Treatment of Molecular and Clinical Relapse of Acute Promyelocytic Leukemia (APL) with Arsenic Trioxide: Results of the European Registry of Relapsed APL
Authors: Lengfelder Eva , Lo-Coco Francesco , Montesinos Pau , Grimwade David , Ades Lionel , Kishore Bhuvan , Pagoni Maria , Ramadan Safaa M. , Breccia Massimo , Holowiecka Alexandra , Pradel Anne , Sauerland Maria Cristina , Fenaux Pierre , Sanz Miguel Angel 
Published: October 2019

Abstract
Abstract 15
Arsenic trioxide (ATO) is presently regarded as the best treatment option in relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). However, given the relative rarity of relapses following standard front-line APL therapy, the optimal management of this group of patients remains to be firmly established. For this reason, and in order to ensure homogeneity in patient data collection and gain insights into the epidemiology and clinical aspects of rAPL, a European registry of rAPL was established in 2008 under the auspices of the European LeukemiaNet (ELN). Patients with a genetically confirmed (PML-RARA+) molecular or clinical relapse of APL occurring from January 2003 onwards were eligible for registration using uniform CRFs. Management of relapse was at the discretion of the treating physician, but could be based on the treatment recommendations developed by an expert panel provided on the ELN website (www.leukemia-net.org/content/). By 15 July 2010, 122 cases of rAPL had been registered by participants of 7 European countries (Spain, Italy, UK, France, Germany, Greece, Poland) representing the starting group of this ongoing initiative open for participation. In 80 pts (69 in first, 11 in 2nd and later relapse), information was available on ATO salvage therapy. At time of first diagnosis median age was 43 years (14-77); all pts had received all-trans retinoic acid (ATRA) and anthracyclines ± ara-C as first-line therapy. No patients received ATO as part of front-line therapy. According to Sanz Score, 26% were low risk, 45% intermediate and 29% high risk. 39% of pts had the bcr1/2 and 61% the bcr3 isoform of PML-RARA. Median duration of first remission was 493 days (93d to 5.7 years). The usual dosage of ATO was 0,15mg/kg/day, or regimens with the same cumulative dose were used. ATO induction therapy was combined with ATRA (45 mg/m2/day) in 40% of pts and during the consolidation cycle in 50% of pts, respectively. The median duration of ATO (± ATRA) for induction was 30 days and for consolidation 25 days. CNS relapses were treated with intrathecal application of methotrexate ± ara-C ± hydrocortisone and ATO. Among the 69 pts with first relapse, there were (Group A) 25 molecular and (Group B) 42 hematological relapses (bone marrow), in three pts combined with CNS involvement. Two pts had isolated CNS or extramedullary relapse. Main characteristics of pts at start of induction therapy in Group A vs. B were: median WBC count (x109/L) 4.4 (1.9-6.2) vs. 2.3 (0.5-102) (p=0.015); median platelet count (x109/L) 178 (40-392) vs. 87 (9-273) (p=0.0007); median Hb (g/L) 14 (10.6-15.7) vs. 12 (7.6-14.8) (p=0.0008). In Group A, none of the pts had coagulopathy compared to 8 of 25 (32%) pts with coagulopathy in Group B (p=0.004). In Group A, ATO therapy was not complicated by hyperleukocytosis and no episodes of differentiation syndrome were observed. In Group B, 9 (21%) pts had suspected or manifest differentiation syndrome (p=0.02), and additional chemotherapy was administered in 14 (33%) pts to control hyperleukocytosis. Other toxicities were rare and had no significant influence on therapy. In Group A, the rate of 2nd molecular remission after induction was 52% (13 of 25 pts) and after consolidation therapy 64%. No pt died. In Group B, 39 (88%) pts achieved 2nd CR, 2 (5%) pts were resistant and 3 (7%) pts died early from cerebral bleeding. Second molecular remission was reached in 12 of 32 (38%) pts after induction and in 62% after consolidation. Information on postconsolidation therapy was available in 45 pts of Group A and B. Of these, 14 pts underwent allogeneic, 18 pts autologous transplantation and 13 pts further therapy with ATO ± gemtuzumab ozogamicin. 11 of the 45 (24%) pts relapsed (median 2nd remission duration 10 months, 4 to 26), and 9 deaths were reported between 9 and 14 months after the end of consolidation therapy. In pts with 2nd and later relapse, despite previous exposure to ATO, further responses with this agent were observed.

Conclusions:
ATO is an effective therapy for all stages of relapsed APL. The results argue in favor of serial PML-RARA monitoring in front-line therapy of APL to allow early treatment of emergent relapses, avoiding hyperleukocytosis and risk of death due to bleeding and differentiation syndrome. Furthermore, the favorable toxicity profile of ATO seems to benefit the feasibility of subsequent transplantation.

Disclosures:
Lengfelder: Cephalon: Research Funding. Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.