Background
Central nervous system (CNS) involvement in adults with acute myeloid leukaemia (AML) is uncommon, and its incidence is far less than that in patients with acute lymphoblastic leukaemia [
1,
2]. Most descriptions of the clinical features of AML with CNS involvement are from studies of paediatric AML patients [
3-
6]. The incidence of CNS involvement in childhood AML ranges from 6% to 29% [
5-
9]. Previous studies have shown that age < 2 years, high white blood cell (WBC) and peripheral blast cell (PBC) counts at diagnosis, French-American-British (FAB) M4 and M5 morphology, inversion of chromosome 16, and a hyperdiploid cytogenetic profile are risk factors for CNS involvement in paediatric AML patients at diagnosis [
6-
8]. On the other hand, isolated CNS relapse in paediatric patients with AML is associated with age < 2 years, high WBC count, hepatosplenomegaly, CNS involvement at diagnosis, FAB M5 morphology, and chromosome 11q abnormalities [
10]. Reports of the outcomes of paediatric AML patients with CNS involvement have varied. Certain studies have shown that CNS involvement confers a poor prognosis, [
11,
12] whereas others have shown that it exerts no effect on survival [
5,
7,
8,
10].
The clinical features and treatment outcomes of adult AML patients with CNS involvement have not been well characterised. Peterson et al [
13] described adult patients with acute nonlymphocytic leukaemia with CNS involvement, but their sample size was relatively small. Shihadeh et al [
14] examined the cytogenetic profiles of AML patients with CNS disease in a cohort of 1354 patients in the United States, but did not examine the clinical outcomes. Rozovski et al [
15] used the same cohort as Shihadeh et al and found that high serum levels of lactate dehydrogenase (LDH) at diagnosis, African-American ethnicity, and young age were risk factors for CNS involvement. Patients who achieved complete remission (CR) after induction chemotherapy had shorter disease-free survival and overall survival (OS) if they had CNS involvement. Bar et al [
16] reported risk factors and outcomes for CNS AML involvement in patients at the pre-haematopoietic stem cell transplantation (HSCT) evaluation. Covariates associated with CNS involvement were higher WBC counts at diagnosis, prior CNS or other extramedullary disease, and disease status at pre-HSCT evaluation. Presence of CNS involvement at pre-HSCT evaluation had no impact on post-HSCT outcome. However, participants in their study were limited to those who had undergone HSCT, which may have confounded their findings. In this study, we investigated the clinical characteristics and outcomes of a large cohort of adult AML patients in Taiwan to determine the risk factors and outcomes associated with CNS involvement in AML. Several characteristics which had not been included in previous studies, such as the immunophenotype of leukaemia cells and 13 relevant molecular gene mutations in AML, were also examined. In addition, we investigated the impact of CNS involvement on outcomes including separate analyses on those with initial CNS disease and those with isolated CNS relapse.
Discussion
Our current study examined the rate of CNS involvement in a large cohort of adult AML patients. The incidence of CNS involvement amongst adult AML patients at our institution was 5.1%. This result is similar to that reported in other studies, that the incidence of CNS involvement concurrent with or subsequent to AML diagnosis in adults is uncommon [
1,
15,
36]. The AML patients with CNS involvement were younger, exhibited higher WBC, platelet, and peripheral blood blast cell counts, and had FAB M4 morphology, and 11q23 abnormalities more frequently than did the AML patients without CNS involvement. By multivariate analysis, the risk factors significantly associated with CNS involvement included age ≤ 45 years, WBC counts ≥ 50,000/μL, and the presence of 11q23 abnormalities. No significant difference in 5-year OS and RFS rates was observed between the AML patients with initial CNS disease and those without it. In contrast, the prognosis of patients who suffered an isolated CNS relapse was as poor as that of patients who suffered a bone marrow relapse.
