Switching from all-trans retinoic acid to arsenic trioxide for newly diagnosed acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is most commonly accompanied by disseminated intravascular coagulation (DIC), which can cause early death from bleeding. Conventional chemotherapeutic drugs can kill APL cells, but they exacerbate DIC. On the other hand, all-trans retinoic acid (ATRA) can quickly alleviate DIC by inducing the differentiation of APL cells. For this reason, the National Comprehensive Cancer Network (NCCN) guidelines [1] emphasize the necessity of early recognition and recommend the prompt initiation of ATRA based on a presumed diagnosis of APL. However, ATRA can induce an increase in APL cell counts. In Japanese trials [2,3], newly diagnosed APL patients with low leukocyte counts (leukocytes <3000/ll and APL cells <1000/ll) started with ATRA alone; cytotoxic chemotherapy was later added only for those whose APL cell counts increased while on ATRA. Most patients treated with ATRA alone or in combination with chemotherapy achieved complete remission (CR); however, the additional chemotherapy was associated with severe infection and bleeding [2–4]. Since a single-agent arsenic trioxide (ATO) regimen has been shown to be safe and effective even in relapsed patients after being treated with ATRA [5,6], we speculated that ATO could be a safe substitute for chemotherapy in patients showing an insufficient response to ATRA. We assessed the safety and efficacy of switching to ATO monotherapy when there is an increase in APL cells due to ATRA therapy. Previously untreated APL patients aged 20 years and older who had leukocyte counts of <3,000/ll and APL cell (myeloblasts and promyelocytes) counts of <1000/ll in peripheral blood were enrolled in this study. A diagnosis of APL was confirmed by the presence of the t(15;17) karyotype or PML-RARA gene rearrangement. After obtaining informed consent, the patients were treated with ATRA alone at 45mg/m daily until hematological CR was achieved. ATRA was discontinued if the APL cell counts increased to over 1000/ll. After ATRA was discontinued, ATO alone at 0.15mg/kg daily was given until hematological CR was achieved. ATO was temporarily stopped if grade 3 to 4 adverse effects, such as QT prolongation on the electrocardiogram or hepatotoxicity, appeared, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. After achieving CR, patients received three courses of 35-day cycle consolidation therapy consisting of ATRA (45mg/m daily on days 1 to 35) and ATO (0.15mg/kg daily on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 and 29 to 33). Neither maintenance treatment nor central nervous system prophylaxis was given to the patients. Disease status was assessed by RT-PCR of the PML-RARA fusion gene using bone marrow samples obtained at diagnosis and after each cycle of consolidation therapy. This study was registered in the UMIN Clinical Trials Registry (number UMIN000012004). Four patients were enrolled and started with ATRA monotherapy (day 1). Two patients were kept on ATRA because they did not show an increase in APL cells, and CR was obtained on days 16 and 34, respectively. The clinical courses during the remission induction therapy of the remaining two patients who switched from ATRA to ATO are shown in Figure 1 (patient #1: 28-year-old male; patient #2: 67-year-old male). At the start of the treatment, patient #1 had a leukocyte count of 1050/ll and an APL cell count of 199/ll, and patient #2 had a leukocyte count of 1530/ll and an APL cell count of 107/ll in peripheral blood. During the ATRA treatment, the number of APL cells increased to over 1000/ll in approximately 2 weeks (patient #1: 1145/ll on day 14; patient #2: 3137/ll on day 13). According to the protocol, ATRA was discontinued and switched to ATO monotherapy. During the ATO treatment, the APL cell counts gradually decreased before disappearing from the peripheral blood on day 28 in patient #1 and on day 22 in patient #2. ATO was temporarily discontinued for 11 days due to grade 3 hepatotoxicity in patient #1, and for 6 days due to grade 3QT prolongation in patient #2. During the temporary discontinuation of ATO, no increase in APL cells was seen