mutations.

“Over the past 5 to 7 years, there’s been a revolution in the availability and ability to sequence genes at a very, very deep level through next-generation DNA sequencing,” Kadia said. “With that technology, many groups have uncovered mutations we didn’t know were there before, but were always there, driving the disease. We can detect them now.”

Despite the early promise of these targeted therapies, it’s important to remember that their long-term efficacy is not yet known, Becker said.

“It’s too early for us to know,” she said. “If we look at the current SEER data, it says that the percent surviving 5 years from 2008 to 2014 is 27.4%. We’ll have to see if that number changes when we look at 2015 to 2020 data. Then we’ll be able to acknowledge that these drug approvals did improve survival.”

Role of HSCT, chemotherapy

Following these approvals, clinicians seek to determine where the agents fit in the treatment armamentarium.

Targeted treatments may improve the outcomes of allogeneic HSCT, which can be curative for appropriate patients who achieve remission. Selecting which patients are eligible for allogeneic HSCT also is a challenge.

“Allogeneic HSCT was the pioneer of immunotherapy, and it is still our most powerful and reliable treatment. It is also our most toxic therapy, with high treatment-related morbidity and mortality,” Gerber said. “Despite these risks, HSCT is still unable to cure far too many patients with AML. Armed with an improved understanding of the disease of the disease at the molecular and stem cell levels, better ways to target leukemic cells and harness the power of the immune system seem finally within reach.”

The targeted therapies are valuable to HSCT in two ways: by improving remission and maximizing patient eligibility for transplantation.

“By incorporating effective targeted therapies into our treatment programs, we’re able to reduce the intensity of the chemotherapy in some cases. The patient remains in decent shape at the end of chemotherapy and is a better candidate for transplant,” Kadia said. “It allows more people to get to transplant and potentially achieve better outcomes.”

Although transplantation is often the goal of chemotherapy, clinicians must weigh the benefits vs. risks for each individual patient, according to Eytan M. Stein, MD, hematologic oncologist at Memorial Sloan Kettering Cancer Center. For example, treatment for a relatively strong patient with intermediate- or unfavorable-risk disease would be very different than for an 85-year-old patient.

“The goal is always to keep the disease away as long as possible, but maybe in this case the goal would be to keep the disease away with the least amount of toxicity,” he said. “You might be willing to have a few months of toxicity in a patient who potentially has a whole life expectancy ahead of them. For someone whose life expectancy isn’t long due to their age, the goals might be different.”

Eytan M. Stein, MD
Eytan M. Stein

Although newer agents or novel therapeutic combinations may be suitable for older, frailer patients, chemotherapy will remain the frontline treatment modality for patients able to tolerate it, Fathi said.

“With the approval of hypomethylating therapy plus the BCL2 inhibitor venetoclax, I believe we’re going to see that combination used more in older patients, or in those ineligible for induction chemotherapy,” he said. “But, in newly diagnosed patients who are candidates for induction chemotherapy, some form of intensive treatment in the upfront setting is still being used to achieve remission.”

Finding the targets

To use these therapies, clinicians first need to identify which targets exist in their patients in real time.

Findings of the Beat AML Master Trial — presented by Burd and colleagues at ASH Annual Meeting and Exposition in December — showed clinicians could not only match patients with molecularly driven treatments for AML, but that they could do so within a week.

The analysis included 285 newly diagnosed patients aged older than 60 years (median age, 72 years; 58.6% men) seen at 12 clinical sites. The patients underwent genetic screening at baseline and were matched with an appropriate treatment based on molecular subtype.

Overall, 273 patients began treatment within 7 days.

At the time of the presentation, 146 patients had been treated with the targeted agents, whereas 139 (48.8%) did not receive targeted treatment. Of those not treated, most opted for standard of care (20%) or other treatments.

“Firstly, this shows that it’s feasible to do this in a reasonable timeframe for an acute disease,” Kadia said. “Secondly, it shows how after dividing patients based on their molecular subtypes and characteristics, researchers found certain therapies that may be more effective in those subgroups.”

Some drugs evaluated in the trial were investigational, such as SYK inhibitors, or agents called neddylation inhibitors. Still, the significance of the study lies in the investigators’ success in profiling the patients ahead of time and then trying different therapies based on the best biological rationale, Kadia said.

“It was an early, preliminary presentation, but there is more to come,” he said.

However, academic medical centers are already using targeted therapies in a real-world setting, and clinicians are finding themselves overwhelmed by the abundance of agents to choose from.

“That’s becoming a challenge,” Daver said. “I get six or seven emails a day from physicians in the U.S. and around the world trying to figure out the right sequence or combination.”

Daver said he and his colleagues at MD Anderson have developed their own algorithm for choosing treatment, which begins with immediate genetic testing.

“We rush the cytogenetics, as well as the molecular mutation panels,” he said. “We don’t jump into treatment right away, because we know it may be significantly different based on what targets we find, and this may have a major impact on response and survival.”

