Similar Outcome of Adolescents and Young Adults (AYA) and Older Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) without Philadelphia Chromosome (Ph-) Included in the Pethema LAL-2019 Trial
Authors: Torrent Anna , Morgades Mireia , Barrera Susana , Ribera Jordi , Soriano Beatriz , 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. The treatment of Ph-negative ALL is based on pediatric-inspired protocols that include allogeneic hematopoietic stem cell transplantation (alloHSCT) based on post-induction/consolidation measurable residual disease (MRD) and genetic characteristics. The PETHEMA LAL-2019 protocol (NCT 04179929) includes patients (pts) aged 18-60 yrs with Ph- ALL. The indication for alloHSCT is based on the post-induction MRD level (≥0.01%) and/or the presence of adverse genetic factors (for B-cell ALL the presence of near/low hypodiploidy &lt;40 chromosomes and &gt;35 yrs, KMT2A translocations, homozygote deletions/mutations of TP53, or IKZF1 and CDKN2A/B deletions. For T-cell ALL the absence of NOTCH1/FBXW7 mutations together with RAS/PTEN mutations as well as ETP-ALL). Preliminary results in AYA (18-40 years) were analyzed and their outcome was compared with those of the older adults (41-60 yrs).

Methods. A centralized immunophenotypic (next-generation cytofluorometry) and genetic (FISH, SNP arrays and NGS) study was carried out in parallel with the induction-1 (Ind-1) treatment (vincristine, prednisone, PEG-asparaginase and daunorubicin). Pts without adverse genetic risk (AGR) and MRD &lt;0.01% received 3 cycles of early consolidation (HD-MTX, HD ARAC and PEG-asparaginase) and reinduction. If MRD was &lt;0.001% at that point, pts received 3 cycles of delayed consolidation and maintenance therapy. The remaining pts were assigned to alloHSCT. Refractory pts or those with MRD ≥0.01% after Ind-1 received a 2nd induction cycle (Ind-2) (FLAG-Ida or Inotuzumab after amendment). Pts with early T cell precursor (ETP) ALL received differentiated treatment (induction with FLAG-Ida, 3 cycles of early consolidation (HD-MTX, HD ARAC and PEG-asparaginase) and alloHSCT.

Results. Between December 2019 and March 2024, 476 valid pts were included, 245 (51%) AYA. Median age 27 (18-40 y), 150 (61%) males, CNS infiltration 19/170 (11%), leukocytes 18x10e9/L (0.4-740), B-cell precursor ALL 178 (73%), T-ALL 67 (27%, ETP 18/67, 27%), standard genetic risk (SGR) 110/187 (59%), AGR 77/187 (41%). The CR rate after Ind-1 was 83%, and after Ind-1+Ind-2 was 94%. There were two deaths in Ind-1 and five in Ind-2. Overall 74/122 (61%) showed MRD&lt;0.01% after Ind-1. Sixty-five pts were assigned to chemotherapy (CT) (RD&lt;0.01% after I-1 and SGR [n=41] or RD&lt;0.01% and genetic risk (GR) not available [n=24]). The remaining were assigned to alloHSCT (AGR only [n=20], RD post Ind-1 ≥0.01% regardless of GR [n= 49] or no CR after Ind-1 [n=25]). The probability of OS at 3 yrs for AYA was 65% (95%CI: 55%-73%), vs. 63% (51%-72%) for those at 41-60 yrs (p=0.676). The cumulative incidence of relapse (CIR) at 3-years in AYA was 39% (28%-49%) vs. 43% (29%-55%) for those aged 41-60 yrs (p=0.676). The subgroup of AYA with MRD &lt;0.01% and SGR had a probability of OS at 3-years of 84% (61%-94%), significantly higher than the remaining groups, with no significant differences between them.

Conclusions. The preliminary results in ALL pts included in the LAL-2019 protocol are comparable to those of other pediatric-inspired protocols. No differences in OS and CIR were observed when compared AYA (18-40 yrs) with adults aged 41-60 yrs. The subgroup of low-risk AYA pts had excellent survival without need for alloHSCT.