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Unmet Clinical Needs and Economic Burden of Disease in the Treatment Landscape of Acute Myeloid Leukemia
Megan Wiese, MS, PA-C, and Naval Daver, MD
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Unmet Clinical Needs and Economic Burden of Disease in the Treatment Landscape of Acute Myeloid Leukemia

Megan Wiese, MS, PA-C, and Naval Daver, MD
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults in the United States, with approximately 19,520 new cases estimated for 2018. Despite advances in the management of hematologic malignancies, the development of novel targeted and immune therapies, and improvements in supportive care, the overall outcome for patients with AML remains poor due to several factors, including increased frequency in the older population, poor response to chemotherapy, high relapse rates, and limited effective therapy options in relapsed patients. In addition, AML presents a substantial clinical and financial burden attributable in part to the heterogenic characteristics at presentation, such as varied age distributions and cytogenetic and molecular abnormalities, coupled with prolonged hospitalizations, high rates of infectious complications, and need for allogeneic stem cell transplants. Several unmet needs exist in AML. For instance, more-effective, less-toxic treatments are urgently needed because many patients with AML are not candidates for standard induction therapy. AML is also characterized by high rates of relapsed/refractory disease; therefore, strategies to reduce relapse are important. Other unmet needs center on poor quality of life from disease- and therapy-related toxicities and inadequate psychosocial support frequently experienced by many patients with AML and by their caregivers. This review will discuss these issues and additional challenges faced both by patients with AML and by caregivers and medical personnel who work in the AML setting.
Am J Manag Care. 2018;24:-S0

Acute myeloid leukemia (AML) poses a substantial clinical burden worldwide. In 2012, more than 350,000 individuals were diagnosed with leukemia globally, including chronic and acute lymphoid and myeloid leukemias.1 AML is the most common form of acute leukemia in adults in the United States, with approximately 19,520 new cases estimated for 2018.2 Cancer statistics from Surveillance, Epidemiology, and End Results demonstrate a trend toward a rise in the number of new cases of AML diagnosed each year, with an increase in incidence of 3.43 to 4.26 per 100,000 from 1975 to 2015.3 The increases in overall incidence of AML may be due, in part, to a growing population of older individuals, because the likelihood of AML increases with age.3 Additionally, an improved awareness of the presenting features of AML, improvements in diagnostic ability, and an increased willingness to work up and consider therapy in older patients with AML may be contributing to the increased incidence.4 Although the incidence of AML is highest among individuals 65 years and over, more than 43% of newly diagnosed patients with AML are younger than 65 years.3 In the population younger than 65, the incidence of AML is 2 per 100,000 individuals, compared with 20.1 per 100,000 individuals 65 years or older.3

Despite recent advances in the management of patients with hematologic malignancies, such as the development of novel and effective targeted and immune therapies and improvements in supportive care measures, the overall survival outcomes for patients with AML remain poor. The 5-year relative survival rate in patients with AML who are younger than 65 is approximately 45%.3 Moreover, this number likely overestimates survival in patients aged 45 to 65 years because the 5-year relative survival rate for patients younger than 45 years is 59.5% (Table 1).3 As patients age, the 5-year relative survival rates decline rapidly. This is partially explained by the increased likelihood of favorable cytogenetic profiles, such as t(8;21), inv(16) and t(15;17), seen in younger patients. Young patients are not only more likely to have favorable cytogenetics, they are also more likely to experience better outcomes relative to their cytogenetic- and treatment-matched older counterparts because of better organ function and lower rates of comorbidities.5

Poor outcomes in AML are related to several factors, including the presence of concomitant comorbidities or organ dysfunction preventing patients from receiving optimal chemotherapy regimens, the expression of high-risk features such as adverse karyotypes and mutations, and an increased risk of second primary malignancies (SPMs).5-7 There are several approaches to the treatment of AML, which include chemotherapy, targeted therapy, immunotherapy, and hematopoietic stem cell transplantation (HSCT). Treatment challenges are largely associated with primary and secondary resistance to therapeutic agents. Treatment-resistant disease or relapsed disease is associated with decreased overall survival (OS). Continued poor outcomes paired with an increase in the number of newly diagnosed AML cases suggests that AML is a disease that represents an increasing economic burden.

