Kinetics of Molecular Response among Newly Diagnosed Patients with PML-RARα+ Acute Promyelocytic Leukemia Treated with Arsenic Trioxide.
Authors: Chendamarai Ezhilarasi , Lakshmi Kavitha M. , Viswabandya Auro , Srivastava Alok , Chandy Mammen , Mathews Vikram 
Published: October 2019

Abstract
Arsenic trioxide (ATO) is an effective agent to induce molecular remission in patients with PML-RARα+ acute promelocytic leukemia (APL). ATO can induce molecular remission in majority of newly diagnosed and relapsed cases. However, there is limited data on the kinetics of this molecular response. From August 2006, fifteen consecutive newly diagnosed cases of APL treated with single agent ATO were serially monitored by real time PCR (RQ PCR) for PML-RARα expression. ATO was initially administered to induce remission for a maximum period of 60 days; this was followed by a 4 week interval and a consolidation course of ATO administered for 4 weeks. Subsequently after second 4 week interval, ATO was administered for 10 days / month for 6 months as a maintenance regimen. Peripheral blood RQ PCR was done at diagnosis, week 1, 2 and 4 and end of induction, onset of consolidation and at end of consolidation. RQ PCR was done using standard primers, probes, conditions and reagents as defined in the EAC program (Leukemia2003; 17: 2318–2357). Abelson (ABL) gene was used as a control gene for normalization. The normalized copy number (NCN) was defined as ratio of PML-RARα/ABL expressed as a percentage. The median age of the patients was 29 years (range: 10 – 60). There were 8 (53%) males and 7 females. 5 (33.3%) belonged to the low risk (WBC < 5 x 109/L and Platelet count >20 x 109/Lt) as defined previously by our group for this regimen. 9 (60%) had the bcr1 isoform and the rest (n=6) had the bcr3 isoform. At diagnosis the median copy number was 5.27% (range: 1.47 – 54). A pattern of increased NCN was noted in the first two weeks in 9 (60%) patients (0.5 – 1.5 log increase) (Illustrated in Figure 1). It is possible that this could be related to the differentiation activity of ATO and the resulting hyperleucocytosis. However, this did not statistically correlate with the WBC count at the same time periods. All patients achieved complete molecular remission. 5 (33.3%) had undetectable levels of PML-RARα by the end of induction, 8 (53%) achieved this by onset of consolidation while 2 (13%) achieved this at the end of consolidation. None of these patients relapsed or died during the follow up period. There did not appear to be any correlation with the pattern of RQ PCR response and age, sex, risk status at diagnosis, bcr isoform and genetic polymorphisms among panel of genes known to be important for ATO biotransformation (GST A1, GST P1, GST M1, GST T1, MTHFR C677T, MTHFR A1298C). In comparison to reported data (Chomienne et al. Leukemia2000; 14: 324–328) the kinetics and quality of molecular response following treatment with ATO is superior to that achieved with conventional ATRA based chemotherapy regimens. Kinetic data of molecular response in a large number of patients would help establish a molecular risk stratification strategy as early predictors of long term responses.
Serial RQ PCR n=15: Median ± SD Serial RQ PCR n=15: Median ± SD