Sequential Treatment of Arsenic Trioxide Followed by All Trans Retinoic Acid with Anthracyclines has Excellent Long-Term Cure in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a unique subset of acute myeloid leukemia (AML) whose pathogenesis revolves around a translocation involving the retinoic acid receptor (RAR) locus on chromosome 17, most commonly the t (15; 17) (q22; q11), giving rise to the PML–RARα fusion gene that encodes an oncoprotein. This oncoprotein disrupts the physiological interaction of the retinoic acid with RARα causing the latter to be converted to a transcription activator. This leads to maturation arrest at the promyelocytic stage which in turn ends in the manifestation of the disease characterized by myeloproliferation and bleeding diathesis [1]. While it is well known that APL is exquisitely sensitive to chemotherapy, the catastrophic intrinsic bleeding manifestation further aggravated by chemotherapy has resulted in significant early mortality with the use of chemotherapy alone. The use of ATRA was a paradigm shift in the management of APL and the molecule induced leukemic cell differentiation leading to remission of the disease with decline in early treatment related mortality. Its single agent use however did not yield as good durable remissions. The combination of ATRA with chemotherapy subsequently became the standard of treatment with excellent long-term outcomes. However, early death still was a problem [2]. Arsenic trioxide (ATO) is a very potent agent for use in APL and is capable of inducing and maintaining long term remissions when used as a single agent especially in low risk disease [3]. More recently the combination of ATRA with ATO has shown that comparable results can be achieved in patient with low and intermediate risk group as defined by the Sanz criteria. Therefore, many investigators believe that chemotherapy need not be used in therapy of APL [4, 5]. However, our premise was that the best therapeutic agents have to be utilized in the frontline setting itself to optimize outcomes while reducing early mortality. Since only ATO when used alone as induction without chemotherapy may reduce early mortality, we embarked on a strategy to use of all three active agents in a sequential manner wherein ATO was used as an agent to induce remissions initially followed by standard ATRA with chemotherapy in consolidation with a primary objective to reduce mortality while optimizing outcomes. The long-term outcomes of this strategy are presented and discussed in this report.

A total of 131 consecutive patients registered at our centre between January 2009 to December 2012 were included in the analysis. The outcomes are summarized in the consort diagram (Fig. 1). The median age at diagnosis was 30 years (range 14–67 years). Median time from initial diagnosis of APL and evaluation at our center was 3 days (range 0–63 days). About 70% of patients had bleeding manifestations from various sites with 3 patients presenting with CNS bleed, 82% of patients had fever at presentation.

The baseline characteristics were as described in Table 1.

Acute promyelocytic leukemia (APL) has emerged from a disease with high early mortality to being the most curable form of leukemia with the incorporation of differentiating agents to chemotherapeutic strategies. This has also been made feasible through a clear understanding of the biology of the disease and how targets when perturbed effectively translate into curative outcomes. The treatment of APL over the past 2 decades has evolved from the use of chemotherapy alone to use of differentiating agent with chemotherapy, starting with ATRA and thereafter Arsenic to using combination of differentiating agents with chemotherapy and more recently without for the low and intermediate risk APL. The former strategy remained a standard yielding remission rates of 95% and cure exceeding 80% in various studies [6‐10]. The demonstration of activity of ATO in relapsed APL and its ability to induce durable remissions in newly diagnosed APL as single agent, particularly in low risk challenged this dogma [3, 4]. The combination of ATRA and ATO in newly diagnosed APL has since demonstrated superior responses (97% EFS at 2 years as compared with 86% in the ATRA plus chemotherapy arm) and the ability to sustain remission in the low and intermediate risk group APL [5].