The first target the algorithm looks for is translocation 15;17, which is indicative of acute promyelocytic leukemia (APL), a subtype of AML. If the patient this translocation on chromosome analysis, Daver diagnoses APL and treats it with a combination of all-trans retinoic acid plus arsenic trioxide.

“This is the only chemotherapy-free treatment available in AML, and it gives us amazing cure rates of 95% or higher,” he said. “APL probably has the best success rate that we’ve had in all of acute leukemia.”

In the absence of translocation 15;17, Daver and colleagues look for two other chromosome changes — inversion 16 and translocation 8;21 — which indicate core-binding factor leukemias. Although the prognoses for these leukemias are not as good as that of APL, they still are favorable, Daver said.

“If we find them, we recommend the addition of the antibody-drug conjugate gemtuzumab ozogamicin, which targets CD33 on the surface of the leukemia cell,” he said. “Gemtuzumab has been shown to improve the long-term cure rate by about 20% to 25% when added to 7 + 3 or FLAG-IDA [fludarabine, cytarabine, filgrastim and idarubicin], specifically in patients who have these core-binding factor chromosome changes.”

In the absence of these chromosomal changes, Daver and colleagues seek molecular changes.

Although historically this testing has been reserved for the research arena, the recent targeted drug approvals have made it a standard of care.

“The first mutation we check for is FLT3, which is seen in about 30% to 35% of all AML across the board,” Daver said.

Midostaurin — currently the only FLT3 inhibitor approved in the frontline setting for use with chemotherapy — has been shown to improve long-term survival and response rates. The benefits of this approach are particularly pronounced if done with HSCT, Daver said.

“Data show that further adding a FLT3 inhibitor as maintenance post-transplant can achieve cure rates of 70% to 75%. This is dramatic, because only 10 or 11 years ago, when we first found out about the negative prognostic value of FLT3, the cure rate in three or four large studies was found to be 20% to 25%,” he said. “This testing is something physicians need to be doing, and I know a lot of them are.”

In parallel, Daver and his team look for IDH1 or IDH2 mutations.

Although no IDH1/IDH2 inhibitors are FDA approved for use in the frontline setting with chemotherapy, ongoing trials and recent data have suggested that this approach may be effective, Daver said.

“We have to get more mature data before we can decide whether this is something we can do across the board,” he said.

For remaining patients, MD Anderson has frontline trials using standard chemotherapy combinations. MD Anderson uses FLAG-IDA or CLIA (cladribine, idarubicin and cytarabine) whereas other centers use a 7 + 3 regimen, Daver said.

“What is added to that is important,” he said. “We have ongoing trials adding either venetoclax in the frontline setting or gemtuzumab ozogamicin, which is the antibody in the nontargeted, nonchromosomally segregated subgroup.”

Kadia agreed genetic testing is increasingly becoming a standard part of AML treatment.

“All patients with AML should undergo a minimum of genetic profiling,” he said. “If you have AML, it’s best to try to get to an academic center or one that has a lot of expertise, where they likely have the infrastructure and processes in place to efficiently perform all the required genetic testing and next-generation sequencing.”

Challenging populations

Despite the promise of these newer agents, refractory and relapsed disease continues to vex clinicians.

For refractory disease, clinicians may try subsequent therapies — enasidenib, gemtuzumab, ivosidenib and gilteritinib are indicated for refractory disease — and some patients may undergo reinduction chemotherapy.

“We’ve had more options in the last 2 years,” Fathi said, adding that molecular testing will likely play an important role in determining treatment for the refractory patient. Testing can help guide a clinician toward treatment with a FLT3 or IDH inhibitor.

“Getting the molecular tests back in time to make your therapeutic decision is a challenge,” he said. “You do not always have the luxury of time when you’re dealing with a diagnosis of AML.”

AML relapse is a particularly serious concern and may occur despite the most aggressive treatment.

Becker said leukemia blasts often start out resistant to standard drugs. Additionally, she said, the blasts can rapidly acquire drug resistance under the selection pressure of a new drug.

“We say a patient has a leukemia but, actually, they have many different clones,” she said. “We call it clonal selection — we give a patient some drugs, and then the resistant population can grow, expand and become the dominant population.”

Due to the resilience of these clones, patients may respond favorably to initial therapy, but subsequent relapse is common, Becker said, adding that even for drugs that yield complete remission rates in the 60% to 70% range, the resistant cells may eventually circumvent the treatment.

“It’s typical to have a relapse after that initial therapy; the typical remissions only last 6 to 12 months,” she said.

Allogeneic HSCT may offer the best option for curative treatment for selected patients, Becker said.

When donor cells replace the patient’s diseased cells, the donor’s immune system is often able to kill the leukemia, a phenomenon known as graft-versus-leukemia. However, if the patient has even a small amount of minimal residual disease, the likelihood of relapse is high.

“So, even if we do all of that very aggressive care, a high proportion of patients relapse,” Becker said. “If they have any minimal residual disease, there is almost uniform relapse.”

Older adults are another challenging population.

