Review
How Center Volumes Affect Early Outcomes in Acute Myeloid Leukemia

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Abstract

Early mortality (EM) is all too frequent during induction chemotherapy for acute myeloid leukemia. Older patients shoulder an undue amount of this burden as a result of the inherent biology of their disease and increased comorbidities. EM rates in academic centers have seen a sharp decline over the past 20 years; however, data from population-based registries show that EM rates for the general population have significantly lagged behind. In this review, we analyze the data available on EM in academic centers and the general population, explore recent improvements in supportive care and the use of predictive models, and finally investigate the relationship between case volume and complications during chemotherapy.

Introduction

Acute myeloid leukemia (AML) is the most acute common leukemia in adults, with an incidence of 3.7 per 100,000, and is primarily a disease of older adults, with a median age at diagnosis of 69 years.1, 2 Outcomes for AML worsen with age, as the 5-year overall survival (OS) rates for younger adults are approximately 50% and are only 3% to 8% for those older than 60 years.3, 4 Unfortunately, clinical outcomes for the majority of AML patients have not improved significantly over the past 40 years.5 Outcomes for older adults with AML are poor because both the biology of the disease and the overall health of the patient change with age.6 Older patients are more likely to have AML with increased expression of multidrug resistance proteins, be therapy related, and have unfavorable cytogenetics and/or molecular features including TP53 mutations, and their disease is more likely to arise from myelodysplastic syndrome or other hematological disorders, making it more resistant to chemotherapy.6, 7, 8, 9, 10, 11, 12, 13, 14

Many older patients with AML have numerous comorbidities and poor performance status (PS), which makes them more vulnerable to excess toxicity from intensive induction chemotherapy. The combination of excess toxicity and biologically resistant disease makes early mortality (EM), or death during within the first 4 weeks, a common complication of AML in older patients.6, 15, 16 The challenges presented by EM and resistant disease have influenced who is offered induction chemotherapy and have led to age cutoffs around 70 years.17, 18 Alternative induction strategies, such as clofarabine, laromustine, decitabine, and tipifarnib, in this patient population have been met with modest success at best. Other variations have also been explored, but again without any clear advantage.19, 20, 21, 22, 23, 24, 25, 26, 27 Improvements in supportive care during intensive induction therapy and appropriate selection of older patients offered intensive induction therapy, with treatment decisions not only made on the basis of chronologic age, have improved outcomes in EM and can translate to improved survival.28

Here we explore the incidence of EM for AML and acute promyelocytic leukemia (APL) in academic centers and the general population. We review the improvements made in supportive care that have facilitated improvements in EM in academic centers. Finally, we consider the predictive tools utilized for EM during induction therapy and how these tools, along with clinical experience, can improve outcomes in older patients with AML.

Section snippets

Incidence and Trends in EM

In spite of the focus on supportive care in treatment of AML, EM remains a significant problem for older patients with AML.2, 6, 29 EM is most commonly due to infection, hemorrhage, or the sequelae of hyperleukocytosis. A landmark study of 5 Southwest Oncology Group (SWOG) clinical trials by Appelbaum et al6 was among the first to demonstrate that older patients with non-M3 AML are more susceptible to EM and reported an EM rate of 12.1% (Table 1).2, 6, 15, 16, 30 They also clearly demonstrated

Improvements in Management of Infectious Complications of AML

The findings of reduced EM by Othus et al15 suggests that improvements in supportive care have been made for patients with AML undergoing induction chemotherapy. Bacterial and fungal infections are major causes of EM in these patients, contributing to up to 71% of deaths within the first week of treatment.40 As a result, the use of effective, broad-spectrum oral prophylactic antimicrobial therapy has become a routine part of supportive care.41 Gooley et al42 first reported decreased hazards of

Improvements in Supportive Care for Blood Lineage Dysfunction

Because AML is a disease of the bone marrow, complications involving all blood lineages contribute to EM in elderly patients, including hyperleukocytosis, hemorrhage, anemia, and DIC. Current NCCN guidelines for supportive care recommend monitoring of blood counts and assessing for coagulopathy in patients undergoing induction chemotherapy with a daily complete blood count (CBC) and coagulation panel, including fibrinogen, 1 to 2 times per week. Monitoring for coagulopathy should be more

Predictive Models for EM

AML carries a high-risk of morbidity and mortality during induction therapy due to bleeding and infection, but the improvements in supportive care highlighted above have contributed to improved EM rates in highly experienced academic centers.28 Over the last 10 years, an important question in the evolution of supportive care for EM is, can we predict which older patients with AML can tolerate the toxicity of intensive induction therapy? This is especially pertinent for those older patients

Why Differences Exist in EM Between Academic Centers and General Population

As reported by Othus and colleagues, the EM rates in experienced academic centers have seen a steep decline from the early 1990s until now; however, data from the general population of both the United States and Sweden have discovered a significant lag in improvements for EM.2, 15, 16 As noted above, improvements in supportive care and predictive models for EM have increased the capabilities of experienced hematologists to prevent and treat complications from induction therapy for AML. This

Conclusion

EM is a common complication of AML in older patients as a result of their poor overall health and the inherent biology of the disease. EM rates have decreased in academic centers over the past 20 years as a result of significant improvements in supportive care, such as the introduction of improved prophylactic antimicrobial therapy, and through the use of predictive models to identify patients at high risk for EM. Unfortunately, the EM rates of the general population have lagged behind, likely

Disclosure

The authors declare that they have no conflict of interest.

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