Outcome of Acute Promyelocytic Leukemia (APL) with Very High WBC Counts Treated with ATRA and Chemotherapy (CT): The European Group Experience.
Authors: Kelaidi C. , Chevret S. , de Botton S. , Raffoux E. , Guerci A. , Thomas X. , Gardin C. , Pigneux A. , Stoppa A. , Lamy T. , Rigal-Huguet F. , Vekhoff A. , Meyer-Monard S. , Chelo R. , Pabst T. , Chevalier P. , Maloisel F. , Deconinck E. , Ferrant A. , Bron D. , Fegueux N. , de la Serna J. , Martin G. , Cahn J. , Ifrah N. , Cassinat B. , Dombret H. , Sanz M.A. , Fenaux Pierre , Ades L. 
Published: April 2020

Abstract
Background: APL is predominantly associated with low WBC counts. APL with very high WBC counts, i.e. &gt;50 × 109/l, is rare, generally associated with severe coagulopathy and, before the ATRA era, was generally fatal due to early death or subsequent relapse.
Methods: we report characteristics and outcome of APL with WBC &gt;50 × 109/l enrolled in two consecutive multicenter trials (APL93 and APL2000) treated with ATRA-CT combinations. In both trials (Blood1999;94:1192, JCO2006;24:5703) pts with WBC &gt;10×109/L received ATRA combined upfront to DNR+AraC followed by 2 consolidation DNR+AraC courses and, in APL93 trial, randomisation for maintenance to intermittent ATRA, continuous low dose CT (6MP+MTX), both treatments (ATRA+CT) or no treatment. In APL2000, they all received maintenance with ATRA +CT, high dose DXM during induction (to further prevent ATRA Sd), and CNS prophylaxis.
Results: Of the 1031 pts included in both trials, 261 (25%), 65 (6.4%) and 14 (1.3%) pts had WBC &gt;10×109/l, 50×109/l and 100×109/l, respectively (resp). As compared to pts with&lt;10×109/l and 10–50×109/l, pts with WBC &gt;50×109/l were younger (48 vs. 44 vs. 40.5 years, p=0.002), had lower baseline plt counts (36 vs. 24.5 vs. 27×109/L, p=0.0002) fibrinogen level (1.8 vs. 1.3 vs. 1.2 g/L, p&lt;0.0001) more often M3 variant (6.7 vs. 27.7 vs. 58.8%, p&lt;0.0001) and BCR3 breakpoint (27.8 vs. 39 vs. 56.4%, p&lt;0.0001) whereas CR rates were 94%, 91% and 87%, resp (p=0.054). All failures were due to early death (ED). 8 (13%) ED occurred in pts with WBC&gt;50×109/L, 6 of them due to ATRA Sd and 1 to bleeding. In pts with WBC &gt; 50×109/l, ED was 6/33 (18%) in APL93 and only 2/32 (6%) in APL 2000 trial (p= 0.25). Thus in APL 2000 trial, the CR rate increased to 94% in pts with WBC&gt;50×109/l (vs. 95% in other pts). 2 year incidence of relapse (CIR), EFS and overall survival (OS) were 31.3%, 17.3%, 8.7% (p&lt;0001), 55.4%, 73%, 82% (p&lt;0.0001) and 62%, 83%, 82% (p=0.0002) in pts with WBC &gt;50, 10–50, &lt;10×109/l, resp. However, in pts with WBC&gt; 50×109/l, only 6/38 (15.7%) of those who received combined maintenance (ATRA + CT) relapsed, vs. 12/16 (75%) of those with no or single maintenance (p&lt;0.001). Therefore in pts who received combined maintenance, there was only a trend for higher 2 year CIR in pts with WBC&gt; 50×109/l: 15.7% (vs. 6.4% and 11% in pts with WBC&gt;10–50 and &lt;10×109/l resp, p=0.067) while 2 year OS did not differ between the 3 groups (87% vs. 91% vs. 89.6%, p=0.86). Post-consolidation PML-RARA RT-PCR, available in 33 WBC&gt;50×109/l pts, was positive in 5 (all relapsed), and negative in 28 (6 relapsed). The 19 relapses in pts with WBC&gt; 50×109/l occurred after a median of 11 months, and included 2 CNS relapses (both in APL93 trial). 16 of those pts achieved CR2, most before the arsenic era. 2 y-OS after relapse was 62%.
Conclusion: APL pts with WBC &gt;50×109/l are rare, may achieve CR rates similar to pts with lower WBC with improved supportive care (including systematic DXM?). They have only a trend for higher risk of relapse with combined ATRA+CT maintenance, and possibly CNS prophylaxis.