The adverse effects and toxicities associated with intensive chemotherapy leave these patients weakened and unable to proceed to HSCT. Although hypomethylating agents or low-dose cytarabine are more tolerable, the outcomes with these drugs generally have been poor.

Recently, however, the BCL2 inhibitor venetoclax has shown promise when added to either of these regimens.

“The approved way we use venetoclax is with low-dose cytarabine or hypomethylating agents, but I think the studies to be on the lookout for are those where it is combined with modified intensive chemotherapy regimens, like FLAG-IDA, Vyxeos or 7 + 3,” Kadia said. “There are a batch of studies looking at FLT3 or IDH inhibitors combined with venetoclax. People are starting to look at permutations of what is the best and the optimal combination.”

Although these regimens appear to have improved outcomes in older patients, the battle against AML is far from won, Stein said.

“I think there’s maybe been a mistaken feeling among some that we don’t have to worry about AML anymore, and I would say very strongly that that is not the case,” he said. “Even among the patients who get azacitidine or low-dose cytarabine and venetoclax, many of them are going to end up relapsing.

“The real question for researchers now is, ‘How do we build upon this incremental improvement we’ve made?’” he added.

The role of immunotherapy

Immunotherapy has emerged as a promising treatment for various types of cancer, and relapsed or refractory AML is no exception.

“We knew from almost 40 to 50 years ago that there was something defective in the immune system of the patient that allowed AML to occur in the first place,” Daver said. “In normal, healthy immune surveillance, our body’s T cells should seek out, find and eradicate abnormal cells.”

In a phase 2 study of 70 patients with relapsed AML, Daver and colleagues showed the combination of the hypomethylating agent azacitidine and nivolumab (Opdivo, Bristol-Myers Squibb) yielded a 33% overall response, with 22% of patients attaining complete remission. The drug combination was particularly effective in hypomethylating agent-naive patients, who had an overall response rate of 58%.

Median OS was 6.3 months overall and 10.6 months in the first relapse population, which was twice that achieved with azacitidine alone in historical data.

“We concluded that biomarker-driven studies selecting patients with high pretherapy CD3 or CD8 are likely to yield superior results and should be pursued,” Daver said. “Awareness, identification and management of immune-related toxicities, especially as checkpoint inhibitor trials are expanded in multicenter settings, will be critical to the success of such therapies.”

Studies into the potential of chimeric antigen receptor (CAR) T cells are also being conducted, but this approach is still in its earlier stages.

“One of the big issues with CAR T cells is that most of the targets that are on myeloid leukemia cells are expressed on other cells that are necessary for normal hematopoiesis,” Stein said. “So, you can target myeloid leukemia cells but, in the past, we ended up wiping out everything else, too. Then you need to rescue the patient with a bone marrow transplant.”

‘We need to push on’

Although there has been significant headway into understanding and treating AML, clinicians agree that more work is needed.

Stein said it is important to watch the impact of QuANTUM-R, a randomized phase 3 study presented at ASH that showed a small OS benefit for FLT3-positive, refractory/relapsed patients with the FLT3 inhibitor quizartinib (Daiichi Sankyo) vs. investigator’s choice chemotherapy.

Stein also awaits the results of a similar study, ADMIRAL, which evaluated gilteritinib vs. investigator’s choice chemotherapy. Interim data from that trial led to approval of gilteritinib for FLT3-mutated relapsed/refractory AML, but full data have yet to be reported.

“There’s also a randomized, phase 2 study of enasidenib with azacitidine vs. azacitidine alone, for which data have not yet been reported,” he said. “If remission rates are similar to azacitidine/venetoclax, the question’s going to be, ‘What should we do in the older, newly diagnosed patient with an IDH mutation? An IDH inhibitor with azacitidine, or venetoclax with azacitidine?’”

Kadia believes future research should focus on achieving deeper remissions and developing safe, long-term maintenance therapy, and he considers CAR T-cell treatment to be an important emerging area of AML research.

“It’s still early, so we shouldn’t be discouraged by these early modest improvements, but we need to push on, extending those remissions,” he said. “We need to do a better job understanding the disease before we treat, and we need to really decipher some difficult subsets.”

Research should focus on incorporating combination approaches into targeted immunotherapy, Daver said.

“It’s no longer OK to treat AML as one disease,” he said. “Cytogenetic and molecular stratification should be done. It is important to wait for those results and select the ideal therapy.”

The convergence of molecularly targeted and immune-based treatment strategies has yielded new promise in AML, for the first time in decades, Gerber said.

“Additionally, with better molecular characterization and detection methods, we are now better able to personalize therapies,” he said. “However, we are just entering into this new era, and much work remains to be done. We still need to identify better targets, particularly on the leukemia stem cells at the root of the disease, in order to deliver treatments for AML that are more effective and less toxic.”

Although the progress that has been made in AML treatment is promising, clinicians should not be satisfied, Stein said.

“Unfortunately, none of these treatments that have been approved are cures,” he said. “None of them last forever, and that’s why continued clinical research is crucial. We’re only going to be happy when those survival curves never drop below the 100% line. We want to see all of our patients survive.” – by Jennifer Byrne

Click here to read the POINTCOUNTER, “Will targeted therapies become the mainstay of AML treatment?”

