Late Relapses in APL Treated with ATRA and Anthracycline Based Chemotherapy: The European APL Group Experience (APL 91 and APL 93 Trials).
Authors: Kelaidi C. , Ades L. , Chevret S. , Sanz M. A. , Guerci A. , Thomas X. , de Botton S. , Raffoux E. , Rayon C. , de la Serna J. , Ferrant A. , Bron D. , Link H. , Fegueux N. , Bordessoule D. , Rigal-Huguet F. , Stoppa A.M. , Vekhoff A. , Meyer-Monard S. , Fey M. , Castaigne S. , Dombret H. , Degos L. , Fenaux P. 
Published: April 2020

The routine use of frontline ATRA and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. The incidence and characteristics of late relapses after this combined treatment, however, are not known.

Methods: Between 1991 and 1997 (APL 91 and 93 trials) 630 newly diagnosed APL pts received ATRA combined to or followed by DNR-AraC chemotherapy (total of 3 courses), with or without (randomisation) maintenance treatment by continuous 6MP + MTX and/or intermittent ATRA (Blood1993; 82:3241–3249, Blood1999; 94:1192–1200). 582 (92.5%) pts achieved CR. 154 (26.4 %) had a first relapse, after 5 to 120 months.

Results: 19 of the first relapses (i.e. 12.3% of the first relapses and 3.2% of pts who achieved CR) occurred more than 4 years after CR achievement (late relapses). Their median age was 45 (range 20–68), and M/F 7/12. Median time to relapse was 72 months (range 50–120). All late relapses involved the bone marrow only. t(15;17) and /or PML-RAR were seen in all cases at relapse. Pts were retreated with ATRA + anthracycline based chemotherapy (CT) (n = 14), ATRA alone (n =2), anthracycline based CT without ATRA (n=1), As2O3 (n =1), ATRA+ As2O3(n =1). 17 of them (89.4%) achieved CR2 and 2 had early death. CR2 pts were allografted (n = 3) autografted (n= 5), received consolidation and maintenance CT +/− ATRA (n = 7), and maintenance ATRA alone (n=2). 14 patients remained in CR2 after 5+ to 78+ months,2 (including 1 of the 2 pts salvaged and maintained with ATRA alone) relapsed after 9 and 22 months and died, and 1 patient developed secondary MDS and died. CR2 was already longer than CR1 in 5 cases. 3 year survival from relapse was 77% (median not reached). By comparison to patients who did not relapse and patients who relapsed &lt; 4 years, patients with late relapse were not different for age and initial platelets. They were more often females and had lower initial WBC counts than patients who relapsed &lt;4 years (M/F=0.54 vs. 2, p=0.01, and mean WBC 7000/mm3 vs. 18000/mm3, p&lt;0.05) but similar to patients who did not relapse (M/F= 0.86 and mean WBC=8100/mm3). Percentages of patients with late relapses having received maintenance treatments (known in APL 93 trial to have reduced the incidence of relapse) were intermediate between those with early relapses and those who did not relapse

Conclusion: late relapse was seen in about 3% of APL treated with ATRA and chemotherapy. Initial characteristics of those patients were rather those of “low risk” APL (especially with WBC&lt; 10000/mm3 and female predominance). Their prognosis was overall favourable, in spite of the fact that they generally occurred before As2O3 was available. Combined maintenance with low dose chemotherapy and ATRA during first line treatment may further reduce their incidence, as it does for earlier relapses.