Pathologic, cytogenetic and molecular assessment of acute promyelocytic leukemia patients treated with arsenic trioxide (As₂O₃)

Arsenic trioxide (As₂O₃) shows great promise as an effective therapy for patient with all-trans retinoic acid (ATRA)-resistant acute promyelotic leukemia (APL). Little data is available adressing the pathology of As₂O₃ treated APL and whether the antileukemic mechanism of As₂O₃ is primarily cytolysis or through stimulation of cell differentiation. In this report, we made a morphologic, cytogenetic, and molecular evaluation of five ATRA-refractory APL patients who were treated with As₂O₃. Four of the five patients had morphologic responses after one or two cyces of As₂O₃ treatment. Of the four responders based on bone marrow morphology, two achieved molecular remission (negative RT-PCR for PML- RARα fusion transcripts) by the end of the second and third cycles of As₂O₃ therapy. Two patients exhibited marked leukocytosis during the first cycle of As₂O₃, and at that time point the APL cells were largely replaced by the cells showing partial differentiation towards myelocytes with co-expression of CD11b and CD33. Nevertheless, these 'myelocyte-like' cells that showed the t(15;17) tanslocation eventually disappeared with continuous As₂O₃ therapy. As₂O₃ treatment appears to be effective therapy for the patients with relapsed APL after the failure of conventional chemotherapy and ATRA therapy. The pathologic findings in these five cases suggest that at low doses As₂O₃ primarily induces differentiation of the APL cells, generating abnormal myelocytes resembling APL cells treated with ATRA, whereas at higher doses As₂O₃ induces marrow necrosis.