Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia

Front-line treatment combining All-trans retinoic acid (ATRA) and chemotherapy is curative in approximately 80% of patients with acute promyelocytic leukemia (APL). As for patients who relapse after this approach, current guidelines recommend the administration of arsenic trioxide (ATO) with or without ATRA.1,2 Given its high efficacy in inducing durable molecular remission (CRm), ATO is considered the most active single agent in APL and is currently also being investigated in various combinations as front-line therapy. While the role of ATO in remission re-induction is well established, the best consolidation strategy to be used in relapsed APL still remains controversial. In fact, because of the few patient numbers involved, no randomized studies are available which offer concrete support for given consolidation (allo-HSCT, auto-SCT, further ATO or chemotherapy). In spite of this, most investigators would nowadays recommend proceeding to HSCT after re-induction of CR.1,2 However, the effect of prolonged ATO administration beyond consolidation, particularly for patients unfit to receive HSCT or as an alternative to the latter for patients with better prognosis (e.g. long duration of first CR) has not been widely investigated. We report here on the outcome of 9 patients with relapsed APL who received prolonged therapy with an ATO plus ATRA combination.3 Nine patients with relapsed APL were treated with prolonged ATRA and ATO at the Department of Cellular Biotechnologies and Hematology of the University La Sapienza (6 cases) and at the Department of Biopathology of the University Tor Vergata (3 cases) in Rome. The main clinico-biological features and treatment outcomes of the 9 patients are shown in Table 1. Two patients (UPN 5 and UPN 6) have been reported previously.4,5 At time of ATO/ATRA initiation, 7 patients were in first molecular relapse whereas UPN 8 and 9 were in second hematologic and second molecular relapse, respectively. The median time of molecular or hematologic first CR duration was 1.9 years (range 1–7). All patients received ATO/ATRA according to the schedule reported by Estey et al.3 for a total of 5 ATO and 8 ATRA courses given at monthly and bi-weekly intervals, respectively. Patients in this series were kept on this prolonged therapy and not offered an HSCT option because of long first CR duration (3 cases), HSCT refusal (3 cases), age (3 cases). Complete molecular response as assessed by nested Rt-PCR of PML/RARA was achieved in all patients after one (n=2) or 2 cycles (n=7). Two patients experienced mild toxicity during reinduction therapy consisting of transient QTc prolongation and grade 2 neutropenia, respectively, requiring temporary discontinuation of ATO. Another patient treated for molecular relapse experienced electrolyte abnormalities with no QTc prolongation which was corrected by electrolyte replacement and did not require discontinuaton of the drug. Only 2 patients required hospitalization one for treatment of hematologic relapse (for a total of 30 days), while all the others were treated as outpatients during induction, consolidation and maintenance treatment. Of the 9 patients, 8 remained in prolonged second CRm for a median time of 25 months (range 11–50) and one (UPN 1) underwent second molecular relapse during PCR monitoring at ten months after initiation of ATO-based salvage therapy (Table 1). The latter patient received allogeneic HSCT and is currently in third CR. Though limited to a small number of patients, our observation suggests that prolonged ATO/ATRA without HSCT represents a valid and potentially curative therapeutic option for relapsed APL. Based on the characteristics of our series, this assumption might particularly apply to patients who are treated with this regimen for late relapse. This parameter, together with patient decision to refuse HSCT and advanced age in some cases, was the criterion for assessing the efficacy of the prolonged ATO/ATRA combination in relapsed APL. The French group reported a randomized study on 20 relapsed APL patients who received ATO alone or in combination with ATRA, showing that 80% of patients achieved hematologic CR after one cycle.6 On the other hand, a recent update of the Estey study3 which first reported this regimen in newly diagnosed patients, demonstrated considerable efficacy with excellent outcome in particular for non-high risk APL.7 As an additional cautionary criterion, all patients in the present series were closely monitored by Rt-PCR in order to allow pre-emptive therapeutic intervention and the use of HSCT in case of a further molecular relapse. Of note, previously reported UPN 6 delivered a healthy baby after ATO/ATRA salvage,5 and her second CR currently already exceeds the duration of first CR induced by ATRA and chemotherapy. Our results are comparable to those obtained in a recently reported series of 13 patients who received autologous HSCT in second molecular CR. In that study, relapses were hematologic in 12 cases and molecular in one case. All patients were treated with chemotherapy and after consolidation all achieved CRm: 10 of 13 patients (77%) were alive and well after a median follow up of 25 months from second CR8. We report here similar results with an ATO-based salvage therapy, with 88% of patients remaining in prolonged CRm without transplant procedures. Further studies in larger series are warranted to better establish whether autologous and allogeneic HSCT might be avoided in patients with late relapse APL receiving a prolonged ATO plus ATRA therapy.

Table 1.Clinical and biological features of patients treated with ATO+ATRA for relapsed APL.

Footnotes

• The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.
• Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.