The Evolution of Care for Acute Myeloid Leukemia and the Challenges of Defining Value


J Clin Pathways. 2018;4(suppl 1):S28-S34.



Atrius Health

Harvard Vanguard Medical Associates

Watertown, MA


William J Cardarelli

Director of Pharmacy Revenue and Supply

Atrius Health/Harvard Vanguard Medical Associates

485 Arsenal Street

Watertown, MA 02472

Phone: (617) 972-5321



The author has no relevant financial relationships to disclose.

Key Words

Abstract: Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. Distinct subtypes of AML have been defined based on morphology, immunophenotyping, and molecular genetics. AML usually progresses very quickly if it is not treated. Managed care needs to appreciate the expanded indications of existing drugs and how this changes the standard of care, whether that be more frequent or longer use. Like many other cancers there are indirect costs and burdens, some of which can be considerable. Managed care organizations can contribute to improved outcomes and reduced costs by increasing the understanding of current therapies, recognizing the potential benefit of future therapies, and developing an understanding of targeted drugs and their place in therapy.

Received April 9, 2018; Accepted April 27, 2018.

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. It is the second most common type of acute leukemia in adults. AML is also sometimes referred to as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia.

In AML, there is a block in differentiation and uncontrolled proliferation of myeloid precursors, and the myeloid stem cells usually become a type of immature white blood cell called myeloblasts (or myeloid blasts).1 The myeloblasts in AML are abnormal and do not become healthy white blood cells. Leukemia cells, or leukemic stem cells (LSCs), can build up in the bone marrow and blood, so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or hemorrhaging may occur. The leukemia cells can spread outside the blood to other parts of the body.

AML is the most common type of acute leukemia in adults, and its incidence increases with age.2 This year, an estimated 21,380 people of all ages (11,960 men and 9420 women) in the United States will be diagnosed with AML.3 It is primarily a disease of older adults; the disease rarely occurs before age 45, and the median age of onset is around 67 years. With post-remission therapy, 5-year survival rates of <5% to 20% and >40% may be achieved for patients older and younger than 60 years, respectively.3

AML Classification

Genetic mutations, often in genes coding for signaling proteins or transcription factors, are required to promote the transformation to LSCs and, consequently, overt AML.3 Genetic alterations in the tumor cell have been recognized as a cause of leukemia, initially described as karyotypic abnormalities (eg, deletions, translocations) that are detectable by cytogenetic analysis in approximately 50% of patients.4

In addition to age and performance status, cytogenetic and molecular aberrations are the most important tools to predict outcome in AML.4 The cytogenetic profile (karyotype or chromosomal aberrations) serves as a prognostic indicator in AML by which patients are stratified into favorable, intermediate, and adverse risk groups (Table 1).2,5 Chromosome alterations and complex karyotype (described as > 3 chromosomal abnormalities) are associated with poor response to therapy and reduced survival. The presence of other cytogenetic abnormalities, such as t(8;21) or inv(16) in core-binding factor AML indicate longer disease remission and survival. Approximately 40% to 50% of all AML cases are cytogenetically normal AML (CN-AML). CN-AMLs have an intermediate risk for relapse. With respect to clinical outcomes, substantial heterogeneity is observed in this group.4


AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories (Box 1). Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signaling molecules (FLT3, TP53, RAS gene family) are typically secondary events that occur later during leukemogenesis.4,6 With a frequency of approximately 30%, AML with NPM1 mutation represents the largest class of AML. About 75% of patients also carry mutations in DNA methylation or hydroxymethylation genes (DNMT3A, IDH1, IDH2R140, TET2); 40% have concurrent FLT3 internal tandem duplication (FLT3-ITD) mutations; 20% have NRAS mutations; and approximately 20% exhibit mutations in cohesion complex genes (RAD21, SMC1A, SMC3).6 These mutations have been found to affect clinical outcomes such as remission rates, disease-free survival, event-free survival, and overall survival (OS).7 Other disease characteristics of the patient (age, comorbidities, disease status, response to chemotherapy, donor availability for hematopoietic stem cell transplantation (HSCT), and patient/prescriber preference) are also considered when individualizing treatment options.2