The difficult problem that is confronted when treating newly diagnosed APL is early mortality encountered due to bleeding diathesis, infection and chemotherapy induced toxicity. Outside of clinical trials the SEER data and Swedish data revealed an early mortality rate of 17.3% and 26% respectively with patients older than 55 years having a higher early mortality [11, 12]. While reports from Asia have shown early death rates of as high as 42%, published data from India put early mortality at 24.3% [13, 14]. More recently data from Brazil showed early mortality of 20% from a single institution study [15]. Data from use of ATO as a single agent in newly diagnosed APL showed a significantly lower early mortality rate of 9.2% [3, 16]. The need to decrease early mortality in our patient diagnosed with APL among all risk groups was the rationale behind implementation of the use of ATO as single agent for treatment of all newly diagnosed APL. The regimen was well tolerated with no increased toxicity relating to ATO in the form of QTc prolongation (20%), transaminitis (3/118 patients) or differentiation syndrome (2.7%). This was much lesser than documented in published studies. This strategy also achieved its primary objective of decreasing early mortality to 12.1% which was still lower at 9.1% when considering only the patients who were initiated and received induction therapy.

The rationale for embarking on use of ATO as primary therapy irrespective of risk group was based on data that single agent ATO is efficacious in maintaining long term remission status in low risk patient. Besides, as a single agent, it maintained activity in the intermediate and high-risk patient with APL [3]. However, this strategy was also tempered with the knowledge that the intermediate and high-risk APL are more likely to relapse without some form of consolidation in addition to ATO alone. Therefore, we used a treatment strategy with ATRA and chemotherapy as a sequential consolidation phase, an approach never considered in other studies and defined by our group as a sequential therapy. This sequential therapy was not only well tolerated but also administered as an outpatient with minimal toxicity encountered. The strategy was successfully implemented in practically all patients who received the planned therapy. All patients were alive after they completed sequential therapy with only 8 relapses occurring on follow up subsequently. There was no cardiac toxicity documented in any of our patients during or after therapy or on follow up and was irrespective of the dose of anthracyclines (60 mg/m² or 45 mg/m²) used. There was no evident compromise in the outcomes either.

The cytogenetic and molecular remission rates (in those analyzed) following induction was 78.7% and 65% respectively indicating the profound single agent activity of ATO in frontline setting. The molecular remission further improved to 84% following consolidation phase. Except for one patient all achieved cytogenetic remission following consolidation documented by fluorescent in situ hybridization. All but three patients received maintenance therapy with ATRA. Patient who did not attain a molecular remission was further consolidated with high dose cytarabine.

The cohort of patient in this study had 48% having high-risk features prone for early mortality and relapse. At a median follow up of 60 months 84% were alive with an EFS of 77.8%. Outside of a clinical trial these outcomes are comparable or even better than those available from population-based data wherein long-term outcomes was only 61% and as low as 59% with a similar duration of follow up in all comers [12, 15]. If one-compared outcomes for patient in the low risk and intermediate/high risk group the EFS was 85% and 76% with overall survival of 100% and 82% respectively. This was again comparable to published studies outside the purview of clinical trial [17].

The outcomes for use of ATRA and ATO in combination, for low and intermediate risk APL, has shown superiority to standard ATRA plus Chemotherapy alone [5]. Therefore, it may be argued that use of this sequential strategy for treating these groups would be an unnecessary overtreatment and hence we have switched over to single agent ATO as described by Lococo et al. in low and intermediate risk APL [5]. However, the long-term data of excellent cure especially in the high-risk group gives credence to this strategy. The relative shorter duration (18 weeks) of implementation as against the 10 months required for the chemotherapy free protocol makes this an effective alternate to patients with all risk group APL especially when follow up can be a challenge in developing countries [18].The maintenance strategy with single agent ATRA was well tolerated and gave the treating team an opportunity to ensure follow-up and compliance. The effectiveness in achieving early cytogenetic and molecular responses which are durable and translates into cure also gives credibility to this approach. The sequential approach for high risk APL could be a recommendation given our long-term data of 6 years post therapy demonstrating lower early mortality with high cures.

To conclude the sequential approach to treating APL stemmed from a need for early control while decreasing mortality which was achieved. The data provides substance for this approach to achieve early responses which also translated into durable remission and cure. The impact on intermediate and high-risk disease would suggest that this strategy may be implemented with conviction as a short-term treatment with low toxicity, low mortality and high cure especially when compliance to long duration treatment may pose a challenge in developing countries.