References:

Daver N, et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-18-0774.

The following were presented at ASH Annual Meeting and Exposition; Dec 1-4, 2018; San Diego:

Assi R, et al. Abstract 905.

Burd A, et al. Abstract 559.

Cortes JE, et al. Abstract 563.

For more information:

Pamela S. Becker, MD, PhD, can be reached at pbecker@uw.edu.

Naval Daver, MD, can be reached at ndaver@mdanderson.org.

Amir T. Fathi, MD, can be reached at afathi@mgh.harvard.edu.

Jonathan M. Gerber, MD, can be reached at jonathan.gerber@umassmemorial.org.

Tapan M. Kadia, MD, can be reached at tkadia@mdanderson.org.

Eytan M. Stein, MD, can be reached at steine@mskcc.org.

Disclosures: Becker reports research funding from AbbVie, Amgen, GlycoMimetics, JW Pharmaceuticals, Novartis, Pfizer and Trovagene; a speaker role with France Foundation; and consultant roles with CVS Caremark and McKesson. Daver reports research funding from or consultant/advisory roles with AbbVie, Agios, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Genentech, GlycoMimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, Karyopharm Therapeutics, Nohla Therapeutics, Novartis, Otsuka, Pfizer, Sunesis Pharmaceuticals and Servier. Fathi reports research funding from or consultant/advisory roles with Agios, Amphivena, Astellas, Boston Biomedical, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, PTC Therapeutics, Seattle Genetics and Takeda. Gerber reports serving as a principal investigator on a study funded by Janssen evaluating a CD123-bispecific agent and holds a patent (but has not collected royalties) on a leukemia stem cell detection assay for AML. Kadia reports research support from or consultant/advisory roles with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer and Takeda. Stein reports no relevant financial disclosures.

Acute myeloid leukemia historically has been one of the more deadly and difficult-to-treat cancers, with a 5-year survival rate below 30%.

Moreover, a one-size-fits-all treatment approach is not applicable to this complex and heterogenous disease, particularly in older adults. These patients — who comprise the majority of the AML population — often present with difficult, chemotherapy resistant or intolerant disease.

“In the past, we treated everyone with the same therapy and found that older people did not tolerate the intensive chemotherapy as well,” Tapan M. Kadia, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “Additionally, the type of AML that is seen in older patients is different than a 20- or 30-year-old with newly diagnosed AML. On the surface, you would call both these patients newly diagnosed AML, but they are very different from each other.”

Tapan M. Kadia, MD
Tapan M. Kadia

However, a greater understanding of the genetic heterogeneity of AML has led to numerous FDA approvals of targeted therapies, which some believe are poised to change the landscape of AML treatment and its prognosis.

“We are entering into a promising new era in the management of AML, brought about by a convergence of molecular discoveries, leukemia stem cell theory and strategies to harness the immune system,” Jonathan M. Gerber, MD, chief of hematology/oncology and medical director of the Cancer Center at UMass Medical School and UMass Memorial Health Care, as well as a HemOnc Today Editorial Board Member, said in an interview. “However, this is just the beginning; and there is much work yet to be done, in order to deliver treatments for AML that are more effective and less toxic.”

HemOnc Today spoke with hematologic oncologists about discoveries related to the biology of AML that have led to new treatments, how new agents fit into the treatment armamentarium, and what research questions and challenging patient populations will be the focus of investigations moving forward.

Beyond ‘7 + 3’

Over the past several decades, the mainstay of AML treatment has been the “7 + 3” induction chemotherapy regimen.

This treatment — still commonly used in younger patients — consists of 7 days of cytarabine, followed by 3 days of either daunorubicin or idarubicin.

“This was what had been used for about 40 to 45 years before the advent of the new drugs,” Naval Daver, MD, associate professor in the leukemia department at MD Anderson Cancer Center, told HemOnc Today. “The prognosis was really divided based on the age of the patient.”

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Naval Daver, MD
Naval Daver

Since 1960, the prognosis of patients aged younger than 65 years has steadily improved, primarily due to improved prognostication tools and appropriate use of hematopoietic stem cell transplantation.

Additionally, improvements in supportive medications — such as antifungals, antivirals and antibacterials — and better transplant-related management have contributed to improved outcomes.

“The overall cure rate for younger AML patients has gone from about 15% to about 45% to 50% in the last 4 decades,” Daver said. “There has been progress there, but we’re still at best at about 50% with standard 7 + 3 and stem cell transplant use.”

However, this progress hasn’t been mirrored in the population of patients aged older than 65 years, for whom survival rates remain in the 5% to 10% range.

The goal of avoiding the morbidity and mortality of intensive chemotherapy in older patients prompted clinicians to begin seeking less-aggressive chemotherapy regimens.

“In older patients, the standard of care recently has been hypomethylating agents, such as azacitidine [Vidaza, Celgene] and decitabine,” Kadia said. “These drugs — initially approved for myelodysplastic syndrome but later approved for AML — were well-tolerated in most patients, but the outcomes were not great.”

