Arsenic Trioxide-Based Therapy Of Relapsed Acute Promyelocytic Leukemia: Updated Results Of The European Registry Of Relapsed APL (PROMYSE)
Authors: Lengfelder Eva , Lo-Coco Francesco , Ades Lionel , Montesinos Pau , Grimwade David , Kishore Bhuvan , Ramadan Safaa , Pagoni Maria , Breccia Massimo , Rivas Concha , Gonzáles-Sanmiguel José , Schmidt Anne , Lambert Jean-Francois , Hofmann Wolf-Karsten , Sauerland Maria Cristina , Fenaux Pierre , Sanz Miguel 
Published: October 2019

Abstract

Background
Arsenic trioxide (ATO) is regarded as the treatment of choice for relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). In 2008, a European online registry of rAPL based on uniform CRFs was established under the auspices of the European LeukemiaNet (ELN) to gain insights in the clinical and biological characteristics of rAPL treated with ATO and to allow an assessment of the different options for postconsolidation therapy.

Methods
Eligibility criteria for prospective or retrospective registration were PML-RARA+ 1st or successive molecular or clinical relapse of APL from the year 2003 onwards. The treatment should be based on the European recommendations for treatment of rAPL (www.leukemia-net.org/content/), which offer induction and consolidation therapy with ATO and several options for post-consolidation therapy including autologous or allogeneic stem cell transplantation or chemotherapy consolidation followed by various modifications of maintenance therapy ± ATO - to be selected depending on several variables including patient age, performance status, PCR status after consolidation, type of frontline therapy, first CR duration and donor availability.

Results
By 30 June 2013, of 220 registered cases, 198 were evaluable (172 in 1st, 26 in ≥2nd relapse). Of these, 149 patients (pts) in 1st relapse received ATO-based salvage therapy after standard frontline therapy based on all-trans retinoic acid (ATRA) and anthracyclines (98 hematological (hematol) relapses of bone marrow combined with CNS relapse in 5 pts, 40 molecular (mol), 11 isolated extramedullary, mainly CNS). Clinical characteristics: median age at relapse 44 years (y) (4 to 81), 67% males, Sanz Risk Score at 1st diagnosis: low 23%, intermediate 48% and high 29% of pts. Median duration of first remission was 565 d (105 d to 7.0 y). The median treatment duration of ATO (0,15 mg/kg/day) plus ATRA (44% of pts) for remission induction (ind) was 30 days (d) and for consolidation (cons) 25 d. CNS relapses received ATO and additional intrathecal chemotherapy ± irradiation.

WBC
white blood cell count; Leuko.: leukocytosis requiring hydroxyurea; ADS: APL differentiation syndrome; 1 median; 2 hematological; 3 RT-PCR of PML-RARA negative.
In non-hematological relapses, no early deaths occurred and no major side effects of ATO were seen. Median follow up of the 149 pts was 2.8 y (6 d to 10 y). Three-year overall survival (OS) was 70%, 95%CI [61;79] and 6-year OS 56% [42;70]. Three-year OS of hematological, molecular and extramedullary relapse was 69% [58;80], 66% [48;84] and 90% [81;99], respectively (p=0.2). Concerning outcome after transplantation, 3-year OS after autologous was 82% [70;94] (n=55), after allogeneic 75% [58;92] (n=32) and without transplantation 66% [48;84] (n=55) (p=0.4).

Conclusions
With ATO-based salvage therapy over 50% of patients in 1st relapse of APL can probably be cured. Pts in molecular relapse have a lower rate of early complications and death. Long-term survival is possible with transplantation-free approaches, but transplantation seems to improve the outcome.

Disclosures:
Lengfelder: TEVA/ Cephalon: Research Funding. Lo-Coco:TEVA: Speakers Bureau.