Cover Story

‘Tide has turned’ in AML: Better understanding of disease biology may lead to treatment advances

The development of highly effective targeted treatments has contributed to dramatic improvements in outcomes for patients with many types of blood cancer.

Acute myeloid leukemia, however, remains a notable exception.

Nearly 74% of all patients diagnosed with AML — and 60% of those aged younger than 60 years — die within 5 years, according to SEER statistics. More than half of those with favorable-risk disease die within a decade.

Survival has improved slightly since 2000, but standard treatment for AML has remained essentially unchanged for a quarter century.

The trend reflects a historical lack of understanding about the genetics of the disease, Eytan M. Stein, MD, and Martin S. Tallman, MD, wrote in a review article published in January in Blood.

Advances in next-generation sequencing led to the identification of several potentially targetable driver mutations in AML.
Advances in next-generation sequencing led to the identification of several potentially targetable driver mutations in AML. “The tide has turned and there has been dramatic progress in the understanding of the biology of [the disease],” Martin Tallman, MD, said. “However, our treatment strategies and therapeutic success continue to lag behind such advances.”

Photo courtesy of Memorial Sloan Kettering Cancer Center

“Promising novel agents evaluated over the past 40 years for the treatment of AML, with rare exceptions, have been relegated to the dustbin of history,” Stein and Tallman wrote.

However, advances in next-generation sequencing in the past decade have yielded tremendous insights and led to the identification of several potentially targetable driver mutations.

“The tide has turned and there has been dramatic progress in the understanding of the biology — and probably the pathogenesis — of AML,” Tallman, chief of the leukemia service at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “However, our treatment strategies and therapeutic success continue to lag behind such advances.”

HemOnc Today spoke with oncologists and investigators about how laboratory breakthroughs have helped focus AML research, the optimism that surrounds novel agents in the pipeline, the challenges that are unique to certain patient subgroups, and the potential that the presence of minimal residual disease could guide treatment decisions or predict outcomes.

A changing landscape

Janet D. Rowley, MD, a longtime faculty member at University of Chicago, made several fundamental discoveries in the 1970s that showed chromosomal changes cause the development of specific types of leukemia. Her efforts redefined leukemia as a genetic disease.

Since then, researchers have strived to identify mutations associated with leukemia, how these mutations trigger leukemic transformation and the prognostic significance of these abnormalities.

“Although most patients have relatively similar manifestations, from the biological perspective they are very different diseases,” Bruno Medeiros, MD, associate professor of medicine/hematology at Stanford University Medical Center, told HemOnc Today. “For this reason, they have extremely different responses to different treatments. We are not treating one disease. We are treating multiple diseases.”

Bruno Medeiros

The so-called 7 + 3 chemotherapy regimen — which consists of 7 days of standard-dose cytarabine and 3 days of daunorubicin — has remained the standard first-line treatment for AML for more than 25 years.

In the past decade, investigators made substantial progress in their quest to tailor treatment based on patients’ genetic profiles.

“We now understand a lot more about the biology — and, in particular, the molecular genetics — of AML and the uniqueness of each individual patient’s disease,” Jeffrey E. Lancet, MD, section head of leukemia and myelodysplasia at Moffitt Cancer Center, told HemOnc Today. “This has translated into an ability to understand which molecular events are likely driving the disease and, in turn, allows for the creation of more targeted therapies against these relevant molecular events.”

FLT3 mutations — the most common in AML — are reported in approximately one-third of cases. Other prevalent abnormalities include mutations in IDH1 and IDH2 — identified in about 20% of AML cases — as well as abnormalities in NPM1 and DNMT3A.

“IDH inhibitors under development are producing fantastic results,” Hagop M. Kantarjian, MD, professor and chair of the department of leukemia and associate vice president for global academic programs at The University of Texas MD Anderson Cancer Center, said in an interview. “Close to 50% of patients with refractory/relapsed AML treated with IDH1 and IDH2 inhibitors achieve responses, with minimal side effects.”

The discovery that gene mutations are not prognostic in isolation — but rather based on their relationships with other mutations — was crucial, Tallman said.

“If a patient has a single mutation, we need to know the relation of the one mutation to another,” he said. “We can’t just know if a patient is FLT3 positive. We need to know if they are FLT3 positive, as well as if they are NPM1 positive or negative, because the prognosis varies significantly depending upon the interaction of these mutations.

The extent of a mutation also is key.

“Take the CEBP- mutation,” Tallman said. “In general, this has conferred a favorable prognosis in patients with a normal chromosome pattern. However, several very recent studies have shown it is only the double mutation of CEBP- — not just the single mutation — that seems to confer this very favorable prognosis.”

These discoveries have accelerated the development of targeted treatments.

“Ten years ago, we knew nothing about the most important mutations in AML — the ones that were critical in driving the disease,” Lancet said. “Now drugs are being developed against these mutations and, slowly but surely, we are seeing success in the clinic with some of these new therapeutics.”

‘Very promising results’

Small molecule inhibitors — specifically those that target FLT, IDH1 and IDH2 mutations — are the most promising class of agents in development for AML.

A randomized phase 3 study presented during the plenary session at the ASH Annual Meeting and Exposition in December revealed the potential of midostaurin (PKC412, Novartis) — a multitargeted small molecule FLT3 inhibitor — in patients with AML who harbor FLT3 mutations.

Results showed the addition of midostaurin to standard chemotherapy, followed by 1 year of maintenance therapy, significantly extended EFS (8 months vs. 3 months; P = .0044) and OS (74.7 months vs. 26 months; P = .007).

Patients who received midostaurin also were more likely to achieve 5-year EFS (27.5% vs. 19.3%; HR = 0.8; 95% CI, 0.67-0.95) and 5-year OS (50.9% vs. 43.9%; HR = 0.77; 95% CI, 0.63-0.95).

The results suggest that — pending FDA approval — midostaurin may fill a tremendous unmet need and become the standard of care for this poor-prognosis AML subtype, researchers said.

Tallman agreed, adding he expects midostaurin will be approved soon.

“The discovery of FLT3 inhibitors will offer great promise,” Tallman said. “Midostaurin may be one of the few advances in AML made ... since 1973, when daunorubicin and cytarabine were introduced.”