Now, the landscape is driven by greater insight into the various biological mechanisms of AML, which have been key to targeting the heterogenous factors characteristic of this disease.

Amir T. Fathi, MD
Amir T. Fathi

“It’s been a slow and gradual process, but over the course of the past decade, there has been a series of significant advances in elucidating the molecular underpinnings of AML and the common alterations that seem to trigger the disease or allow it to persist,” Amir T. Fathi, MD, director of the leukemia program at Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, told HemOnc Today. “Among these are FLT3 mutations — which impact about one-third of AML patients — and IDH1 and IDH2 mutations, which impact about 20% of patients.”

These mutations can be targeted with small molecules that inhibit the altered enzymes generated by the mutations, Fathi said, and inhibitors of altered FLT3 and IDH proteins have been successfully developed in preclinical and clinical studies and are increasingly available and efficacious for patients with AML.

“These drugs appear to have a therapeutic impact to the point that a sizable subset of patients treated with FLT3 and IDH1/IDH2 inhibitors seems to have a clinically meaningful response to treatment,” he said. “Due to their demonstrated tolerability, efficacy and success in clinical trials, some of these agents have achieved FDA approval.”

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Among the targeted drugs approved by the FDA are midostaurin (Rydapt, Novartis) for newly diagnosed patients with a FLT3 mutation; enasidenib (Idhifa, Celgene), an IDH2 inhibitor for relapsed/refractory AML; gemtuzumab ozogamicin (Mylotarg, Pfizer) for newly diagnosed adults with CD33-positive disease; gilteritinib (Xospata, Astellas) for relapsed/refractory patients with a FLT3 mutation; and the IDH1 inhibitor ivosidenib (Tibsovo, Agios Pharmaceuticals).

The armamentarium also has been expanded to include Vyxeos (Jazz Pharmaceuticals), a liposome injection of daunorubicin and cytarabine for adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes; venetoclax (Venclexta; AbbVie, Genentech) for adults aged 75 years or older with chemotherapy-precluding comorbidities; and glasdegib (Daurismo, Pfizer) for newly diagnosed adults for whom intensive chemotherapy is not an option.

Targeting subcategories of AML based on certain mutations is a part of precision medicine, according to Pamela S. Becker, MD, PhD.
Targeting subcategories of AML based on certain mutations is a part of precision medicine, according to Pamela S. Becker, MD, PhD. “We’re trying to target therapeutic vulnerability in these particular patients, rather than giving the same 7 + 3 to everybody, which is what we did for 40 years,” she said.

Source: Seattle Cancer Care Alliance.

“This whole approach — which involves targeting subcategories of AML based on certain mutations — is considered part of precision medicine,” Pamela S. Becker, MD, PhD, professor of medicine in the division of hematology at University of Washington School of Medicine and attending physician at Seattle Cancer Care Alliance, said in an interview with HemOnc Today. “We’re trying to target therapeutic vulnerability in these particular patients, rather than giving the same 7 + 3 to everybody, which is what we did for 40 years.”

Cytogenetics and other next-generation genetic tests have enabled researchers to identify these mutations.

“Over the past 5 to 7 years, there’s been a revolution in the availability and ability to sequence genes at a very, very deep level through next-generation DNA sequencing,” Kadia said. “With that technology, many groups have uncovered mutations we didn’t know were there before, but were always there, driving the disease. We can detect them now.”

Despite the early promise of these targeted therapies, it’s important to remember that their long-term efficacy is not yet known, Becker said.

“It’s too early for us to know,” she said. “If we look at the current SEER data, it says that the percent surviving 5 years from 2008 to 2014 is 27.4%. We’ll have to see if that number changes when we look at 2015 to 2020 data. Then we’ll be able to acknowledge that these drug approvals did improve survival.”

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Role of HSCT, chemotherapy

Following these approvals, clinicians seek to determine where the agents fit in the treatment armamentarium.

Targeted treatments may improve the outcomes of allogeneic HSCT, which can be curative for appropriate patients who achieve remission. Selecting which patients are eligible for allogeneic HSCT also is a challenge.

“Allogeneic HSCT was the pioneer of immunotherapy, and it is still our most powerful and reliable treatment. It is also our most toxic therapy, with high treatment-related morbidity and mortality,” Gerber said. “Despite these risks, HSCT is still unable to cure far too many patients with AML. Armed with an improved understanding of the disease of the disease at the molecular and stem cell levels, better ways to target leukemic cells and harness the power of the immune system seem finally within reach.”

The targeted therapies are valuable to HSCT in two ways: by improving remission and maximizing patient eligibility for transplantation.

“By incorporating effective targeted therapies into our treatment programs, we’re able to reduce the intensity of the chemotherapy in some cases. The patient remains in decent shape at the end of chemotherapy and is a better candidate for transplant,” Kadia said. “It allows more people to get to transplant and potentially achieve better outcomes.”

