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 could 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 genetic features at diagnosis and MRD levels after induction.
Methods. PETHEMA LAL19 was a multicenter study, including data from 94 centers across Spain. It enrolled newly diagnosed Ph-negative ALL pts, both T- and B-lineage, who received a pediatric-inspired treatment. Pts with high-risk (HR) genetics, those requiring two induction cycles to achieve complete remission (CR), and those with CR but MRD ≥0.01% after induction-1 (Ind-1) or MRD ≥0.001% after early consolidation and reinduction were allocated to alloHSCT. The remaining pts, considered standard-risk pts, were assigned to late consolidation and maintenance. HR genetics in B-ALL included: KMT2A rearrangement, hypodiploidy (<40 chromosomes) in pts aged >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 different treatment and all of them were assigned to receive an alloHSCT in first CR. All MRD and genetic studies were centralized.
Results. Between end 2019 and August 2024, 436 eligible pts were enrolled (413 non-ETP and 23 ETP). In the non-ETP group, median age was 40 years (range, 18–60), 56% were male, median WBC count was 12×10⁹/L (0.4–740), and 80% had B-ALL. HR genetics were found in 36% (99/274) of B-ALL pts and 52% (34/65) of T-ALL cases. CR rate after Ind-1 was 84% (348/413) and increased to 95% (387/407) after Ind-1+Ind-2. MRD <0.01% was achieved in 63% (221/348) post-Ind-1 and in 91% (324/357) post-Ind-1+Ind-2. In the ETP-ALL group (n=23), median age was 29 years (range, 18-57), 57% were male, median WBC count was 29.2×10⁹/L (3.5-389), and five patients had CNS involvement. The CR rate was 74% (17/23) with 7 (41%) pts being MRD <0.01% after Ind-1 with FLAG-IDA.
By intention-to-treat, 243 pts (61%) from the non-ETP group were allocated to alloHSCT and 157 (39%) to CT. The 3-year overall survival (OS) was 64% (95% CI, 58%–69%), and the cumulative incidence of relapse (CIR) was 39% (33%–45%). Among pts with CR and MRD <0.01% after Ind-1 and without HR genetics (n=109), 3-year OS was 81% (70%–89%). This compares favorably with 50% (34%–63%) observed in genetically HR pts (n=64) with similar MRD clearance, as well as with 58% for pts with CR and MRD ≥0.01% and 53% for pts who did not achieve CR after Ind-1 (p<0.001). A very-good risk group of patients (absence of HR genetics & CR after ind-1 with MRD<0.01% & MRD<0.001% after Re-Induction) showed a 3-year OS of 89% (78%–95%) and a 3-year CIR of 19% (10%-31%) with CHT only. In ETP-ALL pts, the 3-year OS was 61% (37%–79%), and the CIR was 25% (8%–48%).
Conclusions. In adults with Ph- ALL, assigning post-remission treatment based on MRD and genetic risk is feasible. Genetic risk assessment among pts with good MRD clearance identified a subgroup with excellent prognosis without the need for alloHSCT. Thus, integrating genetic risk with MRD improves the precision of risk stratification.