Although the study “represents a major advance in AML therapy,” several questions remain, according to Timothy Graubert, MD, chair in hematology–oncology and program director for hematologic malignancies at Massachusetts General Hospital Cancer Center.

“One important question is whether the benefits were seen both in patients with internal tandem duplication and tyrosine kinase domain mutations,” Graubert, who was not involved in the research, told HemOnc Today when the study was presented. “Further, the mutations are not present in all cells of patients who harbor the mutation. The researchers plan to analyze whether there is a difference in benefit between patients who have a majority of cells carrying the mutation and patients where it is only present in a small population of cells. Also, is there a benefit in patients who do not carry either class of FLT3 mutations? That was unaddressed in this trial, but that will be a subject for future study.”

Tallman and colleagues conducted a phase 1/phase 2 trial to assess AG-221 (Agios Pharmaceuticals) for the treatment of patients with AML who harbor IDH2 mutations.

Results, also presented at ASH, showed the agent induced response in patients with advanced myeloid malignancies. In a subgroup of 138 patients with relapsed/refractory AML — 64% of whom had received two or more prior therapies — researchers reported a 41% overall response rate, a 23% complete response rate and a median response duration of 6 months (95% CI, 3.7-9.2).

The agent also appeared well tolerated. The most frequently reported treatment-related adverse events in the overall cohort were indirect hyperbilirubinemia (19%) and nausea (18%).

“Going by the presentations from ASH alone, there are several new targeted agents that are being developed based upon next-generation sequencing,” Anthony S. Stein, MD, director of the leukemia program at City of Hope, said in an interview. “Most of these agents are in phase 1 or phase 2 development and will be used in patients with relapsed disease or in older patients who are not eligible for upfront treatment. However, the results presented on these agents appear very promising.”

Other agents in development

The FDA in January granted fast track designation to the experimental agent CPX-351 (Vyxeos, Celator) for the treatment of elderly patients with secondary AML, which encompasses those with a history of environmental, occupational or therapeutic exposure to hematotoxins or radiation.

The agent — which consists of a liposomal formulation of the chemotherapeutic agents cytarabine and daunorubicin — is intended to deliver synergistic drug ratios to leukemia cells.

Lancet and colleagues conducted a randomized phase 2 study to compare CPX-351 with conventional administration of cytarabine and daunorubicin as first-line treatment in 126 older patients with newly diagnosed AML.

Results, published in 2014 in Blood, showed those assigned CPX-351 demonstrated a higher response rate (66.7% vs. 51.2%), although researchers observed no significant differences in EFS or OS.

A planned analysis of patients with secondary AML showed those assigned CPX-351 achieved a higher response rate (57.6% vs. 31.6%), longer EFS (HR = 0.59) and significantly longer OS (HR = 0.46; P = .01).

At the ASCO Annual Meeting this year, Lancet and colleagues presented data from a phase 3 trial that showed CPX-351 conferred a statistically significant improvement in overall response rate (47.7% vs. 33.3%), OS (HR = 0.69; P = .005) and EFS (HR = 0.74; P = .021) compared with the standard 7 + 3 regimen in patients with newly diagnosed secondary AML.

Jeffrey E. Lancet

“In the secondary AML population, this represents a very exciting potential new therapy,” Lancet said. “The data will have to be validated and peer reviewed before we can make final conclusions. However, based upon the conclusions we have so far it looks like a very important step.”

Vosaroxin (Qinprezo, Sunesis), a topoisomerase II inhibitor that causes site-selective DNA damage, also is under evaluation in AML.

A randomized controlled phase 3 study published last year in The Lancet Oncology showed the addition of vosaroxin to cytarabine provided clinical benefit to certain patients with first relapsed or refractory AML. However, researchers observed no significant difference in OS between vosaroxin and placebo.

A new phase 2 trial is underway to assess the vosaroxin–cytarabine combination in treatment-naive patients.

Other potentially effective therapies include BCT-100 (BCT International Ltd.), a pegylated human recombinant arginase; crenolanib (AROG Pharmaceuticals), an FLT3 inhibitor; SGN-CD33A (Seattle Genetics), a novel CD33-targeting antibody–drug conjugate; and venetoclax (ABT-199/GDC-0199; AbbVie and Roche), a BCL2 inhibitor.

“It is amazing how, as technology has developed, we are able to identify distinct molecular abnormalities and then able to develop drugs that are directed against these molecular abnormalities,” Stein said. “This is what is moving the field of AML forward.”

Combinations and sequencing

With so many therapies demonstrating single-agent activity, the next challenge for investigators will be to determine how best to sequence or combine them.

“This is a whole new field of research, and there is a big momentum surrounding it,” Kantarjian said.

Research already is underway to evaluate combinations of IDH1 and IDH2 inhibitors with FLT3 inhibitors, Kantarjian said. Other studies are assessing the synergy between newer agents and standard regimens, such as chemotherapy.

“A broader chemotherapy effect is needed to elicit large-scale disease control. Targeted therapy would complement this and lead to better overall tumor burden reduction and, hopefully, longer remission rates,” Lancet said. “There are multiple molecular apparitions at play in AML. It is unlikely that one pathway, gene or protein drives the disease exclusively. We would really need to target more than one pathway to achieve success.”

Investigators also hope to build on the knowledge that AML cells frequently overexpress the myeloid antigens CD33 and CD123.

“There is a wave of new monoclonal antibodies that target CD33 and CD123, either conjugated or in the form of bispecific monoclonal antibodies,” Kantarjian said. “These will produce major progress because they can be used in 100% of patients with AML, and they can be combined with chemotherapy.”

Challenging populations

Despite greater understanding of AML biology and the ways treatments can be targeted to maximize outcomes, formidable challenges in disease management remain.

For example, treatment-related adverse events are a key concern for older patients.

The median age at AML diagnosis is 67 years. Nearly three-quarters of AML cases occur in those aged 65 years or older, and SEER data show an estimated 50% to 60% of newly diagnosed patients in that age group receive no antileukemia therapy.

