Management and Outcome of Hyperleukocytosis As Early Complication in Childhood AML - an AML-BFM Experience

Introduction While the treatment options of acute myeloid leukaemia (AML) in children improved during the past decades and increased survival chances, hyperleukocytosis at initial diagnosis continues to be a clinical risk factor associated with early morbidity and mortality. Different management strategies are established such as leukapheresis, chemotherapeutic cytoreductive prephase or exchange transfusions. This retrospective analysis focussed on these different therapy concepts in relation to the patient's outcome.

Patients & Methods Defining leukocytosis with WBC > 50,000x10^9/L (n=224, 42%) and hyperleukocytosis and with WBC >100,000 x10^9/L (n=314, 58%), in total n=538 AML patients (male n=279, 52%; female n=259, 48%; aged under 18 years was recorded in the AML-BFM trials and registries between 1993 and 2017 (total n= 2643).

Results Patients median age at diagnosis was 9.07 years ranged from 0.0-17.9 years, median WBC was 113.95x10^9/L (range 50.0-964.3 x10^9/L), while median hemoglobin was 8.2 g/dL (range 1.3-17.1 g/dL), median bone marrow blast counted 80% (range 0.0-100.0%) and 81% (range 0.0-100.0) in peripheral blood. Most patients were classified to FAB M4/5 (n=287, 53.35%) and stratified into the high-risk group (n=349, 67.37%) of the respective treatment protocol. Except of n=15 patients (3%), who got no initial therapy to treat hyperleukocytosis, 77% (n=413) received a cytoreductive prephase with different agents, such as cytarabine, thioguanine, and others, 14% (n=78) underwent leukapheresis and 13% (n=72) got an exchange transfusion to lower the risk of leucostasis or tumor lysis syndrome. Those, who received more than one treatment option were included in each group. Indeed, a multivariate analysis is necessary and ongoing. The outcome (5-year overall-survival (OS) and 5-year event-free-survival (EFS)) in patients who suffer from leukocytosis or hyperleukocytosis significantly differ (OS 68±3% vs. 57±3%, p=0.011; EFS 53±3% vs. 43.±3% p=0.005), not considering additional risk factors. While patients treated with a prephase have the most favorable outcome (OS 65±2% p 0.001; EFS 51±3% p 0.002), patients with exchange transfusion (OS 65±6% p 0.248; EFS 38±6% p 0.015), leukapheresis (OS 47±6% p 0.010; EFS 35±5% p 0.02) or untreated to their hyperleukocytosis (OS 53±6% p 0.052; EFS 39±6% p 0.087) are even worst. OS per protocol seems to improve slightly over time from 53±4% in AML-BFM 1993 to 66±6% in AML-BFM 2012, whereas the EFS remains stable with 44±4% vs. EFS 47±6%. 63 patients (6%) died within 30 days after diagnosis, n=18 died untreated. The cumulative relapse incidence is 33% in this cohort. The median follow up was 5.47 years, ranged from 0.0 to 18.2 years.

Conclusions Since patients were included for a long observation period of 24 years to this analysis, the possible influence of genetic predisposition for the entire cohort like i.e. FLT3-ITD, MLL or NPM1 has to be neglected, due to missing data from earlier protocols than 2004. Whenever clinically possible, patients should receive a cytoreductive prephase as this option has a statistically significant positive impact on OS and EFS. However, it must be considered that especially those patients receiving an exchange transfusion or leukapheresis, which might be in a more critical state of illness already than those receiving the prephase. Since prephase regimes showed up very heterogeneously in terms of used agents, further analysis is necessary to allow better insights which drugs should be in favor and multivariate analyses to assess the impact of combined treatment strategies. Same applies for the consideration of additional risk factors and the relativization of outcome once the patients survived the hyperleukocytosis.

In summary, hyperleukocytosis is still a risk factor and cytoreduction, leukapheresis, or exchange transfusion remain the mainstay for the therapy thereof while showing that the choice of the right strategy can impacted the patient's outcome.

Reinhardt:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cerus: Membership on an entity's Board of Directors or advisory committees; Medac: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Research Funding.