Although transplantation is often the goal of chemotherapy, clinicians must weigh the benefits vs. risks for each individual patient, according to Eytan M. Stein, MD, hematologic oncologist at Memorial Sloan Kettering Cancer Center. For example, treatment for a relatively strong patient with intermediate- or unfavorable-risk disease would be very different than for an 85-year-old patient.

“The goal is always to keep the disease away as long as possible, but maybe in this case the goal would be to keep the disease away with the least amount of toxicity,” he said. “You might be willing to have a few months of toxicity in a patient who potentially has a whole life expectancy ahead of them. For someone whose life expectancy isn’t long due to their age, the goals might be different.”

Eytan M. Stein, MD
Eytan M. Stein

Although newer agents or novel therapeutic combinations may be suitable for older, frailer patients, chemotherapy will remain the frontline treatment modality for patients able to tolerate it, Fathi said.

“With the approval of hypomethylating therapy plus the BCL2 inhibitor venetoclax, I believe we’re going to see that combination used more in older patients, or in those ineligible for induction chemotherapy,” he said. “But, in newly diagnosed patients who are candidates for induction chemotherapy, some form of intensive treatment in the upfront setting is still being used to achieve remission.”

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Finding the targets

To use these therapies, clinicians first need to identify which targets exist in their patients in real time.

Findings of the Beat AML Master Trial — presented by Burd and colleagues at ASH Annual Meeting and Exposition in December — showed clinicians could not only match patients with molecularly driven treatments for AML, but that they could do so within a week.

The analysis included 285 newly diagnosed patients aged older than 60 years (median age, 72 years; 58.6% men) seen at 12 clinical sites. The patients underwent genetic screening at baseline and were matched with an appropriate treatment based on molecular subtype.

Overall, 273 patients began treatment within 7 days.

At the time of the presentation, 146 patients had been treated with the targeted agents, whereas 139 (48.8%) did not receive targeted treatment. Of those not treated, most opted for standard of care (20%) or other treatments.

“Firstly, this shows that it’s feasible to do this in a reasonable timeframe for an acute disease,” Kadia said. “Secondly, it shows how after dividing patients based on their molecular subtypes and characteristics, researchers found certain therapies that may be more effective in those subgroups.”

Some drugs evaluated in the trial were investigational, such as SYK inhibitors, or agents called neddylation inhibitors. Still, the significance of the study lies in the investigators’ success in profiling the patients ahead of time and then trying different therapies based on the best biological rationale, Kadia said.

“It was an early, preliminary presentation, but there is more to come,” he said.

However, academic medical centers are already using targeted therapies in a real-world setting, and clinicians are finding themselves overwhelmed by the abundance of agents to choose from.

“That’s becoming a challenge,” Daver said. “I get six or seven emails a day from physicians in the U.S. and around the world trying to figure out the right sequence or combination.”

Daver said he and his colleagues at MD Anderson have developed their own algorithm for choosing treatment, which begins with immediate genetic testing.

“We rush the cytogenetics, as well as the molecular mutation panels,” he said. “We don’t jump into treatment right away, because we know it may be significantly different based on what targets we find, and this may have a major impact on response and survival.”

The first target the algorithm looks for is translocation 15;17, which is indicative of acute promyelocytic leukemia (APL), a subtype of AML. If the patient this translocation on chromosome analysis, Daver diagnoses APL and treats it with a combination of all-trans retinoic acid plus arsenic trioxide.

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“This is the only chemotherapy-free treatment available in AML, and it gives us amazing cure rates of 95% or higher,” he said. “APL probably has the best success rate that we’ve had in all of acute leukemia.”

In the absence of translocation 15;17, Daver and colleagues look for two other chromosome changes — inversion 16 and translocation 8;21 — which indicate core-binding factor leukemias. Although the prognoses for these leukemias are not as good as that of APL, they still are favorable, Daver said.

“If we find them, we recommend the addition of the antibody-drug conjugate gemtuzumab ozogamicin, which targets CD33 on the surface of the leukemia cell,” he said. “Gemtuzumab has been shown to improve the long-term cure rate by about 20% to 25% when added to 7 + 3 or FLAG-IDA [fludarabine, cytarabine, filgrastim and idarubicin], specifically in patients who have these core-binding factor chromosome changes.”

In the absence of these chromosomal changes, Daver and colleagues seek molecular changes.

Although historically this testing has been reserved for the research arena, the recent targeted drug approvals have made it a standard of care.

“The first mutation we check for is FLT3, which is seen in about 30% to 35% of all AML across the board,” Daver said.

Midostaurin — currently the only FLT3 inhibitor approved in the frontline setting for use with chemotherapy — has been shown to improve long-term survival and response rates. The benefits of this approach are particularly pronounced if done with HSCT, Daver said.

“Data show that further adding a FLT3 inhibitor as maintenance post-transplant can achieve cure rates of 70% to 75%. This is dramatic, because only 10 or 11 years ago, when we first found out about the negative prognostic value of FLT3, the cure rate in three or four large studies was found to be 20% to 25%,” he said. “This testing is something physicians need to be doing, and I know a lot of them are.”