“AML in the elderly is still a significant issue. This remains an extremely challenging patient population to treat, which probably accounts for some of the lack of improvement we have seen in the management of AML in general,” Medeiros said.

“Fifty percent of patients are presenting in their 70s, and patients in their 70s have a number of different comorbidities,” he added. “Biologically speaking, AML is probably a different disease in older patients compared with their younger counterparts, and this influences our ability to treat these patients with chemotherapies that are known to be active against leukemia.”

A study by Amadori and colleagues, published in January in Journal of Clinical Oncology, showed first-line monotherapy with low-dose gemtuzumab ozogamicin (Mylotarg, Pfizer) extended OS compared with best supportive care among older patients with AML who were ineligible for intensive chemotherapy.

Patients aged at least 61 years were randomly assigned 1:1 to either a single induction course of 6 mg/m2 gemtuzumab ozogamicin on day 1 and 3 mg/m2 on day 8 or best supportive care. Patients who did not progress after induction therapy with gemtuzumab ozogamicin received up to eight monthly infusions of the immunoconjugate at 2 mg/ m2.

Researchers reported longer median OS (4.9 months vs. 3.6 months; HR = 0.69; 95% CI, 0.53-0.9) and a higher 1-year OS rate (24.3% vs. 9.7%) among patients assigned gemtuzumab ozogamicin. No unexpected adverse events occurred and toxicity appeared manageable.

“Until recently, agents were not able to be used in patients older than 65 years,” Stein said. “However, some of these newer agents that are under development are less toxic and appear to be safe and effective ... in the older population.”

There is increasing interest in administering investigational therapies to treatment-naive older adults before conventional induction chemotherapy.

“This is really a novel strategy,” Tallman said. “We are in the practice of routinely administering chemotherapy to older adults, but the outcome is poor enough that we may well give serious thought to using an investigational strategy first.”

Support of preclinical research to improve understanding of the biological processes that cause leukemia development is crucial, Medeiros said.

“This will allow for the possibility of enrollment of this particularly frail patient population into clinical trials, which has certainly been a challenge,” he said. “This will help ensure key questions can be answered in a timely fashion and hopefully be translated to progressing or advancing the standard of care.”

More clinical trials also are needed to identify new treatments for patients with AML who are unfit for induction chemotherapy.

“This is always tricky because of the lack of consensus about what defines an ‘unfit’ patient,” Lancet said. “There are no well-validated methods to determine fitness or lack of fitness, and it often is a subjective decision. For patients who are clearly not well enough or who are refusing chemotherapy ... our hope is that we will be able to combine a lower-intensity chemotherapy with a more targeted therapy, with the goal of achieving a greater overall effect than we see with low-intensity chemotherapy alone.”

Minimal residual disease

Studies suggest the presence of minimal residual disease in patients with AML may help guide treatment decisions or predict outcomes, but considerable uncertainty remains.

“There is no question that minimal residual disease is going to be a very important prognostic indicator, but we are learning that different gene mutations may not be as predictive as others,” Lancet said. “One size does not fit all but, by and large, the presence of minimal residual disease seems to predict inferior outcomes. Knowing how to act upon this is key.”

Some experts suggest minimal residual disease could possibly be used as a surrogate trial endpoint for OS.

“For most studies of AML, we have to wait 4 to 5 years [until OS data are available] to know whether a drug is effective,” Stein said. “If future studies confirm that minimal residual disease is a major prognostic point for OS, we can get an answer much quicker — and hopefully get the drug approved much quicker.”

Ivey and colleagues used a reverse-transcriptase quantitative polymerase chain reaction assay to assess minimal residual disease in 2,569 samples obtained from 346 patients with NPM1–mutated AML. All patients had undergone intensive treatment in the National Cancer Research Institute AML17 trial.

The results, published in January in The New England Journal of Medicine, showed that the presence of minimal residual disease provided significant prognostic information independent of other risk factors. In multivariate analysis, the presence of minimal residual disease was the only independent prognostic factor for death (HR = 4.84; 95% CI, 2.57-9.15).

In an accompanying editorial, Michael J. Burke, MD, associate professor in the department of pediatrics at Medical College of Wisconsin and Children’s Hospital of Wisconsin, called the results “provocative” but noted they raised additional questions. Among them: Would the addition of minimal residual disease assessment to risk stratification lead to better outcomes, and could it help guide treatment plans to minimize relapse risk?

Although time will tell, the findings from Ivey and colleagues could be pivotal, Burke wrote.

Lancet agreed.

“The role of minimal residual disease is emerging but remains a somewhat unclear entity,” Lancet said. “It is fairly evident that people with minimal residual disease will do worse in the long run, but we have not discovered how to effectively intervene to eradicate it without putting patients through more nonspecific and potentially toxic therapy. However, we are in the dawn of a new era in which this will become possible, and this will be an area of keen interest in targeted therapy development.” – by Jennifer Southall

References:

Amadori S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.0060.

Burke MJ. N Engl J Med. 2016;doi:10.1056/NEJMe1515525.

Celator Pharmaceuticals. Celator Pharmaceuticals announces positive induction response results from a phase 3 study of CPX-351 in patients with high-risk (secondary) acute myeloid leukemia. Available at: http://ir.celatorpharma.com/releasedetail.cfm?ReleaseID=919224. Accessed on March 31, 2016.

Erba HP. Hematology Am Soc Hematol Educ Program. 2007;doi:10.1182/asheducation-2007.1.420.

Ivey A, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1507471.

Lancet JE, et al. Blood. 2014;doi:10.1182/blood-2013-12-540971.

Klco JM, et al. JAMA. 2015;doi:10.1001/jama.2015.9643.

NCI. SEER Stat Fact Sheets: Acute Myeloid Leukemia. Available at: seer.cancer.gov/statfacts/html/amyl.html. Accessed on March 31, 2016.

Ravandi F, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00201-6.

Stein ME, et al. Abstract 323. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.

Stone RM, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.

For more information:

Hagop M. Kantarjian, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX 77030; email: hkantarjian@mdanderson.org.

Jeffrey E. Lancet, MD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612; email: jeffrey.lancet@moffitt.org.

