Management of Relapse in Acute Promyelocytic Leukemia Treated with Upfront Arsenic Trioxide Based Regimens
Authors: N. Fouzia , Sharma Vibhor , Korula Anu , Devasia Anup Joseph , Kulkarni Uday Prakash , Samoon Yasir Jeelani , Mani Thenmozhi , Lakshmanan Jeyaseelan , Srivastava Alok , Abraham Aby , Balasubramanian Poonkuzhali , George Biju , Mathews Vikram 
Published: October 2019

Abstract
The standard of care for patients with acute promyelocytic leukemia (APL) relapsing after frontline treatment with arsenic trioxide (ATO) based regimens remains to be defined. Available data on response and survival outcomes in patients who had received ATO as part of upfront therapy suggests that there is a high incidence of resistance to ATO and ATRA resulting in inferior response and survival (Zhu HH et al. N Engl J Med. 2014). We present our experience on management of relapse in APL patients treated with frontline ATO based therapy.
Data on all consecutive patients with relapsed APL diagnosed and treated in the Depatment of Haematology, Christian Medical College, Vellore, from January, 1998-December, 2015 were included in this retrospective analysis.
One hundred and four (29%) out of the total 358 APL patients diagnosed during the study period had relapsed. Out of these 73 (70%) patients received upfront ATO based therapy. Six out of 73 refused treatment and got discharged at request following the diagnosis of relapse, the remaining 67 (91.8%) were included in the analysis. Median age of patients was 28 years (range: 4-54), 44 (65.7%) were males. Median time to relapse from initial diagnosis was 19.6 months (range: 6 - 128). Relapses were isolated molecular in one, isolated CNS in 6 [9%], bone marrow + CNS in 13 [19.4%] and medullary only in 47 [70.1%] patients. All 67 patients received ATO based therapy (ATO ± ATRA +/- Anthracycline/Bortezomib) as re-induction. 63/67 (94%) achieved molecular remission post re-induction, while 3 (4.5%) died during re-induction and one discontinued treatment. An autologous SCT was offered to all patients who achieved molecular remission, however only a proportion of cases opted for SCT due to financial constraints. Those that did not opt for an autologous SCT were given ATO+ATRA maintenance therapy. 35/63 (55.6%) opted for autologous SCT while 28 (44.4%) continued on maintenance therapy alone. Median time to autologous SCT from relapse was 5.8 months (range: 2 - 32). There were no treatment related deaths following autologous SCT. At a median follow up of 46 months (range: 1-224), the 5 year estimate of OS and EFS (Fig 1) of the whole cohort (n=67) was 73.6% ± 5.7% and 67% ± 6.1%. The 5 year estimate of OS and EFS (Fig 2) of those who received autologous SCT vs those who were on chemotherapy were 90.3% ±5.3 vs 58.6±10.4 %, (P=0.004) and 87.1% ±6.0% vs. 47.7% ±10.3%, (P=0.001) respectively. In unadjusted analysis, those who received chemotherapy as post relapse consolidation had 5.73 (95%CI: 1.86 - 17.65) times risk of relapse as compared to those who received autologous SCT, which was statically significant (P=0.002). In the adjusted analysis (Table 1) those who received chemotherapy the risk of relapse was 7.6 (95%CI: 1.98 - 28.87) times compared to those who received autologous SCT, which was statically significant (P=0.003) after adjusting for age, total WBC at relapse and duration of CR1.
Remission induction with ATO based regimens followed by an autologous SCT in patients with relapsed APL who were treated with frontline ATO based regimens is associated with excellent long term survival and should be considered the standard of care even in this setting.

Disclosures
No relevant conflicts of interest to declare.