Arsenic by degrading the PML/RARA fusion protein (NICE
Arsenic Trioxide (ATO) has been shown to be the most effective, widely used drug so far in APL. This has been widely used as a single agent drug by intravenous infusion, in many Asian countries (Bassi and Rego, 2012; Zeidan and Gore, 2014; Zhou et al., 2007). This is a form of naturally occurring arsenic which has multiple mechanisms of action including inducing apoptosis by degrading the PML/RARA fusion protein (NICE guidelines). Unlike ATRA, ATO target the PML moiety in the fusion oncoprotein. ATO led to the sumoylation of PML at aminoacids K65, K160 and K490. The sumoylation at lysine 160 mediated by ATO result in recruitment of 11S proteasome, resulting ubiquitination. This process results in the degradation of fusion protein (Z. Y. Wang and Chen, 2008; Zeidan and Gore, 2014). The mechanism of action of ATRA and ATO in APL are schematically shown in Fig:*****. In some patients, ATO treatments are associated with serious side effects such as electrolyte abnormalities and QT prolongation, which can be fatal (Sanz et al., 2009).
· Combination therapy
Clinical trials combining anthracycline-containing chemotherapy (idarubicin) with ATRA showed complete remission (CR) in 90-95% of patients with a disease-free survival up to 5 years in 50-75% of cases (Zhou et al., 2007; NICE, 2017). There was little difference observed in the combination of ATRA with daunorubicin against ATRA with cytarabine and daunorubicin (A.K Burnett et al., 2007). Recent studies show treatment with ATRA with traditional chemotherapy including anthracyclines alone excluding cytarabine results in effective treatment of APL (A. K. Burnett et al., 2015). Another study shows cytosine-arabinoside (Ara-C) in combination with ATRA and anthracycline improves the prognosis in high risk APL (Lengfelder et al., 2013). Several multicentre studies including clinical trials conducted by MRC (UK), PETHEMA (Spain), US intergroup (USA), MD Anderson Cancer centre (MDACC) and JALSG (Japan) summarised the findings as:
o ATRA along with chemotherapy is superior to ATRA alone in antileukaemic effect and better control of ATRA syndrome
o Exclusion of cytarabine from APL therapy is of low significance
o ATRA has a significant role in maintenance therapy
o Novel agents such as ATO, callicheamicin anti-CD33, anti-CD44 are promising in light of non cross-resistance with retinoids.
o Significance of high WBC as a prognostic factor in APL (Mandelli et al., 2002)
Allogeneic and autologous stem cell transplant is the last option in APL patients who fail to achieve second molecular remission (MR) after ATO and ATRA treatment. The overall survival (OS) rate of 75% of patients who had PCR negative autologous HSCT, while it reduced to 52% in allogeneic HSCT (de Botton et al., 2005). The reduced OS in allogeneic HSCT may be due to the higher treatment related mortality (Baljevic et al., 2011(Baljevic et al., 2011).
Measures to minimise haemorrhage:
· Initiate ATRA at 45mg/m2 per day in divided doses immediately at suspicion of APL
· Maintain a platelet count of ?50 x 109/L by platelet transfusion
· Maintain a fibrinogen level >150mg/dL by cryoprecipitate transfusion or fibrinogen concentrate
· If PT or APTT is elevated, consider FFP transfusion (Abedin and Altman, 2016) (NCCN guidelines)
Disease staging and Treatment strategies
The European Leukaemianet guidelines classified APL patients into three groups based on the WBC count before induction therapy as low risk of relapse (WBC=40 x 109/L), intermediate risk of relapse (WBC=10 x 109/L, Platelet =