Prognostic Assessments

AML is a heterogeneous disorder with regard to morphology, including, but not limited to, chromosome and molecular aberrations detected in the leukemic cells.8 Different subtypes of AML may have distinct causal mechanisms, suggesting functional links among specific molecular abnormalities and mutations and the presumed causal agents.9 Although most cases of AML arise de novo, environmental factors, such as prolonged exposure to paints, benzene, alcohol, tobacco, or other chemical toxins, may be associated with AML pathogenesis in a small minority of cases. Previous cytotoxic or radiation therapy and the presence of antecedent hematologic conditions, such as myelodysplastic syndrome or myeloproliferative neoplasms, are known to increase the incidence of AML and are associated with poorer prognosis than for patients who develop AML de novo.9,10

Chromosomal abnormalities are found in the majority of patients with AML.11 Frequent cytogenetic abnormalities include loss or deletion of chromosome 5, 7, 17, and Y; translocations such as t(8;21), t(15;17), and trisomy 8 and 21; and other abnormalities involving chromosomes 1, 3, 9, 11, and 16.8,11-13 The cytogenetic landscape of AML is further complicated by the fact that these abnormalities occur at different frequencies in different age groups and in de novo versus secondary AML.11,12

Multiple studies have demonstrated the prognostic importance of cytogenetic abnormalities in AML as predictors of response and OS as well as a useful tool to guide treatment (Table 2 12-16).8,11-13,17 According to multiple large studies, patients with t(8;21), inv(16)/t(16;16), and del(9q) tend to have significantly better outcomes, whereas patients with inv(3)/t(3;3), –5/5q–, –7, loss of 7q, +8, abn(12p), –17/17p–, –18, –20, and loss of 20q tend to have significantly poorer outcomes.5,8,12,13,17 Furthermore, patients with t(8;21) and inv(16)/t(16;16) had a significantly improved chance of 5-year survival and relapse-free survival compared with patients with a normal karyotype.8 Aside from aiding in predicting outcomes in AML, cytogenetics may help guide treatment, suggesting that cytogenetic profiling should be performed in all newly diagnosed patients with AML.

Traditionally, AML classification and risk stratification relied predominantly on cytogenetic studies. However, in the past decade the molecular detection of gene mutations has become an increasingly important tool for classification, risk stratification, and management of patients with AML. Molecular analysis plays a complementary role to cytogenetic testing by helping further refine prognosis, especially within specific AML subgroups such as patients with intermediate or diploid cytogenetics. In addition to their role as a prognostic tool, some molecular abnormalities have emerged as potential therapeutic targets.18 Some of the most important AML-related gene mutations include transcription-factor fusion genes; NPM1, RUNX1, TP53, and CEBPA, FLT3 mutations (both ITD and D835); other tyrosine kinases, serine–threonine kinases, protein tyrosine phosphatases; and RAS family protein mutations, mutations in IDH1/2, and mutations in DNMT3A, ASXL1, RUNX1, and PTPN11.18 Mutations in these AML-related genes can co-occur (ie, mutations either in NPM1 and DNMT3A or in NPM1 and FLT3) or can be mutually exclusive (ie, mutations in RUNX1 and TP53 are frequently mutually exclusive of FLT3 and NPM1 mutations). Based on these mutations, researchers and physicians have identified subtypes of AML with significant differences in prognosis and treatment.18,19 Although mutational aberrations may be distinct from epigenetic aberrations, they often interact with each other to determine prognosis, as demonstrated in patients with AML with IDH1/2 mutations.20 Several reviews have described the prognostic significance of cytogenetic and molecular markers associated with AML, and those in younger adults are outlined in Table 3.12,14-16

Current Standards of Care in AML

The treatment of AML is divided into 2 phases: remission induction and consolidation. Remission induction with chemotherapy aims to reduce the leukemic burden and restore normal hematopoiesis to produce complete remission (CR). Although most patients will achieve CR after induction therapy, 50% to 60% of patients with AML will experience disease recurrence if treatment is discontinued after induction.21 Therefore, a favorable response to induction therapy should be followed by consolidation therapy, usually composed of intermediate- or high-dose cytarabine-based therapy or alloHSCT, to eradicate residual disease (detectable or nondetectable) and aid in achieving lasting remission.

Induction Therapy

Cytarabine and an anthracycline-based induction has remained the standard of care for patients with AML for the past 4 decades.19,22 The most frequently used iteration of the cytarabine and anthracycline combination has been the “7 + 3” regimen, which includes a 7-day continuous infusion of cytarabine at the dosage of 100 or 200 mg/m2 per day on days 1 to 7 and 12 mg/m2 idarubicin or 45 to 60 mg/m2 daunorubicin on days 1 to 3. Several studies have evaluated the comparative benefits of anthracycline dose escalation in the 7 + 3 regimen to improve CR and survival outcomes; benefits varied by age and molecular and cytogenetic risk profiles.

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