Bruno Medeiros, MD, can be reached at Stanford Comprehensive Cancer Center, 875 Blake Wilbur Drive, CC2329 MC 5821, Stanford, CA 94305; email: bruno.medeiros@stanford.edu.

Anthony Stein, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010-3000; email: astein@coh.org.

Martin Tallman, MD, can be reached at Memorial Sloan Kettering Cancer Center, 633 Third Ave., Second Floor, New York, NY 10017; email: tallmanm@mskcc.org.

Disclosure: Kantarjian, Lancet, Medeiros, Stein and Tallman report no relevant financial disclosures.

 

POINTCOUNTER 

Is OS the appropriate endpoint for clinical trials in AML?

POINT 

The goal of initiating therapy for any cancer can be summed up in the reductive phrase “lives longer or lives better.”

As we sit across from our patients with AML and discuss treatment options, the “benefit” part of our discussion is where the rubber really meets the road.

Mikkael Sekeres

This is why our patients have come to us. They want to know how we can try to fix them. What resonates with our patients, and what should guide our therapeutic recommendations, are drugs that can prolong their survival — and maybe even cure them — but at the very least allow them to feel less miserable. These are clinically meaningful outcomes.

Imagine what it would sound like if, instead, we focused our treatment discussion with patients on the interim markers of benefit used as endpoints in many cancer trials: “I propose treating you with myeloblastkillamab. It will not extend your survival or improve the quality of your life and may even lead to a premature death, but it has been shown to prolong the time it will take for your disease to progress.”

Not very convincing, is it? If we cannot imagine the discussion we would have with a patient to justify a therapy, why design trials with these endpoints?

Earlier-phase studies use such interim markers of efficacy to justify larger registration studies, and that makes good sense. If a new drug does not have a substantial impact on even interim endpoints, it is hard to justify exposing large cohorts of patients to the drug or using the attendant resources such trials require. If these earlier studies show a new drug has an incredible impact on interim endpoints, it also makes sense to use some of the mechanisms available through the FDA — such as breakthrough designation or accelerated approval — to bring a drug to market quickly, with the requirement that a subsequent study still must demonstrate a clinically meaningful benefit.

But using interim markers of benefit as ends unto themselves — and justifying this approach by arguing we are ”moving the bar” in increments, or that it is difficult to show an improvement in OS because of subsequent therapies patients receive — is specious. An adequately powered trial either will demonstrate an improvement in OS or it will not, obviating interim markers of efficacy. The subsequent therapies patients receive — at which point patients can be considered to have relapsed or refractory leukemia — have never been shown to impact survival.

 

Mikkael Sekeres, MD, MS, is director of the leukemia program and vice chair for clinical research at Cleveland Clinic Taussig Cancer Institute. He can be reached at sekerem@ccf.org. Disclosure: Sekeres reports no relevant financial disclosures.

COUNTER

Clinical trials evaluating new therapies should attempt to improve outcomes that are measurable and clinically meaningful to patients.

Prolongation of OS has been the traditional goal of studies that involve patients with cancer because of the expected short survival of those with many types of cancer and the objective, unequivocal nature of the OS endpoint. However, other measures of benefit can be important for different types or stages of cancer. Improvements in PFS and quality of life have been used as the basis for regulatory approval in solid tumors and lymphoproliferative diseases, with the understanding that there is less precision in the quantification of these and other surrogates.

Charles A. Schiffer

Gemtuzumab ozogamicin (Mylotarg, Pfizer) is the only new drug approved for AML treatment in recent decades, based on a phase 2 trial of patients in relapse. Although the failure to identify newer, more potent cytotoxic agents is due to the recalcitrant nature of the disease rather than regulatory constipation, defining the burden of proof for approval remains a critical issue, particularly for new molecularly targeted and immunotherapeutic agents.

In AML, considerations are potentially different for younger vs. older patients, and for upfront treatment — a setting in which new treatments could have the greatest impact — vs. the relapsed/refractory setting. In addition, AML is a biologically heterogeneous disease. Standard therapy is life threatening and cannot easily be administered to many older patients. There also is a background rate of ”success” with standard therapy, so there are real hurdles that new approaches have to surpass.

The rate of complete remission (CR) with standard cytotoxic therapy is quite high in younger patients, a substantial fraction of whom can be cured. Because allogeneic transplantation is used in a nonsystematic fashion in many younger patients in CR, the evaluation of the effect of a new intervention on OS can be complex, even in randomized trials, and the use of EFS could be relevant.

Even in older patients, for whom the cure rate is disappointingly low, CR can be achieved in 30% to 60% of patients. Although there is some debate about the survival advantage of CR in older patients, there is a real clinical benefit to having normal blood counts and the quality-of-life improvement that accompanies this.

In addition, benefit — as defined by any endpoint — must be balanced by the side-effect profile and the convenience of administration. Thus, an oral therapy with few side effects might be approvable if the results were similar to those achieved with more intensive therapies that require hospitalization. This latter consideration is relevant for targeted therapies, the most recent examples of which are the IDH inhibitor AG221 (Agios) and the FLT3 inhibitor quizartinib (Ambit Biosciences), which have produced CR as single agents in phase 2 trials in molecularly selected patients with relapsed AML.

Randomized trials are underway to compare these agents with chemotherapy regimens commonly used in such patients. One wonders whether the same requirement would have been applied to gemtuzumab ozogamicin if it were a new drug being developed in 2016.

This raises the question of what response rate in phase 2 trials, taking into account the toxicity profile, would be sufficient for accelerated approval. For example, agents that target new resistance mutations in the epidermal growth factor receptor that produced at best partial responses recently were approved for patients with lung cancer.

The answer for patients with AML should depend on the clinical situation, the observed effect and side-effect profile of the new therapy in preliminary trials, and whether the target is known and inhibited. Regulatory agencies and clinical investigators utilize this thought process, and endpoints other than OS should be suitable in many circumstances.

 

Charles A. Schiffer, MD, is professor of medicine and oncology, Joseph Dresner chair for hematologic malignancies and chief of the multidisciplinary leukemia/lymphoma group at Barbara Ann Karamanos Cancer Institute and Wayne State University School of Medicine. He can be reached at schiffer@karamanos.org. Disclosure: Schiffer reports no relevant financial disclosures.