Young age has previously been considered as a risk factor for CNS involvement and it was also observed in this study [
14,
15,
37]. Since certain FAB subtypes, such as M4 AML, or cytogenetic abnormalities, such as the chromosome 16 inversion, are commoner in younger adults and are also more frequently associated with extramedullary infiltrates, this is likely to at least partly explain the association between CNS disease and younger age found in this and other studies. A large leukaemic cell burden, as represented by high WBC counts and high serum LDH levels, has been shown to be significantly associated with CNS involvement [
3,
8,
13-
16]. We observed that AML patients with high WBC counts at diagnosis had a significantly higher incidence of CNS involvement (Table
3). However, the association between serum LDH levels and CNS involvement was not statistically significant in our study (
P = 0.069).
Chromosomal changes or molecular gene mutations in AML have clinical implications. Karyotype abnormalities, such as the chromosome 16 inversion, chromosome 11q23 abnormality, trisomy 8, t(9;11) translocation, and hyperdiploidism have been shown to be significantly associated with CNS involvement in paediatric AML [
7,
8,
10,
14]. We observed that the chromosome 16 inversion was more prevalent amongst patients with initial CNS disease, whereas the 11q23 abnormalities were more common amongst patients that suffered an isolated CNS relapse. These findings are consistent with those of previous studies of paediatric AML patients [
8,
10]. On the other hand, no relevant molecular gene mutation associated with CNS involvement was identified in this study.
Reports of outcome about CNS involvement in adults with AML are limited. Chang et al reported that extramedullary infiltrates were associated with poor outcome in adult patients with AML, but their investigation did not focus specifically on CNS involvement [
38]. Mayadev et al [
39] showed that CNS involvement was associated with poor prognosis in adult AML patients. On the contrary, other two studies [
16,
37] showed that the outcomes for AML with CNS involvement were comparable with those for AML without CNS involvement. However, participant selection for these three studies was limited to patients who had undergone HSCT, which may have confounded their results. In our study, the 5-year OS and RFS of patients with initial CNS disease were similar to those of AML patients without CNS disease. These findings may be partially explained by the higher frequency of favorable cytogenetics (inversion of chromosome 16), the absence of CNS relapse, and low rate of BM relapse (16.7%, Table
4) amongst the patients with initial CNS disease. By contrast, our data demonstrated that the outcome of patients who suffered an isolated CNS relapse was actually poor. Three of four patients (75%) who suffered an isolated CNS relapse developed a subsequent BM relapse and died, despite receiving cranial irradiation or allogeneic HSCT.
No consensus exists regarding the treatment of AML patients with CNS involvement. The preference of treatment protocols used in our study is largely based on the capacity of intrathecal chemotherapy to clear the leukaemic cells of CSF quickly in most patients and the efficacy of high doses of cytarabine for penetrating the CNS [
40,
41]. Moreover, the potential acute and long-term complications associated with cranial irradiation often limit its use. Aoki et al [
37] reported that allogeneic HSCT may improve outcomes for CNS involvement in patients with AML. However, further prospective studies are necessary to clarify this point. Future investigations of more effective CNS-directed treatment strategies are warranted to improve the outcomes of such patients, particularly those who suffer an isolated CNS relapse.
The limitation of our study is that this is a single centre, retrospective study. Nevertheless, most published studies concerning this subject have also been retrospective. Identifying adult patients with AML who are at risk for CNS involvement will enable us to restrict the use of CNS prophylactic therapy to those who are most likely to benefit. In this study three significant risk factors for CNS involvement in adult patients with AML were recognized. Further studies with large cohorts are necessary to validate this point.
Acknowledgements
This work was partially sponsored by Grants NSC 97-2314-B002-015-MY3, NSC-97-2628-B-002-002-MY3, NSC 100-2325-B002-032 and NSC 100-2628 -B-002-003-MY3 from the National Science Council (Taiwan), DOH99-TD-C- 111-001 from the Department of Health (Taiwan) and NTUH 99P14 and 100P07 from the Department of Medical Research, National Taiwan University Hospital.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
CLC had the original idea for the study, analysed and interpreted data, did statistical analyses, and wrote the manuscript. CCL and H-AH helped to design the study and performed collection and assembly of data. W-QF and C-HC were responsible for statistical analyses. CTL, JLT, WCC, CYC, MY, SYH, BSK, SJW, and WT participated in data collection and provision of patients. HFT coordinated the study over the entire period and participated in editing and proofreading. All authors read and approved the final manuscript.