Excellent prognosis for adult patients with Philadelphia chromosome-negative ALL with standard genetic risk and EARLY clearance of MRD. sub-analysis of pethema LAL19 trial

Abstract Introduction. Adults with Ph-negative acute lymphoblastic leukemia (Ph- ALL) may not require allogeneic hematopoietic stem cell transplantation (alloHSCT) if they achieve negative measurable residual disease (MRD) after induction and consolidation therapy. However, it is unclear whether baseline genetic risk can more accurately identify patients (pts) who should receive chemotherapy (CHT) or alloHSCT. The aim of the PETHEMA LAL19 protocol (NCT04179929) was to evaluate the outcomes of pts assigned to differentiated post-induction therapy (CHT or alloHSCT) according to MRD levels and genetic features at diagnosis, both centrally assessed. Methods. The pediatric-inspired PETHEMA LAL19 was a multicenter study conducted across 94 centers in Spain, enrolling newly diagnosed Ph-negative ALL pts, both T- and B-lineage. Pts with MRD <0.01% after induction 1 (Ind-1) and without high-risk (HR) genetics –defined here as standard-risk pts (SRp)- were allocated to receive blocks of consolidation CHT, reinduction and maintenance treatment. HR patients (HRp) were allocated to an AlloHSCT. HR genetics in B-ALL included: KMT2A rearrangement, hypodiploidy (<40 chromosomes) and age >35 years, homozygous TP53 mutations/deletions, or co-occurrence of IKZF1 and CDKN2A deletions. HR genetics in T-ALL included absence of NOTCH1/FBXW7 mutations and/or mutations in K/NRAS or PTEN. Early T-cell precursor (ETP) ALL pts received a separate treatment protocol and were not included in this analysis. Our aim was to perform a sub-analysis of the outcome of the SRp from the PETHEMA LAL19 trial. Results. Between December 2019 and August 2024, 413 eligible pts were enrolled. 13 pts died in induction-1, and 48 pts had no genetic information available. From this genetically evaluable population, 109/352 pts (31%) were SRp and 243/352 pts (69%) HRp. Median age was 35 years (range, 18-60), 54% male and 82% were B-ALL. Comparing the SRp vs. the remaining pts (n=243), SRp were younger (35 vs. 40 years), had lower WBC (11.3x10e9/L vs. 14.8x10e9/L), lower proportion of pro-B phenotypes and had higher proportion of high hyperdiploid, t(1;19)/TCF3::PBX1 and PAX5 P80R subtypes. No differences were observed in the distribution of immunophenotypically defined T-ALL subgroups. Interestingly, the SRp had a higher proportion of MRD<0.01% at day +14 (mid Ind-1) compared with HR pts, 46% vs. 18% (p<0.001), respectively. By intention to treat, the 3-year overall survival (OS) comparing the SRp vs. the remaining pts were 81% (95%CI, 70-89%) vs. 54% (46-62%) (p<0.001), and the cumulative incidence of relapse (CIR) were 32% (22-42%) vs. 46% (38-54%), respectively (p=0.028). Within the SRp, we studied the pts with sustained MRD negativity beyond induction therapy. These were pts with deeper MRD negativity (<0.001%) after early consolidation and reinduction CHT, defined in this study as very good-risk pts (VGRp) (n=70/109, 64.2%). Those VGRp were younger (29.5 vs 40 years), had less frequency of hyperleukocytosis (WBC>100x10e9/L), and were enriched with favorable genetic profile (high hyperdiploid, t(1;19)/TCF3::PBX1 and PAX5 P80R) compared with the remaining pts. The 3-year OS of this VGRp subgroup was 89% and their 3-year CIR was 19% with CHT only. Of them, 12 pts relapsed at a median time of 1.22 years (range, 0.5 to 2.44 years). No significant differences were found in relapsed vs. non-relapsed patients in age, gender, WBC, phenotype or CNS involvement, but this group had a trend towards a lower proportion of pts with MRD<0.01% at day +14 of Ind-1 vs. the VGRp who did not relapsed (18% vs. 51%, respectively, p=0.091). According to genetics, the VGRp had a higher proportion of good risk genetic profiles. Conclusion. Pts with SR genetics and good MRD clearance had an excellent prognosis without the need of alloHSCT. They are mainly enriched with younger pts, lower WBC count and early achievement of MRD negativity compared with the remaining. Despite these favorable characteristics, there is still a significant risk of relapse.