Prognostic Impact of the Genetic Risk at Baseline Associated to the MRD Clearance in Adult Patients with Newly Diagnosed Acute Lymphoblastic Leukemia. Preliminary Results of Pethema LAL19 Trial
Authors: Torrent Anna , Morgades Mireia , Soriano Beatriz , Ribera Jordi , Barrera Susana , Montesinos Pau , Genescà Eulàlia , González-Campos José , Barba Pere , Esteve Jordi , Sitges Marta , Queipo De Llano Maria Paz , Botella Carmen , Maluquer Artigal Clara , García-Cadenas Irene , Calabuig Marisa , Hernández Sánchez Alberto , Torres Laura , Granada Isabel , Hernandez Rivas Jesus Maria , Orfao Alberto , Ribera Josep-Maria 
Published: December 2024

Introduction. Young and middle-aged adults with ALL (18-60 years) who receive a pediatric-inspired chemotherapy (CHT) regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they had a negative MRD after induction therapy. It is not clear if the genetic risk at baseline associated with this MRD approach, would allow identifying with more accuracy those patients who will receive CHT or alloHSCT. The aim of the prospective LAL19 trial from the Spanish PETHEMA Group was to evaluate the outcomes of pts assigned to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction -week 5- and consolidation therapy -week 17-) and genetic features at diagnosis.

Patients and methods. Pts with HR genetic features and/or those without good MRD response (MRD≥0.01% at end of induction-1 (ind-1) and ≥0.001% at end of consolidation) were assigned to receive an alloHSCT after consolidation. Pts with genetic HR features included for B-ALL: KMT2A translocation, near/low hypodiploidy (&lt;40 chromosomes) and &lt;35 years old, mutations/deletions of TP53 in homozygosis, or the presence of IKZF1 and CDKN2A/B mutations concomitantly, and all T-ALL except those with NOTCH1/FBXW7 isolated mutations. This analysis excluded pts with ETP-ALL because they received a different protocol.

Results. From December 2019 to March 2024, 452 pts with ALL were included. Median age was 40 (range 18-60) yrs, 57% male, 82% B-ALL, 40% HR genetic features. After Ind-1 83% (257/309) achieved CR, and it increased to 93% (286/309) after ind-2. After Ind-1+Ind-2, pts with CR and negative MRD (&lt;0.01%) were 162/250 (65%): SR 30% (75/250), HR 19% (48/250) and unavailable genetics 16% (39/250). Overall, 179 pts (61%) were assigned to alloHSCT. The median follow-up was 12.1 (range 0.12-50.04) months. The 2-year probability of OS and CIR (95%CI) for the whole series were 66% (59% to 73%) and 35% (28% to 42%) respectively. For pts with neg-MRD/SR, neg-MRD/HR, pos-MRD and those without CR the 2-year probability of OS (95%CI) were 86% (71% to 94%), 59% (36% to 77%), 56% (41% to 69%) and 55% (33% to 73%), respectively (p=0.001). The 2-year CIR (95%CI) for pts with neg-MRD/SR, neg-MRD/HR, pos-MRD and those without CR were 15% (7% to 26%), 42% (24% to 59%), 49% (34% to 62%) and 54% (24% to 77%), respectively (p=0.001). A subgroup of patients with negative MRD (&lt;0.001%) at day 14 and 35 have a very good prognosis with a 2-year probability OS of 87% (56% to 97%). Compared with the prior HR ALL11 trial (in which the decision to transplant or not was made based only in the MRD level) the 2-year CIR was reduced from 37% (29% to 44%) to 19% (10% to 28%) in patients allocated to CHT.

Conclusions. In adult ALL patients the inclusion of the genetic risk together with the MRD response to allocate the post-consolidation therapy, allow a better selection of patients who will receive CHT (neg-MRD and SR genetics at baseline). Patients with poor genetic risk at baseline had similar OS and CIR than those pts who were refractory, suggesting that the genetic risk highly relevant for prognosis assessment in adult ALL.