Plasmapheresis Is an Effective Approach Preventing Clinically Significant Tumor Lysis Syndrome during Induction Therapy in AML Patients with Hyperleukocytosis

Introduction. Most studies have found that hyperleukocytosis (HL >100*10⁹/l) is a poor prognostic factor in acute myeloid leukemia (AML). It is diagnosed in 5-13 % of cases and is more common in AML with monocytes’ differentiation (M4, M5), as well as in cases with poor prognostic molecular markers, such as FLT3-ITD and others.

According to the literature the early (during the first week) mortality in AML due to HL may reach 90%. The main cause of death are leukostasis, leading to neurological symptoms, respiratory distress syndrome (RDS) with lung lesions, disseminated intravascular coagulation (DIC) syndrome with the development life-threatening bleedings and massive tumor lysis syndrome during induction therapy.

Aim. National Research Center for Hematology (NRCH) has initiated a prospective clinical study aiming to develop a feasible clinical approach preventing severe tumor lysis syndrome during induction in AML patients with initial WBC >100*10⁹/l by using serial plasmapheresis (PA).

Patients and Methods. From Jan 2010 till June 2014, 92 patients with de novo AML were treated in the NRCH according to AML-10 protocol (ClinicalTrials.gov Identifier: NCT01587430). Initial white blood cell (WBC) count more than 100x10⁹/l was detected in 18 patients (19,5%): median age - 38 y (17-56yy), M/F - 10/8, WBC - 130x10⁹/l (100-408x10⁹/l), LDH -1765 µ/l (720-6653). 2 patients were in the favorable, 13 – in the intermediate, 2 - in the poor cytogenetic risk group. 83,3% (15/18) patients had hepatosplenomegaly and lymphadenopathy, 38.8 % (7/18) - gingival hyperplasia, 16,6 % (3/18) - neuroleukemia, 16,6% (3/18) - skin leukemids. All patients had infectious complications at diagnosis.

Lung infiltrates due to leukostasis were revealed - in 77,8% (14/18), including 5 patients (27,8%) with RDS; neurological symptoms (headache, blurred consciousness) - in 33,3% (6/18), DIC syndrome - in 8/18 (44,4%) with 1 intracranial hemorrhage.

All patients received allopurinole 600 mg/day. PA procedures were started during cytoreductive therapy (hydroxyurea 10 mg/kg/day 1-2 days) sometimes with leukapheresis (LA) and were continued within 1 or 2 days of conventional 7+3 (ARA-C 100 mg/m2 bid iv 1-7 d, DNR 60 mg/m2 x 3d) 2 hours after short (30 min) ARA-C infusion. DNR was applied on days 3 to 5 or 5 to 7, thus PA did not interfere with its pharmacokinetic properties. All patients concomitantly have got intensive hydrating (3-4 l) and diuretic therapy with electrolytes and albumin support.

Results: Cytoreductive therapy with hydroxyurea was used for a median 2 days (1-7 dd). Half of the patients (9/18) have got 1-2 procedures of LA (median 2). Median 2 (1-4) procedures of PA were performed in 17/18 patients. The volume of removed plasma for 1 PA procedure was 1200 ml (900-1500 ml), the volume of compensation was – plasma 1100 ml (500-1600 ml) +/- 20% albumin 50-150,0 and 0,9% NaCl 500-1000,0.

Median WBC count after cytoreductive therapy at the 1^st day of 7+3 was 60x10⁹/l (5,6-124x10⁹/l). DNR was administered on days 5-7 in 16 and on days 3-5 - in 2 patients. No severe cytolysis with the development of multiple organ failure was observed. Only 1 patient with massive extramedullary involvement has developed just laboratory signs of acute renal failure without stopping the urinary function. Less than third of the patients (5/18) developed the transient signs of volemic overload within the first days of chemotherapy treated successfully with diuretics and plasmapheresis.

CR after the 1^st induction was achieved in 50% of (9/18) patients. Additional 7 patients achieved CR after the 2^nd induction, resulting in 89% overall CR rate. Only 1 patient (5,5%) died with severe infectious complications during aplasia. Allogeneic bone marrow transplantation was performed in 8 of 16 CR patients. The median OS and DFS was 28 and 23 months, 3-years OS and DFS was 32% and 35% respectively.

Conclusions. Our small study brought us to a conclusion that serial PA procedures during cytoreductive phase and the first days of 7+3 may prevent the development of tumor lysis syndrome and its complications. This clinical approach is feasible, easy to perform and decreases early mortality.