The development of highly effective targeted treatments has contributed to dramatic improvements in outcomes for patients with many types of blood cancer.

Acute myeloid leukemia, however, remains a notable exception.

Nearly 74% of all patients diagnosed with AML — and 60% of those aged younger than 60 years — die within 5 years, according to SEER statistics. More than half of those with favorable-risk disease die within a decade.

Survival has improved slightly since 2000, but standard treatment for AML has remained essentially unchanged for a quarter century.

The trend reflects a historical lack of understanding about the genetics of the disease, Eytan M. Stein, MD, and Martin S. Tallman, MD, wrote in a review article published in January in Blood.

Advances in next-generation sequencing led to the identification of several potentially targetable driver mutations in AML.
Advances in next-generation sequencing led to the identification of several potentially targetable driver mutations in AML. “The tide has turned and there has been dramatic progress in the understanding of the biology of [the disease],” Martin Tallman, MD, said. “However, our treatment strategies and therapeutic success continue to lag behind such advances.”

Photo courtesy of Memorial Sloan Kettering Cancer Center

“Promising novel agents evaluated over the past 40 years for the treatment of AML, with rare exceptions, have been relegated to the dustbin of history,” Stein and Tallman wrote.

However, advances in next-generation sequencing in the past decade have yielded tremendous insights and led to the identification of several potentially targetable driver mutations.

“The tide has turned and there has been dramatic progress in the understanding of the biology — and probably the pathogenesis — of AML,” Tallman, chief of the leukemia service at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “However, our treatment strategies and therapeutic success continue to lag behind such advances.”

HemOnc Today spoke with oncologists and investigators about how laboratory breakthroughs have helped focus AML research, the optimism that surrounds novel agents in the pipeline, the challenges that are unique to certain patient subgroups, and the potential that the presence of minimal residual disease could guide treatment decisions or predict outcomes.

A changing landscape

Janet D. Rowley, MD, a longtime faculty member at University of Chicago, made several fundamental discoveries in the 1970s that showed chromosomal changes cause the development of specific types of leukemia. Her efforts redefined leukemia as a genetic disease.

Since then, researchers have strived to identify mutations associated with leukemia, how these mutations trigger leukemic transformation and the prognostic significance of these abnormalities.

“Although most patients have relatively similar manifestations, from the biological perspective they are very different diseases,” Bruno Medeiros, MD, associate professor of medicine/hematology at Stanford University Medical Center, told HemOnc Today. “For this reason, they have extremely different responses to different treatments. We are not treating one disease. We are treating multiple diseases.”

Bruno Medeiros

The so-called 7 + 3 chemotherapy regimen — which consists of 7 days of standard-dose cytarabine and 3 days of daunorubicin — has remained the standard first-line treatment for AML for more than 25 years.

In the past decade, investigators made substantial progress in their quest to tailor treatment based on patients’ genetic profiles.

“We now understand a lot more about the biology — and, in particular, the molecular genetics — of AML and the uniqueness of each individual patient’s disease,” Jeffrey E. Lancet, MD, section head of leukemia and myelodysplasia at Moffitt Cancer Center, told HemOnc Today. “This has translated into an ability to understand which molecular events are likely driving the disease and, in turn, allows for the creation of more targeted therapies against these relevant molecular events.”

FLT3 mutations — the most common in AML — are reported in approximately one-third of cases. Other prevalent abnormalities include mutations in IDH1 and IDH2 — identified in about 20% of AML cases — as well as abnormalities in NPM1 and DNMT3A.

PAGE BREAK

“IDH inhibitors under development are producing fantastic results,” Hagop M. Kantarjian, MD, professor and chair of the department of leukemia and associate vice president for global academic programs at The University of Texas MD Anderson Cancer Center, said in an interview. “Close to 50% of patients with refractory/relapsed AML treated with IDH1 and IDH2 inhibitors achieve responses, with minimal side effects.”

The discovery that gene mutations are not prognostic in isolation — but rather based on their relationships with other mutations — was crucial, Tallman said.

“If a patient has a single mutation, we need to know the relation of the one mutation to another,” he said. “We can’t just know if a patient is FLT3 positive. We need to know if they are FLT3 positive, as well as if they are NPM1 positive or negative, because the prognosis varies significantly depending upon the interaction of these mutations.

The extent of a mutation also is key.

“Take the CEBP- mutation,” Tallman said. “In general, this has conferred a favorable prognosis in patients with a normal chromosome pattern. However, several very recent studies have shown it is only the double mutation of CEBP- — not just the single mutation — that seems to confer this very favorable prognosis.”

These discoveries have accelerated the development of targeted treatments.

“Ten years ago, we knew nothing about the most important mutations in AML — the ones that were critical in driving the disease,” Lancet said. “Now drugs are being developed against these mutations and, slowly but surely, we are seeing success in the clinic with some of these new therapeutics.”

‘Very promising results’

Small molecule inhibitors — specifically those that target FLT, IDH1 and IDH2 mutations — are the most promising class of agents in development for AML.

A randomized phase 3 study presented during the plenary session at the ASH Annual Meeting and Exposition in December revealed the potential of midostaurin (PKC412, Novartis) — a multitargeted small molecule FLT3 inhibitor — in patients with AML who harbor FLT3 mutations.

Results showed the addition of midostaurin to standard chemotherapy, followed by 1 year of maintenance therapy, significantly extended EFS (8 months vs. 3 months; P = .0044) and OS (74.7 months vs. 26 months; P = .007).

Patients who received midostaurin also were more likely to achieve 5-year EFS (27.5% vs. 19.3%; HR = 0.8; 95% CI, 0.67-0.95) and 5-year OS (50.9% vs. 43.9%; HR = 0.77; 95% CI, 0.63-0.95).

The results suggest that — pending FDA approval — midostaurin may fill a tremendous unmet need and become the standard of care for this poor-prognosis AML subtype, researchers said.

Tallman agreed, adding he expects midostaurin will be approved soon.

“The discovery of FLT3 inhibitors will offer great promise,” Tallman said. “Midostaurin may be one of the few advances in AML made ... since 1973, when daunorubicin and cytarabine were introduced.”

