Acute promyelocytic leukemia (APL) remains the most curable amongst myeloid leukemias though early morbidity and mortality remains an issue. The use of differentiating agents, All Trans Retinoic acid (ATRA) and Arsenic trioxide (ATO) with chemotherapy has been integral to decreasing morbidity and mortality while achieving high cure rates in APL. However, there is some uncertainty about the best combination, sequence and durationfor their use in order to achieve optimal response with minimum toxicity. The understanding that attaining complete cytogenetic and molecular response yields improved long term cures led us to investigate sequential use of ATO followed by ATRA and Daunorubicin in treating APL patients as frontline therapy in order to achieve such response.
Consecutive adult patients with APL irrespective of their Sanz risk group were treated using a protocol of ATO (10mg IV infusion over 3 hours daily for 45 days) in the first phase followed by ATRA (45mg/m2 for 60 days) in combination with Daunorubicin (60mg/m2 for 3 days × 3 cycles) in second phase. All patients received maintenance ATRA (45m/m2 for 15 days every 3 months) for a period of 18 months in phase 3. Patients were monitored for cytogenetic and molecular responses after phase 1 and 2. They were monitored for treatment related toxicity and were also followed up for survival post treatment.
Between January 2008 and February 2012, 106 patients with APL were treated with the sequential regimen. Median age was 30 years with a male to female ratio of 1.3:1. Only 16% were in Sanz class I risk while 39% and 45% were in class II and III, respectively. Cytogenetic remission was achieved in 71% (data available in 80/106 patients) while molecular remission was seen in 66.6% (data available in 40/106 patients) following phase 1. Molecular remission improved to 96% (data available 74/106) following phase II. Relapse was encountered in 8.4% while 11.3% died early, within 7 days of initiating therapy. One patient died due to unrelated cause during phase III. At a median follow up of 16.5 months, 86.2% are alive with an overall relapse free survival (RFS) of 72%. Class I and class II patients fared better (73% and 77% respectively) versus class III patients who had a 63% RFS. Median survival was not reached at the time of analysis. The regimen was well tolerated with differentiation syndrome occurring in 18% of treated patients and transient QT prolongation occurring in 20%. Only 5% of patients developed peripheral neuropathy (gradeII).
Our data involving use of all active agents in APL in a sequential schedule has resulted in significant early cytogenetic and molecular response. The strategy has so far translated into an excellent relapse free survival. Further follow up with molecular monitoring is required to derive conclusions pertaining to late relapses. Early deaths due to disease related complication continue to be a problem. The need to intensify therapy based on early responses (remission versus persistence at the molecular level) needs to be explored. The sequential schedule has shown excellent tolerance and toxicity profile, thereby decreasing morbidity particularly in early phase of treatment of APL.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.