ReviewHow Center Volumes Affect Early Outcomes in Acute Myeloid Leukemia
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.
References (108)
- et al.
Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry
Blood
(2009) - et al.
Age and acute myeloid leukemia
Blood
(2006) - et al.
Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study
Blood
(1997) - et al.
Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study
Blood
(1999) - et al.
The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial
Blood
(2001) - et al.
Karyotype and age in acute myeloid leukemia. Are they linked?
Cancer Genet Cytogenet
(2001) - et al.
Dependence of age-specific incidence of acute myeloid leukemia on karyotype
Blood
(2001) - et al.
Early mortality in acute myeloid leukemia
Leuk Res
(2015) - et al.
Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia
Blood
(2010) - et al.
Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival
Blood
(2013)
Early death rate in acute promyelocytic leukemia remains high despite all–trans retinoic acid
Blood
Impact of hospital volume on outcomes of patients undergoing chemotherapy for acute myeloid leukemia: a matched cohort study
Blood
Acute myeloid leukemia in the real world: why population-based registries are needed
Blood
15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia
Lancet
The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells
Cell
Reassessing the hemostatic disorder associated with acute promyelocytic leukemia
Blood
Molecular remission in PML/RAR alpha–positive acute promyelocytic leukemia by combined all–trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups
Blood
A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group
Blood
Reducing mortality associated with immediate treatment complications of adult leukemias
Semin Hematol
A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031)
Blood
A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490)
Blood
Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study
Lancet
How I treat hyperleukocytosis in acute myeloid leukemia
Blood
Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination
Blood
Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100
Blood
Association of monocytic leukemia in patients with extreme leukocytosis
Am J Med
Hyperleukocytosis, leukostasis and leukapheresis: practice management
Blood Rev
Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia
Blood
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT
Blood
Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a Web-based application for prediction of outcomes
Lancet
The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients
Leuk Res
Geriatric assessment in older patients with acute myeloid leukemia: a retrospective study of associated treatment and outcomes
Leuk Res
Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia
Blood
Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study
Ann Oncol
Acute myeloid leukemia: epidemiology and etiology
Cancer
Survival for older patients with acute myeloid leukemia: a population-based study
Haematologica
Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs
Appl Health Econ Health Policy
Outcomes and quality of care in acute myeloid leukemia over 40 years
Cancer
Acute myeloid leukaemia in the elderly: a review
Br J Haematol
Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis
J Clin Oncol
TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis
Leukemia
Declining rates of treatment-related mortality in patients with newly diagnosed AML given “intense” induction regimens: a report from SWOG and MD Anderson
Leukemia
Management of older or unfit patients with acute myeloid leukemia
Leukemia
A comparison of low-dose cytarabine and hydroxyurea with or without all–trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment
Cancer
Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia
J Clin Oncol
Combination of azacitidine and lenalidomide in myelodysplastic syndromes or acute myeloid leukemia—a wise liaison?
Leukemia
Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia
Leukemia
Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia
Leukemia
Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia
J Clin Oncol
The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML
Br J Haematol
Cited by (9)
Effects of Distance From Academic Cancer Center on Overall Survival of Acute Myeloid Leukemia: Retrospective Analysis of Treated Patients
2020, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :AML patients usually travel long distance to receive care at academic and specialist cancer centers.6,7 Prior studies have demonstrated that treatment at large-volume or academic centers is associated with better OS in AML.6,8-10 The reasons for improved OS are likely multifactorial and may include early diagnosis of AML and prompt initiation of chemotherapy, timely and effective multidisciplinary management of leukemia emergencies, and availability of expertise and a broad range of specialized services, including hematopoietic cell transplantation (HCT) and clinical trials.9,11
Observation Versus Immediate Reinduction for Acute Myeloid Leukemia Patients With Indeterminate Day 14 Bone Marrow Results
2020, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :Additionally, the treatment of patients with AML (excluding those with acute promyelocytic leukemia) who are fit to undergo intensive chemotherapy has continued to typically consist of induction therapy with cytarabine for 7 days and an anthracycline for 3 days.4 The goal of the induction phase is to achieve complete remission (CR) and proceed to consolidation therapy with either high doses of cytarabine or allogeneic hematopoietic stem cell transplantation (HSCT) according to the underlying karyotype and molecular aberrations.5,6 Of the patients with newly diagnosed AML, 10% to 40% will not achieve CR after anthracycline-containing induction therapy.7,8
Outcomes of fludarabine, high dose cytarabine and granulocyte-colony stimulating factor (FLAG) as re-induction for residual acute myeloid leukemia on day 14 bone marrow
2018, Leukemia ResearchCitation Excerpt :Acute myeloid leukemia (AML) is primarily a disease of the elderly with the median age at diagnosis being 68 years and nearly 20,000 new cases are diagnosed annually in the United States [1,2]. Patients diagnosed with non-M3 AML fit to receive intensive chemotherapy are treated with induction therapy consisting of an anthracycline and cytarabine [2–4]. Prognosis of AML is affected by karyotype and molecular aberrations with the majority of patients remaining at risk of relapse.
Enhanced anticancer activity and endocytic mechanisms by polymeric nanocarriers of n-butylidenephthalide in leukemia cells
2021, Clinical and Translational Oncology