In parallel, Daver and his team look for IDH1 or IDH2 mutations.

Although no IDH1/IDH2 inhibitors are FDA approved for use in the frontline setting with chemotherapy, ongoing trials and recent data have suggested that this approach may be effective, Daver said.

“We have to get more mature data before we can decide whether this is something we can do across the board,” he said.

For remaining patients, MD Anderson has frontline trials using standard chemotherapy combinations. MD Anderson uses FLAG-IDA or CLIA (cladribine, idarubicin and cytarabine) whereas other centers use a 7 + 3 regimen, Daver said.

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“What is added to that is important,” he said. “We have ongoing trials adding either venetoclax in the frontline setting or gemtuzumab ozogamicin, which is the antibody in the nontargeted, nonchromosomally segregated subgroup.”

Kadia agreed genetic testing is increasingly becoming a standard part of AML treatment.

“All patients with AML should undergo a minimum of genetic profiling,” he said. “If you have AML, it’s best to try to get to an academic center or one that has a lot of expertise, where they likely have the infrastructure and processes in place to efficiently perform all the required genetic testing and next-generation sequencing.”

Challenging populations

Despite the promise of these newer agents, refractory and relapsed disease continues to vex clinicians.

For refractory disease, clinicians may try subsequent therapies — enasidenib, gemtuzumab, ivosidenib and gilteritinib are indicated for refractory disease — and some patients may undergo reinduction chemotherapy.

“We’ve had more options in the last 2 years,” Fathi said, adding that molecular testing will likely play an important role in determining treatment for the refractory patient. Testing can help guide a clinician toward treatment with a FLT3 or IDH inhibitor.

“Getting the molecular tests back in time to make your therapeutic decision is a challenge,” he said. “You do not always have the luxury of time when you’re dealing with a diagnosis of AML.”

AML relapse is a particularly serious concern and may occur despite the most aggressive treatment.

Becker said leukemia blasts often start out resistant to standard drugs. Additionally, she said, the blasts can rapidly acquire drug resistance under the selection pressure of a new drug.

“We say a patient has a leukemia but, actually, they have many different clones,” she said. “We call it clonal selection — we give a patient some drugs, and then the resistant population can grow, expand and become the dominant population.”

Due to the resilience of these clones, patients may respond favorably to initial therapy, but subsequent relapse is common, Becker said, adding that even for drugs that yield complete remission rates in the 60% to 70% range, the resistant cells may eventually circumvent the treatment.

“It’s typical to have a relapse after that initial therapy; the typical remissions only last 6 to 12 months,” she said.

Allogeneic HSCT may offer the best option for curative treatment for selected patients, Becker said.

When donor cells replace the patient’s diseased cells, the donor’s immune system is often able to kill the leukemia, a phenomenon known as graft-versus-leukemia. However, if the patient has even a small amount of minimal residual disease, the likelihood of relapse is high.

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“So, even if we do all of that very aggressive care, a high proportion of patients relapse,” Becker said. “If they have any minimal residual disease, there is almost uniform relapse.”

Older adults are another challenging population.

The adverse effects and toxicities associated with intensive chemotherapy leave these patients weakened and unable to proceed to HSCT. Although hypomethylating agents or low-dose cytarabine are more tolerable, the outcomes with these drugs generally have been poor.

Recently, however, the BCL2 inhibitor venetoclax has shown promise when added to either of these regimens.

“The approved way we use venetoclax is with low-dose cytarabine or hypomethylating agents, but I think the studies to be on the lookout for are those where it is combined with modified intensive chemotherapy regimens, like FLAG-IDA, Vyxeos or 7 + 3,” Kadia said. “There are a batch of studies looking at FLT3 or IDH inhibitors combined with venetoclax. People are starting to look at permutations of what is the best and the optimal combination.”

Although these regimens appear to have improved outcomes in older patients, the battle against AML is far from won, Stein said.

“I think there’s maybe been a mistaken feeling among some that we don’t have to worry about AML anymore, and I would say very strongly that that is not the case,” he said. “Even among the patients who get azacitidine or low-dose cytarabine and venetoclax, many of them are going to end up relapsing.

“The real question for researchers now is, ‘How do we build upon this incremental improvement we’ve made?’” he added.

The role of immunotherapy

Immunotherapy has emerged as a promising treatment for various types of cancer, and relapsed or refractory AML is no exception.

“We knew from almost 40 to 50 years ago that there was something defective in the immune system of the patient that allowed AML to occur in the first place,” Daver said. “In normal, healthy immune surveillance, our body’s T cells should seek out, find and eradicate abnormal cells.”

In a phase 2 study of 70 patients with relapsed AML, Daver and colleagues showed the combination of the hypomethylating agent azacitidine and nivolumab (Opdivo, Bristol-Myers Squibb) yielded a 33% overall response, with 22% of patients attaining complete remission. The drug combination was particularly effective in hypomethylating agent-naive patients, who had an overall response rate of 58%.

Median OS was 6.3 months overall and 10.6 months in the first relapse population, which was twice that achieved with azacitidine alone in historical data.

