Clinical Features and Outcome of Patients with Acute Myeloid Leukaemia (AML) and Central Nervous System Involvement at the Time of Diagnosis and during the Course of AML - Retrospective, Multicentre Study of the Polish Adult Leukemia Group (PALG)
Authors: Patkowska Elzbieta , Gora Tybor Joanna , Lech Maranda Ewa , Kazmierczak Maciej , Baranska Marta , Szczepaniak Andrzej , Paluszewska Monika , Jedrzejczak Wieslaw W , Guzicka Kazmierczak Renata , Knopinska Posluszny Wanda , Grzybowska Izydorczyk Olga , Piszcz Jaroslaw , Deren Wagemann Izabela , Warzocha Krzysztof 
Published: October 2019

Abstract
Introduction: Central nervous system involvement (CNSi) in acute myeloid leukemia (AML) can be found both at the time of diagnosis and during the AML course, with an incidence of 5-15%. However, there is lack of precise clinical characteristics and commonly recommended therapies for AML patients with the CNSi. Such patients demonstrate worse prognosis and reduced survival compared to those without CNSi, therefore allocation them to the allogeneic hematopoietic stem cell transplantation (allo-HSCT) regardless of their cytogenetic risk seems to be the best treatment option.
Aims: The aim of the study was to assessed clinical characteristics and treatment outcome of patients with AML and the CNSi who were treated between 2004 and 2014 in 8 hematology departments of the Polish Adult Leukemia Group (PALG).
Results: The analysis comprised 65 patients (62% males and 38% females) with the median age of 45 years (range 20-81 years). The CNSi was observed in 33 (51%) patients at the time of AML diagnosis (group 1) and in 32 (49%) subjects during the course of AML (group 2).
The most common neurological symptoms were headaches (47% vs 48%, p= 0.99) and altered mental status (21% vs 30%, p= 0.32) observed in the group 1 and 2, respectively. Higher rates of paraparesis (39% vs 9%, p= 0.002) and motor deficits (33% vs 9%, p= 0.011) were noted in the group 2 compared to the group 1.
The CNSi was the most frequently found in the AML not otherwise specified (AML NOS) subtype (61% in the group 1 and 50% in the group 2; p= 0.39). The AML subtype with recurrent cytogenetic abnormalities was diagnosed in 30% of patients form the group 1 and 28% of subjects from the group 2 (p= 0.85). The therapy and dysplasia related AML subtype was diagnosed in 6% of patients from the group 1 compared to the 16% of patients from the group 2 (p= 0.21). Using the FAB classification of AML, the CNSi in the group 1 occurred more often among patients with the M4 (42%) and the M5 (30%) subtype, whilst in the group 2 it was found in the M2 (25%) and the M5 (22%) subtype. The cytogenetic risk distribution according to the SWOG (ie. favorable, intermediate and poor) were 13%, 28% and 16% in the group 1 and 18%, 15% and 21 % in the group 2, respectively (p=0,39). The group 1 was more likely to have abnormal cytogenetics involving the chromosome 8 or 16 compared to the group 2 (62% vs 27%, p= 0.012).
After the diagnosis of the CNSi, systemic chemotherapy was administered to 100% of patients from the group 1 and to 80% of patients from the group 2. Intrathecal chemotherapy was administered to 94% patients in both groups, whereas 19% of patients were subjected to subsequent brain radiation therapy. The cytarabine with methotrexate with corticosteroid was given intrathecally to 83% of patients, whilst the cytarabine monotherapy, the methotrexate with or without corticosteroid and liposomal cytarabine were given intrathecally to 1.5%, 9.1% and 18.2% patients, respectively. The CNS remission rate was higher in the group 1 compared to the group 2 (72% vs 39%, p= 0,003).
Allo-HSCT in the first complete remission (CR1) as well as allo-HSCT after the AML relapse were performed with similar frequency in the both groups (21% vs 25%; p= 0.72 and 12% vs. 16%; p=0.73, respectively).
The probability of a 1-year overall survival (OS) between the group 1 and 2 was not significantly different (52% vs 58% , p= 0.8). However, the OS rate was significantly higher in patients who underwent allo-HSCT in their CR1 compared to that in the patients without allo-HSCT (94% vs 39%; p<0.001). It is worth noting that the OS rate was also higher when more consolidation courses were given before allo-HSCT (17% vs 67% vs 83% ; p<0.001 for 0-1 vs 2-3 vs 4 courses, respectively).
Conclusions: The cytogenetic profile seems to be a key difference in patients' characteristics with the CNSi at the time of diagnosis or during the course of AML, with the chromosome 8 or 16 aberrations observed more often in the former group. The survival of AML patients with CNSi was short with the 1-year OS rate below 60%. However, the OS rate was significantly improved in those patients who underwent allo-HSCT in their CR1.

Disclosures
No relevant conflicts of interest to declare.