Real-world outcomes of acute myeloid leukaemia (AML) are poor compared to the results of clinical trials. This partially reflects population differences due to patient selection criteria in trials (excluding older and unfit patients who are unsuitable for aggressive treatment), and lack of improvement in the efficacy of intensive chemotherapy over time. However, there have been successful developments in AML management including improved non-intensive therapies, laboratory diagnostics to stratify patient risk, donor selection for allogeneic stem cell transplantation (allo-SCT) and supportive care. We have performed a retrospective analysis of all cases of AML in Western Australia from 2009 to 2018 with respect to clinical and laboratory characteristics, treatments and outcomes, compared to a historical cohort.
AML was defined as per the 2016 WHO classification1. Cases were identified by hospital discharge summary records at 3 tertiary public hospitals in WA and the laboratory cytogenetics records for new diagnoses of AML between 2009 and 2018 in patients aged 16 years or older. Medical records were reviewed for clinical data and correlated with cytogenetic and molecular data from Pathwest laboratory. Cytogenetic and molecular risk stratification was defined according to 2017 European LeukemiaNet guidelines2. Intensive chemotherapy regimens were defined as those delivered with curative intent including 7+3 and FLAG. Non-intensive therapy was defined as chemotherapy unlikely to result in prolonged remission, such as subcutaneous azacytidine and cytarabine. These results were compared with a cohort of AML patients in WA diagnosed between 1991-2005, previously published3 which used the modified Grimwade criteria for cytogenetic classification4.
GraphPad Prism version 8 for macOS was used for statistical analysis. Unpaired t-test, Mann-Whitney test and Fisher’s exact test was used to compare populations of AML patients. Kaplan-Meier method was used to calculate overall survival (OS) and logrank analysis was used to compare survival curves.
This research project was approved by the South Metropolitan Health Service Human Research Ethics Committee.
734 diagnosis of AML were identified between 2009-2018. Demographic details are presented in Table 1.
A greater proportion of patients were male, and 446 (60.8%) were over the age of 60 years. Secondary AML was present in 220 patients and the most common predisposing factor was myelodysplastic syndrome in 133 (60%). Cytogenetic studies were available in 710 (96.8%) patients and in 98.9% of patients treated intensively. Cytogenetic risk groups are presented in Table 2A and 2B.
Rates of specific cytogenetic abnormalities are shown in Table 3. Most patients were of intermediate risk regardless of age, secondary disease or type of therapy. The rate of adverse cytogenetics was greater in older patients, and in patients with secondary AML. For patients with a normal karyotype (n = 284), molecular studies for FLT3 (FLT3-TKD and FLT3-ITD) and Nucleophosmin (NPM1) mutations were performed in 57%, and in 73% of patients managed with intensive therapy.
Results of molecular studies for mutations are presented in Table 4.
A summary of therapy is present in Table 5. Median age of patients who received intensive therapy was 56 years (range 16-89). 48 of these patients received an allo-SCT as primary therapy. Median age in this group was 47 years (range 16-65). Median time to allo-SCT from diagnosis was 189 days (range 28-565). Of patients who received non-intensive therapy, 87 (30%) received a hypomethylating agent and 52 (18%) received an alternative cytotoxic agent including subcutaneous cytarabine, hydroxycarbamide and clinical trial agent.
The proportion of patients managed intensively was not significantly different (61% vs 58%, p=0.2607) from the corresponding datum in the 1991-2005 cohort. There was no significant difference of the age of patients managed intensively (mean 55 vs 54 years, p=0.51). For patients 60 years old or younger, there was no difference in rates of allo-SCT in first remission compared with the 1991-2005 cohort (16.9% vs 14.3%, p=0.41). The mean age of patients undergoing primary allo-SCT in the current cohort was significantly older than before (45 vs 39 years, p=0.0245). Time from diagnosis to allo-SCT was longer in the contemporary cohort; median 189 vs 125 days (p=0.0011).
Overall median survival from diagnosis in the current populations was 10.3 months. For patients treated intensively, median OS was 56.6 and 10 months according to age (≤ 60 and > 60 y, respectively). Cytogenetic stratification predicted OS (Figure 1). Patients who received allo-SCT as primary therapy had improved OS compared with patients who received intensive chemotherapy alone (Figure 2).
When compared to the 1991-2005 cohort, OS in patients managed both intensively and non-intensively was significantly improved (Figure 3 and 4). There was no significant difference in median survival of patients undergoing primary allo-SCT between the historical (108.5 m) and current cohort (not reached) (HR 1.075, 95% CI 0.5785 to 1.998) (not shown).
The current cohort of AML treated between 2009-2018 has improved survival compared with treatment during 1991-2005 for both intensively and non-intensively managed patients. The improvement in non-intensively treated patients may be due to newer therapeutic options such as hypomethylating agents5 or subcutaneous cytarabine-based treatments6, 7 which demonstrate favourable response rates in a group of patients with historically poor outcome. In addition, improved supportive care became available including anti-fungal treatments such as posaconazole which may reduce the morbidity and mortality associated with infections due to prolonged neutropenia from disease or therapy8.
The superior survival for patients managed with intensive chemotherapy may also reflect improved supportive care. However the chemotherapy regimens remain similar to that of the 1991-2015 era, consisting of a backbone of intravenous cytarabine and anthracycline-based chemotherapy. Modifications of these agents have failed to demonstrate improvement in survival in clinical trials9, 10.
Better patient selection for intensive management and primary allo-SCT could partially explain the improved survival in this group. High rates of cytogenetic and molecular testing was noted, which is required for accurate risk stratification according to modern European LeukemiaNet2 guidelines to help identify high-risk patients which may benefit from primary allo-SCT. The higher rates of adverse cytogenetics observed in the current cohort compared with the historical cohort are likely to reflect the differing classification systems used for decision-making at the time. Despite this, rates of primary allo-SCT were similar to that of the historic cohort, and outcomes of these patients were similar. Other confounding factors such as increased age at allo-SCT and alternative donor availability with non-related and mismatched donors could influence survival from allo-SCT while in first remission11. This is supported by the relative long lead time from diagnosis to transplant, which may reflect the donor search.
Improvement in survival for AML patients over time is promising, however this appears unrelated to improvements in induction or consolidative chemotherapy, as these regimens have not changed significantly. Advancements in risk stratification, allogeneic transplant and supportive care are likely to account for the modest but significant increased OS in these patients. Overall outcomes remain poor and development of chemotherapy agents with improved efficacy is required. Emerging novel agents such as FLT3 inhibitors, liposomal cytarabine, venetoclax and IDH inhibitors demonstrate promise for AML in specific groups12-17. Some of these are currently being incorporated into contemporary AML care. Pursing these agents in practice and identifying the patients who benefit is likely to improve outcomes for future patients with AML.
Provenence: Externally reviewed
Ethics: Approval obtained.
Corresponding author: Dr Shane Gangatharan, Department of Haematology, Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia. email@example.com