Although the study “represents a major advance in AML therapy,” several questions remain, according to Timothy Graubert, MD, chair in hematology–oncology and program director for hematologic malignancies at Massachusetts General Hospital Cancer Center.

“One important question is whether the benefits were seen both in patients with internal tandem duplication and tyrosine kinase domain mutations,” Graubert, who was not involved in the research, told HemOnc Today when the study was presented. “Further, the mutations are not present in all cells of patients who harbor the mutation. The researchers plan to analyze whether there is a difference in benefit between patients who have a majority of cells carrying the mutation and patients where it is only present in a small population of cells. Also, is there a benefit in patients who do not carry either class of FLT3 mutations? That was unaddressed in this trial, but that will be a subject for future study.”

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Tallman and colleagues conducted a phase 1/phase 2 trial to assess AG-221 (Agios Pharmaceuticals) for the treatment of patients with AML who harbor IDH2 mutations.

Results, also presented at ASH, showed the agent induced response in patients with advanced myeloid malignancies. In a subgroup of 138 patients with relapsed/refractory AML — 64% of whom had received two or more prior therapies — researchers reported a 41% overall response rate, a 23% complete response rate and a median response duration of 6 months (95% CI, 3.7-9.2).

The agent also appeared well tolerated. The most frequently reported treatment-related adverse events in the overall cohort were indirect hyperbilirubinemia (19%) and nausea (18%).

“Going by the presentations from ASH alone, there are several new targeted agents that are being developed based upon next-generation sequencing,” Anthony S. Stein, MD, director of the leukemia program at City of Hope, said in an interview. “Most of these agents are in phase 1 or phase 2 development and will be used in patients with relapsed disease or in older patients who are not eligible for upfront treatment. However, the results presented on these agents appear very promising.”

Other agents in development

The FDA in January granted fast track designation to the experimental agent CPX-351 (Vyxeos, Celator) for the treatment of elderly patients with secondary AML, which encompasses those with a history of environmental, occupational or therapeutic exposure to hematotoxins or radiation.

The agent — which consists of a liposomal formulation of the chemotherapeutic agents cytarabine and daunorubicin — is intended to deliver synergistic drug ratios to leukemia cells.

Lancet and colleagues conducted a randomized phase 2 study to compare CPX-351 with conventional administration of cytarabine and daunorubicin as first-line treatment in 126 older patients with newly diagnosed AML.

Results, published in 2014 in Blood, showed those assigned CPX-351 demonstrated a higher response rate (66.7% vs. 51.2%), although researchers observed no significant differences in EFS or OS.

A planned analysis of patients with secondary AML showed those assigned CPX-351 achieved a higher response rate (57.6% vs. 31.6%), longer EFS (HR = 0.59) and significantly longer OS (HR = 0.46; P = .01).

At the ASCO Annual Meeting this year, Lancet and colleagues presented data from a phase 3 trial that showed CPX-351 conferred a statistically significant improvement in overall response rate (47.7% vs. 33.3%), OS (HR = 0.69; P = .005) and EFS (HR = 0.74; P = .021) compared with the standard 7 + 3 regimen in patients with newly diagnosed secondary AML.

Jeffrey E. Lancet

“In the secondary AML population, this represents a very exciting potential new therapy,” Lancet said. “The data will have to be validated and peer reviewed before we can make final conclusions. However, based upon the conclusions we have so far it looks like a very important step.”

Vosaroxin (Qinprezo, Sunesis), a topoisomerase II inhibitor that causes site-selective DNA damage, also is under evaluation in AML.

A randomized controlled phase 3 study published last year in The Lancet Oncology showed the addition of vosaroxin to cytarabine provided clinical benefit to certain patients with first relapsed or refractory AML. However, researchers observed no significant difference in OS between vosaroxin and placebo.

A new phase 2 trial is underway to assess the vosaroxin–cytarabine combination in treatment-naive patients.

Other potentially effective therapies include BCT-100 (BCT International Ltd.), a pegylated human recombinant arginase; crenolanib (AROG Pharmaceuticals), an FLT3 inhibitor; SGN-CD33A (Seattle Genetics), a novel CD33-targeting antibody–drug conjugate; and venetoclax (ABT-199/GDC-0199; AbbVie and Roche), a BCL2 inhibitor.

“It is amazing how, as technology has developed, we are able to identify distinct molecular abnormalities and then able to develop drugs that are directed against these molecular abnormalities,” Stein said. “This is what is moving the field of AML forward.”

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Combinations and sequencing

With so many therapies demonstrating single-agent activity, the next challenge for investigators will be to determine how best to sequence or combine them.

“This is a whole new field of research, and there is a big momentum surrounding it,” Kantarjian said.

Research already is underway to evaluate combinations of IDH1 and IDH2 inhibitors with FLT3 inhibitors, Kantarjian said. Other studies are assessing the synergy between newer agents and standard regimens, such as chemotherapy.

“A broader chemotherapy effect is needed to elicit large-scale disease control. Targeted therapy would complement this and lead to better overall tumor burden reduction and, hopefully, longer remission rates,” Lancet said. “There are multiple molecular apparitions at play in AML. It is unlikely that one pathway, gene or protein drives the disease exclusively. We would really need to target more than one pathway to achieve success.”

Investigators also hope to build on the knowledge that AML cells frequently overexpress the myeloid antigens CD33 and CD123.

“There is a wave of new monoclonal antibodies that target CD33 and CD123, either conjugated or in the form of bispecific monoclonal antibodies,” Kantarjian said. “These will produce major progress because they can be used in 100% of patients with AML, and they can be combined with chemotherapy.”

Challenging populations

Despite greater understanding of AML biology and the ways treatments can be targeted to maximize outcomes, formidable challenges in disease management remain.

For example, treatment-related adverse events are a key concern for older patients.

The median age at AML diagnosis is 67 years. Nearly three-quarters of AML cases occur in those aged 65 years or older, and SEER data show an estimated 50% to 60% of newly diagnosed patients in that age group receive no antileukemia therapy.

“AML in the elderly is still a significant issue. This remains an extremely challenging patient population to treat, which probably accounts for some of the lack of improvement we have seen in the management of AML in general,” Medeiros said.