Two staging systems are commonly used for AML. The French-American-British (FAB) classification system8 is based on morphology to define specific immunotypes. The World Health Organization (WHO) classification reviews chromosome translocations and evidence of dysplasia.9 While the FAB classification system is useful and is still commonly used to group AML into subtypes, it does not take into account many of the factors that are known to affect prognosis. The WHO system is a newer system that divides the diagnosis into specific groups (Table 2). This classification of AML is more clinically useful and produces more meaningful prognostic information than the FAB criteria.10


The current WHO classification is based on lineage demonstrated by cell surface antigen expression. Distinct subtypes within each lineage are further defined based on morphology, immunophenotyping, and molecular genetics.2 New somatic/acquired gene mutations have refined the classification of myeloid neoplasms and have been incorporated into the 2016 update of the WHO classification.9,11 Eight balanced translocations and inversions and their variants are included in the WHO category “AML with recurrent genetic abnormalities”, but there is broad heterogeneity within each of these classes.9 AML with mutated NPM1 and AML with mutated CEBPA have both been formally accepted in the 2016 WHO classification as distinct clinical entities. Additionally, 2 new provisional entities, AML with mutated RUNX1 and AML with BCR-ALB1, have been included in the current update of the WHO classification.9

Current Paradigm for AML Diagnosis and Treatment

AML usually progresses very quickly if it is not treated. Treatment of AML should be sufficiently aggressive to achieve a complete remission (CR), because partial remission offers no substantial survival benefit.

Current treatment for AML involves 2 phases. The first, induction therapy, is an intensive chemotherapeutic regimen that attempts to eradicate the leukemia and normalize blood counts. Treatment with 7 days of cytarabine and 3 days of an anthracycline (“7 + 3” regimen) remains the current standard for remission-induction therapy. For patients with FLT3-mutated AML, midostaurin, an inhibitor of FLT3-ITD and FLT3-TKD mutations, may be added to the chemotherapy regimen.11 Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 IgG3 antibody conjugated to the cytotoxin calicheamicin.12 CD33 is a transmembrane glycoprotein frequently expressed on adult and childhood AML blasts (85%-90% of patients presenting with AML). GO binds to the surface CD33, and the complex is internalized.1 Patients shown to have high CD33 expression may be given GO as part of the induction regimen.11 The presence of greater than 5% of leukemic blasts necessitates reinduction therapy.2

The goals of treatment are to eradicate the disease as quickly as possible and induce complete remission, often at the cost of other aspects of the patient’s health. The traditional chemotherapeutic regimen is associated with a number of side effects that range from unpleasant to life threatening, including alopecia (hair loss), mucositis (sores in the mouth and intestines), organ damage, and myelosuppression, which may lead to deadly infections.13

Advances in the treatment of AML have resulted in substantially improved CR rates. Approximately 60% to 70% of adults with AML can be expected to attain CR status following appropriate induction therapy, depending on patient age and the presence or absence of specific somatically acquired genetic alterations.2 Remission rates in adult AML are inversely related to age, with an expected remission rate of more than 65% for those younger than 60 years.

The second phase of treatment, post-remission therapy or consolidation, involves chemotherapy, possibly allogenic HSCT (alloHSCT), or both. Midostaurin or GO may be used as adjuvant therapy for appropriate patients.11 Despite the use of intensive chemotherapy and HSCT, a high proportion of patients who achieve CR eventually relapse. Half of young patients (age younger than 60 years) and 80% of patients older than 60 years experience treatment failures, relapses, or treatment-related complications.2 Even though second and even third remissions may be achieved, these are of progressively shorter duration, and cure is rarely accomplished. Together with post-remission therapy (additional chemotherapy and/or HSCT), 5-year survival rates or < 5% to 20% and > 40% are achieved for patients older and younger than 60 years, respectively.3 An estimated 10,590 deaths (6110 men and boys and 4480 women and girls) from AML will occur this year. More than 25% of adults with AML can be expected to survive 3 or more years. The 5-year survival rate for people with AML is approximately 27%.14

Improvements in therapeutic regimens and supportive care (including infection control and transfusion support) have led to improved survival for AML. However, relapse, and the associated resistance to currently available therapies, represents one of the central problems in the treatment of AML.3