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“We concluded that biomarker-driven studies selecting patients with high pretherapy CD3 or CD8 are likely to yield superior results and should be pursued,” Daver said. “Awareness, identification and management of immune-related toxicities, especially as checkpoint inhibitor trials are expanded in multicenter settings, will be critical to the success of such therapies.”

Studies into the potential of chimeric antigen receptor (CAR) T cells are also being conducted, but this approach is still in its earlier stages.

“One of the big issues with CAR T cells is that most of the targets that are on myeloid leukemia cells are expressed on other cells that are necessary for normal hematopoiesis,” Stein said. “So, you can target myeloid leukemia cells but, in the past, we ended up wiping out everything else, too. Then you need to rescue the patient with a bone marrow transplant.”

‘We need to push on’

Although there has been significant headway into understanding and treating AML, clinicians agree that more work is needed.

Stein said it is important to watch the impact of QuANTUM-R, a randomized phase 3 study presented at ASH that showed a small OS benefit for FLT3-positive, refractory/relapsed patients with the FLT3 inhibitor quizartinib (Daiichi Sankyo) vs. investigator’s choice chemotherapy.

Stein also awaits the results of a similar study, ADMIRAL, which evaluated gilteritinib vs. investigator’s choice chemotherapy. Interim data from that trial led to approval of gilteritinib for FLT3-mutated relapsed/refractory AML, but full data have yet to be reported.

“There’s also a randomized, phase 2 study of enasidenib with azacitidine vs. azacitidine alone, for which data have not yet been reported,” he said. “If remission rates are similar to azacitidine/venetoclax, the question’s going to be, ‘What should we do in the older, newly diagnosed patient with an IDH mutation? An IDH inhibitor with azacitidine, or venetoclax with azacitidine?’”

Kadia believes future research should focus on achieving deeper remissions and developing safe, long-term maintenance therapy, and he considers CAR T-cell treatment to be an important emerging area of AML research.

“It’s still early, so we shouldn’t be discouraged by these early modest improvements, but we need to push on, extending those remissions,” he said. “We need to do a better job understanding the disease before we treat, and we need to really decipher some difficult subsets.”

Research should focus on incorporating combination approaches into targeted immunotherapy, Daver said.

“It’s no longer OK to treat AML as one disease,” he said. “Cytogenetic and molecular stratification should be done. It is important to wait for those results and select the ideal therapy.”

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The convergence of molecularly targeted and immune-based treatment strategies has yielded new promise in AML, for the first time in decades, Gerber said.

“Additionally, with better molecular characterization and detection methods, we are now better able to personalize therapies,” he said. “However, we are just entering into this new era, and much work remains to be done. We still need to identify better targets, particularly on the leukemia stem cells at the root of the disease, in order to deliver treatments for AML that are more effective and less toxic.”

Although the progress that has been made in AML treatment is promising, clinicians should not be satisfied, Stein said.

“Unfortunately, none of these treatments that have been approved are cures,” he said. “None of them last forever, and that’s why continued clinical research is crucial. We’re only going to be happy when those survival curves never drop below the 100% line. We want to see all of our patients survive.” – by Jennifer Byrne

Click here to read the POINTCOUNTER, “Will targeted therapies become the mainstay of AML treatment?”

References:

Daver N, et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-18-0774.

The following were presented at ASH Annual Meeting and Exposition; Dec 1-4, 2018; San Diego:

Assi R, et al. Abstract 905.

Burd A, et al. Abstract 559.

Cortes JE, et al. Abstract 563.

For more information:

Pamela S. Becker, MD, PhD, can be reached at pbecker@uw.edu.

Naval Daver, MD, can be reached at ndaver@mdanderson.org.

Amir T. Fathi, MD, can be reached at afathi@mgh.harvard.edu.

Jonathan M. Gerber, MD, can be reached at jonathan.gerber@umassmemorial.org.

Tapan M. Kadia, MD, can be reached at tkadia@mdanderson.org.

Eytan M. Stein, MD, can be reached at steine@mskcc.org.

Disclosures: Becker reports research funding from AbbVie, Amgen, GlycoMimetics, JW Pharmaceuticals, Novartis, Pfizer and Trovagene; a speaker role with France Foundation; and consultant roles with CVS Caremark and McKesson. Daver reports research funding from or consultant/advisory roles with AbbVie, Agios, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Genentech, GlycoMimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, Karyopharm Therapeutics, Nohla Therapeutics, Novartis, Otsuka, Pfizer, Sunesis Pharmaceuticals and Servier. Fathi reports research funding from or consultant/advisory roles with Agios, Amphivena, Astellas, Boston Biomedical, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, PTC Therapeutics, Seattle Genetics and Takeda. Gerber reports serving as a principal investigator on a study funded by Janssen evaluating a CD123-bispecific agent and holds a patent (but has not collected royalties) on a leukemia stem cell detection assay for AML. Kadia reports research support from or consultant/advisory roles with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer and Takeda. Stein reports no relevant financial disclosures.

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