“Fifty percent of patients are presenting in their 70s, and patients in their 70s have a number of different comorbidities,” he added. “Biologically speaking, AML is probably a different disease in older patients compared with their younger counterparts, and this influences our ability to treat these patients with chemotherapies that are known to be active against leukemia.”

A study by Amadori and colleagues, published in January in Journal of Clinical Oncology, showed first-line monotherapy with low-dose gemtuzumab ozogamicin (Mylotarg, Pfizer) extended OS compared with best supportive care among older patients with AML who were ineligible for intensive chemotherapy.

Patients aged at least 61 years were randomly assigned 1:1 to either a single induction course of 6 mg/m2 gemtuzumab ozogamicin on day 1 and 3 mg/m2 on day 8 or best supportive care. Patients who did not progress after induction therapy with gemtuzumab ozogamicin received up to eight monthly infusions of the immunoconjugate at 2 mg/ m2.

Researchers reported longer median OS (4.9 months vs. 3.6 months; HR = 0.69; 95% CI, 0.53-0.9) and a higher 1-year OS rate (24.3% vs. 9.7%) among patients assigned gemtuzumab ozogamicin. No unexpected adverse events occurred and toxicity appeared manageable.

“Until recently, agents were not able to be used in patients older than 65 years,” Stein said. “However, some of these newer agents that are under development are less toxic and appear to be safe and effective ... in the older population.”

There is increasing interest in administering investigational therapies to treatment-naive older adults before conventional induction chemotherapy.

“This is really a novel strategy,” Tallman said. “We are in the practice of routinely administering chemotherapy to older adults, but the outcome is poor enough that we may well give serious thought to using an investigational strategy first.”

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Support of preclinical research to improve understanding of the biological processes that cause leukemia development is crucial, Medeiros said.

“This will allow for the possibility of enrollment of this particularly frail patient population into clinical trials, which has certainly been a challenge,” he said. “This will help ensure key questions can be answered in a timely fashion and hopefully be translated to progressing or advancing the standard of care.”

More clinical trials also are needed to identify new treatments for patients with AML who are unfit for induction chemotherapy.

“This is always tricky because of the lack of consensus about what defines an ‘unfit’ patient,” Lancet said. “There are no well-validated methods to determine fitness or lack of fitness, and it often is a subjective decision. For patients who are clearly not well enough or who are refusing chemotherapy ... our hope is that we will be able to combine a lower-intensity chemotherapy with a more targeted therapy, with the goal of achieving a greater overall effect than we see with low-intensity chemotherapy alone.”

Minimal residual disease

Studies suggest the presence of minimal residual disease in patients with AML may help guide treatment decisions or predict outcomes, but considerable uncertainty remains.

“There is no question that minimal residual disease is going to be a very important prognostic indicator, but we are learning that different gene mutations may not be as predictive as others,” Lancet said. “One size does not fit all but, by and large, the presence of minimal residual disease seems to predict inferior outcomes. Knowing how to act upon this is key.”

Some experts suggest minimal residual disease could possibly be used as a surrogate trial endpoint for OS.

“For most studies of AML, we have to wait 4 to 5 years [until OS data are available] to know whether a drug is effective,” Stein said. “If future studies confirm that minimal residual disease is a major prognostic point for OS, we can get an answer much quicker — and hopefully get the drug approved much quicker.”

Ivey and colleagues used a reverse-transcriptase quantitative polymerase chain reaction assay to assess minimal residual disease in 2,569 samples obtained from 346 patients with NPM1–mutated AML. All patients had undergone intensive treatment in the National Cancer Research Institute AML17 trial.

The results, published in January in The New England Journal of Medicine, showed that the presence of minimal residual disease provided significant prognostic information independent of other risk factors. In multivariate analysis, the presence of minimal residual disease was the only independent prognostic factor for death (HR = 4.84; 95% CI, 2.57-9.15).

In an accompanying editorial, Michael J. Burke, MD, associate professor in the department of pediatrics at Medical College of Wisconsin and Children’s Hospital of Wisconsin, called the results “provocative” but noted they raised additional questions. Among them: Would the addition of minimal residual disease assessment to risk stratification lead to better outcomes, and could it help guide treatment plans to minimize relapse risk?

Although time will tell, the findings from Ivey and colleagues could be pivotal, Burke wrote.

Lancet agreed.

“The role of minimal residual disease is emerging but remains a somewhat unclear entity,” Lancet said. “It is fairly evident that people with minimal residual disease will do worse in the long run, but we have not discovered how to effectively intervene to eradicate it without putting patients through more nonspecific and potentially toxic therapy. However, we are in the dawn of a new era in which this will become possible, and this will be an area of keen interest in targeted therapy development.” – by Jennifer Southall

References:

Amadori S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.0060.

Burke MJ. N Engl J Med. 2016;doi:10.1056/NEJMe1515525.

Celator Pharmaceuticals. Celator Pharmaceuticals announces positive induction response results from a phase 3 study of CPX-351 in patients with high-risk (secondary) acute myeloid leukemia. Available at: http://ir.celatorpharma.com/releasedetail.cfm?ReleaseID=919224. Accessed on March 31, 2016.

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Erba HP. Hematology Am Soc Hematol Educ Program. 2007;doi:10.1182/asheducation-2007.1.420.

Ivey A, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1507471.

Lancet JE, et al. Blood. 2014;doi:10.1182/blood-2013-12-540971.

Klco JM, et al. JAMA. 2015;doi:10.1001/jama.2015.9643.

NCI. SEER Stat Fact Sheets: Acute Myeloid Leukemia. Available at: seer.cancer.gov/statfacts/html/amyl.html. Accessed on March 31, 2016.

Ravandi F, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00201-6.

Stein ME, et al. Abstract 323. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.

Stone RM, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.

For more information:

Hagop M. Kantarjian, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX 77030; email: hkantarjian@mdanderson.org.

Jeffrey E. Lancet, MD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612; email: jeffrey.lancet@moffitt.org.

Bruno Medeiros, MD, can be reached at Stanford Comprehensive Cancer Center, 875 Blake Wilbur Drive, CC2329 MC 5821, Stanford, CA 94305; email: bruno.medeiros@stanford.edu.

