glycine receptors While it has been reported that the
While it has been reported that the combination therapy of As2O3 and ATRA is highly effective not only as the front-line treatment , but also in relapsed and treatment-refractory APL patients , showing fewer adverse events than the combination of ATRA and chemotherapeutic drugs, the efficacy and tolerability of the combination of As2O3 and tamibarotene are unknown. We herein report a patient with APL successfully treated with the combination therapy of As2O3 and tamibarotene, in whom both As2O3 and tamibarotene monotherapies had not been effective.
Case report A 40-year-old Japanese male was admitted to our hospital because he presented with purpura on both legs in May 2011. Laboratory examinations revealed significantly abnormal findings, including a white blood cell (WBC) count of 41,400/µL with 65.5% blasts and 22.5% promyelocytes, a glycine receptors level of 12.2g/dL, and a platelet count of 20,000/µL. Blood coagulation parameters showed a fibrinogen level of 154mg/dL, FDP level of 320.8µg/mL, and D-dimer level of 70.9μg/mL. A bone marrow aspiration study revealed the proliferation of blasts (65.5%) and promyelocytes (22.5%). A chromosome analysis based on a G-banding analysis showed the karyotype 46,XY,t(15;17)(q22;q21) [20/20]. On the basis of these findings, a diagnosis of acute promyelocytic leukemia was made. The patient received an induction therapy with JALSG APL 204 regimen-group C, which consisted of ATRA, cytarabine (Ara-C), and idarubicin, and achieved hematological complete remission (CR). Accordingly, he received three cycles of post-remission therapies and achieved molecular CR (Table 1). However, although hematological relapse was not detected, the PML/RARA mRNA transcripts came to be recognized by an RT-PCR test during the period of maintenance therapy using ATRA. Thus, the patient was diagnosed as having molecular relapse and received tamibarotene (6mg/m2/day) for eight weeks, but the PML/RARA mRNA transcripts did not disappear. He then received a therapy with JALSG APL 205R regimen composed of As2O3 single treatment as a re-induction therapy and two cycles of As2O3 single treatment as post-remission therapy. However, the PML/RARA mRNA transcripts did not disappear during the following consolidation therapy. He received high-dose cytarabine (2000mg/m2 twice a day) for five days and achieved second molecular CR. Accordingly, autologous peripheral blood stem cell transplantation (aPBSCT) was performed after the high-dose chemotherapy consisting of busulfan (1mg/kg four times a day) for three days and melphalan (70mg/m2/day) for two days in August 2014. Engraftment was subsequently observed and he was discharged while remaining in molecular CR. Then, we attempted to use both tamibarotene and As2O3 as a combination therapy. He achieved hematological and molecular CR on day 28 and on day 61, respectively (Fig. 1). Hematologic toxicities and hypertriglyceridemia were not detected, and grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy.
Discussion Reports have included speculation on the molecular mechanisms of resistance to ATRA and As2O3. In terms of the mechanism of resistance to ATRA, genetic mutations (i.e. missense, nonsense, and deletions) have been identified on the RARA ligand binding domain (LBD) in PML-RARA. These mutations accumulate in the three subregions of the LBD domain . In vitro analyses using ATRA-resistant NB4 cells and mutated-PML-RARA expressing Cos-1 cells  indicated that ATRA-binding affinity with mutated PML-RARA was lower than that with PML-RARA without mutations because of conformational changes in LBD. Furthermore, ligand-dependent N-CoR/SMRT co-repressor release and co-activator recruitment, which are critical for the transcriptional activation of genes with RARE sites and morphological cell differentiation, are impaired under the therapeutic dose of ATRA . On the other hand, information on As2O3 resistance remains limited compared with that on ATRA resistance. Goto et al. reported the first molecular basis for clinical resistance to As2O3 in APL using two As2O3-resistant patients . The authors concluded that PML-B2 domain mutations may play an important role in aberrant molecular responses to As2O3 and may be critical for As2O3 resistance in APL.