Oral Hydroxyurea Before Intensive Chemotherapy For Hyperleucocytic Acute Myeloid Leukemia Patients
Authors: Mamez Anne-claire , Raffoux Emmanuel , Chevret Sylvie , Lemiale Virginie , Boissel Nicolas , Canet Emmanuel , Schlemmer Benoît , Dombret Herve , Azoulay Elie , Lengliné Etienne 
Published: October 2019

Abstract

Aim
Acute myeloid leukemia (AML) with high white blood cells count (WBC) is a medical emergency. In these patients, leucostasis, disseminated intravascular coagulation (DIC) and tumor lysis syndrome lead to frequent death before achieving complete remission. Smooth reduction of tumor burden with oral hydroxyurea (HU) has been suggested as an efficient strategy to prevent dramatic clinical worsening induced by frontline intensive chemotherapy but has never been assessed or compared to other strategies. We aimed to evaluate the benefit of administration of HU before intensive chemotherapy in patients with hyperleucocytic AML.

Methods
We retrospectively reviewed all medical charts of patients admitted to our institution from 1997 to 2011 with newly diagnosis of AML and WBC over 50 G/L excluding promyelocytic AML, patients unfit for intensive induction chemotherapy or with insufficient follow up data. We compared in-hospital mortality (occurring during the hospitalization time or before day 90) and other early outcomes (early death, occurring before day 14, intensive care admission, life’s support therapy) of patients that received HU cytoreduction before chemotherapy versus upfront chemotherapy.

Results
One hundred and sixty patients were included. Median age was 47 years, median WBC was 120 G/L (interquartile range 82-199), 67% had FAB M4/M5, 11% had secondary AML and 49% had normal karyotype, 35% had FLT3 Internal Tandem Duplication, with no difference between the two groups. 107 patients received HU before chemotherapy initiation with a median dose of 50 mg/kg daily for 4, interquartile range [2-6] days. 56 received emergency induction chemotherapy first (median time after diagnostic 0 [0-1] days). In-hospital death rate was lower for patients treated with HU (19% vs. 34%, p= 0.047). In addition, univariate analysis of in hospital mortality identified the role of preexisting conditions, tumor burden markers and the presence of inaugural complications, as shown in Table 1.
As Hydroxyurea was not prospectively randomized, a propensity score was used to adjust the comparison of the 2 groups on other significant prognostic factors and shows that oral hydroxyurea treatment remains significantly associated with a reduction of in-hospital mortality. Monocytic morphology, secondary AML, and year of diagnosis were not predictive of early death. After multivariate analysis, Treatment group (p=0,02), age (p<0.01) and initial WBC (p=0.02) were the 3 remaining factors associated with in-hospital death. DIC was the only parameter associated with death before day 14 in multivariate analysis (p=0,03). Additionally, a non-parametric analysis showed that mortality was linearly related to WBC decline during the 3 first days in HU group. Also, an analysis of HU response (defined by achievement of WBC count below 20 G/L before chemotherapy) reveals that baseline characteristics were insufficient to predict HU sensitivity. Myelotoxicity and WBC decreasing kinetic were similar in both groups. Relapse rate (p=0.85) and one-year event free survival (p=0.87) was not inferior in patients of the HU group achieving complete remission. Finally, patients in the HU group were more likely to be included in a prospective multicenter trial (31% vs. 16% p=0,04) thanks to the longer time available to clinicians and patients to be included.

Conclusion
This study provides the first systematic review of HU use in hyperleucocytic AML. Oral HU before chemotherapy seems a safe and efficient strategy to reduce early death of these high-risk patients. Also it could help clinicians to include theses patients in prospective treatment trials. These results remain to be confirmed in a randomized trial

Disclosures:
No relevant conflicts of interest to declare.