Changes in microrheology of acute promyelocytic leukemia cells during all-trans retinoic acid (ATRA) differentiation therapy : a mechanism for ATRA-induced hyperleukocytosis ?

According to French and European experience, hyperleukocytosis occurs during ATRA differentiation therapy in about 70% of de novo and 25% of relapsed APL cases. The most frequently suggested cause for this side-effect is an ATRA-induced proliferation of APL cells. However, no definite explanation for such a proliferative effect has been clearly established. Another mechanism directly related to the differentiation of marrow leukemic cells could be a change in their microrheology, allowing their release from the bone marrow and their transfer toward peripheral blood (PB) and tissues. Using a single cell aspiration assay into a glass restrictive channel, we measured APL cell viscosity values in five de novo APL patients. A deformability index (DI) was defined as the ratio of mean normal neutrophil viscosity x 100/mean APL cell viscosity. Results were the following : (1) at diagnosis, two patients had high marrow DI (96 and 250%) and three patients had low marrow DI (16, 17, and 40%) ; (2) when PB and marrow APL cells were simultaneously tested, PB APL cells display higher DI than marrow APL-cells ; (3) the two patients with high initial marrow DI experienced an ATRA-induced hyperleukocytosis after only 1 day of treatment ; (4) in the three patients with low initial marrow DI, the DI was increasing during ATRA therapy and hyperleukocytosis seemed to occur when a large amount of maturing APL cells reached a viscosity value similar to that of mature neutrophils. These results suggest that an asynchronism between rheological and morphological maturation in each APL cell might explain the occurrence of hyperleukocytosis in some patients during ATRA differentiation therapy.