Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

Abstract

Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis.

Keywords: AML; DIC; acute myeloid leukemia; disseminated intravascular coagulation; hyperleukocytosis; leukostasis; tumor lysis syndrome.

Figure 1

Current and potential future treatment options for complications of hyperleukocytosis in AML: Hyperleukocytosis is associated with a higher rate of leukostasis, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC). Current treatment options for leukostasis include mechanical removal of leukemic blasts with leukapheresis and cytoreduction with chemotherapy or hydroxyurea. As adhesion of leukemic cells to the endothelium is essential to the pathophysiology of leukostasis, targeting blast-endothelial cell interactions might become a future therapeutic strategy. TLS in AML is due to rapid cell turnover leading to electrolyte imbalances and increased serum levels of uric acid that can culminate in renal failure and fatal cardiac arrhythmias. Treatment of TLS entails supportive management of electrolytes, intravenous fluids to maintain urine output, and allopurinol or rasburicase to reduce the production of uric acid. DIC can be managed with transfusion of platelets, fibrinogen, and fresh frozen plasma (FFP). In sepsis-associated DIC as well as in small studies of AML patients, heparin, recombinant thrombomodulin, and other agents have been tested with mixed results and are not part of routine management of DIC associated with AML.

Figure 2

Selected interactions between leukemic blasts and other cells in the bone marrow niche: AML blasts interact via various mechanisms with bone marrow stromal cells and endothelial cells. Among those mechanisms are the interaction of chemokine receptor CXCR4 on leukemic blasts with its soluble ligand CXCL12 (also known as SDF-1), which can be blocked with plerixafor. Additionally, the interaction between E-selectin on endothelial cells and various ligands on leukemic cells such as PSGL-1, CD43, and CD44 has become an increasingly studied therapeutic target with GMI-1271 (uproleselan) currently being studied in advanced phase clinical trials. Other interactions between bone marrow stromal cells and both regular HSCs and leukemic cells include VLA-4/VCAM-1, VLA-5/fibronectin, and cadherins. Finally, the CCL2/CCR2 axis has been shown to be expressed in the majority of monocytoid AML blasts and to play a role in cell proliferation [52].

Figure 3

Pathophysiology of leukostasis in AML: Leukostasis in AML is due to various factors. First, myeloblasts are less pliable than mature granulocytes or lymphoblasts and cause mechanical obstruction of small blood vessels leading to hypoperfusion and ischemic damage in distal areas. Second, leukemic blasts produce pro-inflammatory cytokines such as TNF-α or IL-1β that induce the expression of cell adhesion molecules such as E-/P-selectin, ICAM-1, and VCAM on endothelial cells that interact with adhesion molecules on leukemic blasts (L-selectin, CD43, CD44, P-selectin glycoprotein ligand-1 [PSGL-1]). Third, leukemic blasts release matrix metalloproteinases (MMP) that damage endothelial integrity and enable extravasation of leukemic blasts into tissues and can cause microhemorrhages.

Figure 4

Pathophysiology of disseminated intravascular coagulation: DIC is characterized by an imbalance of pro- and anticoagulant factors due to both excess activation of the coagulation system and increased fibrinolysis. Prothrombotic factors in AML include the release of tissue factor from endothelial cells which is at least partly stimulated by the production of pro-inflammatory cytokines by leukemic blasts as well as external factors that promote endothelial injury such as infections, chemotherapy, or indwelling catheters. Simultaneously, anticoagulant factors contributing to the development of DIC include increased activity of plasminogen activator in conjunction with reduced levels of plasminogen activator inhibitor, increased expression of annexin II by leukemic cells, and disease-related thrombocytopenia.