Anthony Stein, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010-3000; email: astein@coh.org.

Martin Tallman, MD, can be reached at Memorial Sloan Kettering Cancer Center, 633 Third Ave., Second Floor, New York, NY 10017; email: tallmanm@mskcc.org.

Disclosure: Kantarjian, Lancet, Medeiros, Stein and Tallman report no relevant financial disclosures.

 

POINTCOUNTER 

Is OS the appropriate endpoint for clinical trials in AML?

POINT 

The goal of initiating therapy for any cancer can be summed up in the reductive phrase “lives longer or lives better.”

As we sit across from our patients with AML and discuss treatment options, the “benefit” part of our discussion is where the rubber really meets the road.

Mikkael Sekeres

This is why our patients have come to us. They want to know how we can try to fix them. What resonates with our patients, and what should guide our therapeutic recommendations, are drugs that can prolong their survival — and maybe even cure them — but at the very least allow them to feel less miserable. These are clinically meaningful outcomes.

Imagine what it would sound like if, instead, we focused our treatment discussion with patients on the interim markers of benefit used as endpoints in many cancer trials: “I propose treating you with myeloblastkillamab. It will not extend your survival or improve the quality of your life and may even lead to a premature death, but it has been shown to prolong the time it will take for your disease to progress.”

Not very convincing, is it? If we cannot imagine the discussion we would have with a patient to justify a therapy, why design trials with these endpoints?

Earlier-phase studies use such interim markers of efficacy to justify larger registration studies, and that makes good sense. If a new drug does not have a substantial impact on even interim endpoints, it is hard to justify exposing large cohorts of patients to the drug or using the attendant resources such trials require. If these earlier studies show a new drug has an incredible impact on interim endpoints, it also makes sense to use some of the mechanisms available through the FDA — such as breakthrough designation or accelerated approval — to bring a drug to market quickly, with the requirement that a subsequent study still must demonstrate a clinically meaningful benefit.

But using interim markers of benefit as ends unto themselves — and justifying this approach by arguing we are ”moving the bar” in increments, or that it is difficult to show an improvement in OS because of subsequent therapies patients receive — is specious. An adequately powered trial either will demonstrate an improvement in OS or it will not, obviating interim markers of efficacy. The subsequent therapies patients receive — at which point patients can be considered to have relapsed or refractory leukemia — have never been shown to impact survival.

 

Mikkael Sekeres, MD, MS, is director of the leukemia program and vice chair for clinical research at Cleveland Clinic Taussig Cancer Institute. He can be reached at sekerem@ccf.org. Disclosure: Sekeres reports no relevant financial disclosures.

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COUNTER

Clinical trials evaluating new therapies should attempt to improve outcomes that are measurable and clinically meaningful to patients.

Prolongation of OS has been the traditional goal of studies that involve patients with cancer because of the expected short survival of those with many types of cancer and the objective, unequivocal nature of the OS endpoint. However, other measures of benefit can be important for different types or stages of cancer. Improvements in PFS and quality of life have been used as the basis for regulatory approval in solid tumors and lymphoproliferative diseases, with the understanding that there is less precision in the quantification of these and other surrogates.

Charles A. Schiffer

Gemtuzumab ozogamicin (Mylotarg, Pfizer) is the only new drug approved for AML treatment in recent decades, based on a phase 2 trial of patients in relapse. Although the failure to identify newer, more potent cytotoxic agents is due to the recalcitrant nature of the disease rather than regulatory constipation, defining the burden of proof for approval remains a critical issue, particularly for new molecularly targeted and immunotherapeutic agents.

In AML, considerations are potentially different for younger vs. older patients, and for upfront treatment — a setting in which new treatments could have the greatest impact — vs. the relapsed/refractory setting. In addition, AML is a biologically heterogeneous disease. Standard therapy is life threatening and cannot easily be administered to many older patients. There also is a background rate of ”success” with standard therapy, so there are real hurdles that new approaches have to surpass.

The rate of complete remission (CR) with standard cytotoxic therapy is quite high in younger patients, a substantial fraction of whom can be cured. Because allogeneic transplantation is used in a nonsystematic fashion in many younger patients in CR, the evaluation of the effect of a new intervention on OS can be complex, even in randomized trials, and the use of EFS could be relevant.

Even in older patients, for whom the cure rate is disappointingly low, CR can be achieved in 30% to 60% of patients. Although there is some debate about the survival advantage of CR in older patients, there is a real clinical benefit to having normal blood counts and the quality-of-life improvement that accompanies this.

In addition, benefit — as defined by any endpoint — must be balanced by the side-effect profile and the convenience of administration. Thus, an oral therapy with few side effects might be approvable if the results were similar to those achieved with more intensive therapies that require hospitalization. This latter consideration is relevant for targeted therapies, the most recent examples of which are the IDH inhibitor AG221 (Agios) and the FLT3 inhibitor quizartinib (Ambit Biosciences), which have produced CR as single agents in phase 2 trials in molecularly selected patients with relapsed AML.

Randomized trials are underway to compare these agents with chemotherapy regimens commonly used in such patients. One wonders whether the same requirement would have been applied to gemtuzumab ozogamicin if it were a new drug being developed in 2016.

This raises the question of what response rate in phase 2 trials, taking into account the toxicity profile, would be sufficient for accelerated approval. For example, agents that target new resistance mutations in the epidermal growth factor receptor that produced at best partial responses recently were approved for patients with lung cancer.

The answer for patients with AML should depend on the clinical situation, the observed effect and side-effect profile of the new therapy in preliminary trials, and whether the target is known and inhibited. Regulatory agencies and clinical investigators utilize this thought process, and endpoints other than OS should be suitable in many circumstances.

 

Charles A. Schiffer, MD, is professor of medicine and oncology, Joseph Dresner chair for hematologic malignancies and chief of the multidisciplinary leukemia/lymphoma group at Barbara Ann Karamanos Cancer Institute and Wayne State University School of Medicine. He can be reached at schiffer@karamanos.org. Disclosure: Schiffer reports no relevant financial disclosures.