Central Nervous System (CNS) at First Relapse In APL. A Report on 2 Multicenter Trials.
Authors: Ferini Gonzalo Ariel , Raffoux Emmanuel , Guerci Agnès , Pigneux Arnaud , Huguet Françoise , Vey Norbert , Lamy Thierry , Muller Beatrice , Chevallier Patrice , Castaigne Sylvie , Turlure Pascal , Ferrant Augustin , Ifrah Norbert , de Botton Stephane , Dombret Hervé , Ades Lionel , Fenaux Pierre 
Published: October 2019

Abstract
Abstract 1084

Background:
CNS relapse is rare in APL, and predominates in patients (pts) with increased WBC counts. (De Botton, Leukemia, 2006,20,35; Montesinos, Haematologica,2009,94,1242). We report the incidence, risk factors and outcome of CNS relapse in 2 multicenter clinical trials of the European APL group.

Methods:
Between 1993 and Feb 2004 (when randomization for AraC in APL 2000 trial ended), 916 APL patients (pts) were included in APL93 (n=576) and APL 2000 (n=340) trials, and 92.2% of them achieved CR (Ades L, Blood 2010, Ades L, JCO 2006). In both trials, induction treatment consisted of ATRA (45 mg/m2/d until CR) and DNR 60mg/m2/d x3 + AraC 200 mg/m2/dx7 followed by a first similar consolidation course and a second course with DNR 45 mg/m2/d x3 and AraC 1g/m2/12hx8 (except in one arm of APL 2000 trial where pts with WBC<10G/L received no AraC for induction and consolidation). A 2 year maintenance treatment, consisting of intermittent ATRA (15d/3 months) and continuous 6MP+ MTX, was administered or not (randomized) in APL 93 trial, and was systematic in APL 2000 trial. In APL 2000 trial, intrathecal CNS prophylaxis with MTX+ AraC (5 injections) was made during consolidation cycles in all pts with baseline WBC > 10G/L. Median follow up was 10 and 5 years, respectively, in APL 93 and APL 2000 trial.

Results:
6 first relapses involving the CNS were seen (3 in APL 93 and 3 in APL 2000 trial), after 6 to 37 months (median 15 months), representing 3% of the relapses (2% and 6% in APL 93 and 2000, respectively) and 0.7% of the pts who had achieved CR (0.56% and 0.9% in APL 93 and 2000, resp). Of the 6 CNS relapses, 1 was isolated and 5 accompanied by relapse in the bone marrow (haematological in 4 cases, and only molecular in 1 case). Median age was similar (46y) in pts who had or not CNS relapse. Median WBC count was 7.9 G/l in pts with CNS relapse vs 2.5G/l in pts without CNS relapse (p=0.07). 5 of the 6 pts with CNS relapses had WBC> 5G/L, but only 2 had WBC > 10G/l. Among pts who achieved CR, 3 of the 146 (2.05%) pts who received no Ara C had CNS relapse versus 3 of the 699.
(0.4%) pts who received AraC (with HD araC in the last consolidation course) (p= 0.06). In pts with WBC > 10G/l, none of 72pts in APL 2000 (who received both HD araC and intrathecal CNS prophylaxis) had CNS relapse, compared 2 of the the 123 (1.6%) pts in APL 93 trial (who received HD araC and no intrathecal CNS prophylaxis). The 6 pts with CNS relapse were all salvaged by intrathecal CT, combined to ATRA and systemic CT in APL 93, and ATO in APL 2000 trial.
4 of them were durably salvaged, 3 after auto SCT and 1 after ATO and CT.

Conclusion:
CNS relapse was very rare in APL in our experience, and only 2 of 6 pts with CNS relapse had baseline WBC > 10G/l. CNS relapse was generally associated to concomitant marrow relapse (sometimes only molecular), and was seen in 0.4% and 2.05% pts treated with and without HD AraC, respectively (p=0.06), suggesting a possible preventive role of HD AraC, although numbers were small to conclude. Interestingly, by comparison, in the Spanish PETHEMA experience where pts received no AraC, 1.6% of the 667 pts who achieved CR had CNS relapse (Montesinos, Haematologica, 2009, 94, 1242). On the other hand, the role of intrathecal CNS prophylaxis was unclear in our experience. Finally, outcome of CNS relapses was better than in our previous report (De Botton, Leukemia, 2006,20,35), possibly due in part to the recent treatment of relapses by ATO, known to penetrate the blood brain barrier (Au et al, Blood, 2008,3587) and which could also play a role in CNS prophylaxis when administered during first line treatment.

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