Economic Impact of AML

There are few published articles that have examined the cost burden of AML specifically. One study published in 2010 set the cost of induction therapy at $63,000.15 In another study, health care costs and utilization during the first year after a diagnosis of AML for privately insured non-Medicare patients in the United States aged 50 to 64 years who were treated with either chemotherapy or chemotherapy and alloHCT were estimated based on MarketScan (Truven Health Analytics) adjudicated total payments for inpatient, outpatient, and prescription drug claims from 2007 to 2011. Adjusted mean 1-year costs were $280,788 for chemotherapy and $544,178 for alloHCT.16

In a more recent study, AML patients were identified in MarketScan claims databases between 1 January 2009 and 31 January 2015. Mean (SD) health care expenditures for patients from first-line induction to remission (n = 681) were $208,857 ($152,090). Of the patients who had a second remission (n = 70, expenditures from relapse to remission were $142,569 ($208,307).17

Given the need to hospitalize the patient upon diagnosis, the driver of costs would be related to hospital-based costs and physician payments. Once induction therapy is complete, the costs then shift to outpatient costs for drugs and laboratory as we see with many other cancers. Like many other cancers there are indirect costs and burdens; some of which can be considerable.

Defining Value in AML Care

In addition to the run up in costs, and the pressures of newly-approved drugs and others in the pipeline that are expected to come to market, the existing drugs will gain new indications and will be prescribed more frequently. Treatment cycles will extend beyond current recommendations. Many drugs will also be used in post-acute treatment maintenance. There is also the issue of off-label or outside-of-approval use of therapies. An important question to ask is: Where is the evidence of success? How do we evaluate and determine the value of extending treatment? This creates several legal and ethical questions around balancing the appropriate use of agents with the perception (often cited by advocates) of care.

Managed care needs to appreciate the expanded indications of existing drugs and how this changes the standard of care, whether that be more frequent or longer use. Our biggest source of concern is the off-label use of biologics, determining what level of evidence is acceptable in order to allow this use, and what issues, if any, are created by this use. As treatments evolve and new lines of therapy are added, we are seeing treatments designed to maintain the patient beyond the acute phase of treatment. This is another area where organizations will need to appreciate the value of these therapies.

I think we can all agree that the treatment of cancer is very complex and expensive. Managed care organizations struggle to find the right benefit design that allows the patient to access the care that they need at a price that is affordable to both the patient and society. The Institute of Medicine (now part of the National Academy of Medicine) has described quality medical care as patient-centered, safe, timely, equitable, effective, efficient, and sustainable.18 To me, “efficient and sustainable” means that cost is central to quality. Cost is also central to achieving an equitable distribution of health care with timely access. Organizations attempt to provide this by balancing and developing coverage and benefit language that enables access while controlling utilization and managing costs in order to ensure the organizations survival. Challenges are plentiful, and companies have well-defined mechanisms for decision-making and implementation. Organizations are always looking for new and more efficient models of care not only to control costs by also to improve quality. 

In addition, patients should not be excluded from this discussion. What patients really want is to build a partnership with their treatment team. They want access to quality care with compassion and respect. While all of these domains are very important, what is most important is that patients and their families want hope. Partnering requires that clinicians actively interact with patients, provide them with the necessary medical information to make an informed decision and engage the patient in both the conversation and decision making. In short, a working partnership of patient and clinician provides the foundation for patient engagement and empowers the patient to be the steward of their own health care.

Is there a place here for a collaborative practice such as the medical home? While many of the services are similar to what oncology practices currently offer could an organized medical team with highly defined responsibilities and workflows provide efficient, patient-centered care that improves outcomes, lowers treatment costs, and provides an enhanced patient experience?

Although the concept of the medical home has been around since the 1960s, it has in the past decade been adopted in many primary care settings. In oncology, the care would be directed by the patient’s oncologist who would lead the team depicted here, who collectively take responsibility for the care of the patient. Each team member would apply his or her expertise toward improving the overall health status of the patient. The major challenge to this approach is in setting the correct reimbursement levels to support this type of practice.19

Managed care organizations can contribute to improved outcomes and reduced costs by increasing the understanding of current therapies, recognizing the potential benefit of future therapies, and developing an understanding of targeted drugs and their place in therapy.


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