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 pa tients with all-trans retinoic acid (ATRA)-resistant acute promyelocytic le ukemia (APL). Little data is available addressing the pathology of As2O3 tr eated APL and whether the antileukemic mechanism of As2O3 is primarily cyto lysis or through stimulation of cell differentiation. In this report, we ma de a morphologic, cytogenetic, and molecular evaluation of five ATRA-refrac tory APL patients who were treated with As2O3. Four of the five patients ha d morphologic responses after one or two cycles of As2O3 treatment. Of the four responders based on bone marrow morphology, two achieved molecular rem ission (negative RT-PCR for PML- RAR alpha fusion transcripts) by the end o f the second and third cycles of As2O3 therapy. Two patients exhibited mark ed leukocytosis during the first cycle of As2O3, and at that time point the APL cells were largely replaced by the cells showing partial differentiati on towards myelocytes with coexpression of CD11b and CD33. Nevertheless, th ese "myelocyte-like" cells that showed the t(15;17) translocation eventuall y disappeared with continuous As2O3 therapy. As2O3 treatment appears to be effective therapy for the patients with relapsed APL after the failure of c onventional chemotherapy and ATRA therapy. The pathologic findings in these five cases suggest that at low doses As2O3 primarily induces differentiati on of the APL cells, generating abnormal myelocytes resembling APL cells tr eated with ATRA, whereas at higher doses As2O3 induces marrow necrosis.