AFFILIATIONS
1 Hematology Department. Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
2 Hematology Department. Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
3 Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
4 Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
5 Centro de Investigación del Cáncer (IBMCC-CSIC/USAL-IBSAL); Servicio de Citometría (NUCLEUS), Departamento de Medicina, Universidad de Salamanca, Salamanca; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC), Instituto de Salud Carlos II, Madrid, Spain
6 osep Carreras Leukemia Research Institute (IJC), Badalona, Spain
7 osep Carreras Leukemia Research Institute (IJC), Badalona, Spain
8 Hematology Department. Hospital Universitario Virgen del Rocío. Instituto de Biomedicina de Sevilla (IBIS)/CSIC/CIBERONC. Universidad de Sevilla, Sevilla, Spain
9 Hematology Department. Hospital Clínic, Barcelona, Spain
10 Hematology Department. Hospital Universitari i Politècnic La Fe, Valencia, Spain
11 Hematology Department. Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain
12 Biochemical Department. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
13 Hematology Department. Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
14 Hematology Department. Hospital Son Espases, Palma de Mallorca, Spain, Palma, Spain
15 Hematology Department. ICO-Hospital Universitari Doctor Josep Trueta, Girona, Spain
16 Hematology Department. ICO-Duran i Reynals, L'Hospitalet de Llobregat, Spain
17 Laboratory of Cytogenetics and Molecular Biology. Hospital Universitari i Politècnic La Fe, Valencia, Spain
18 Hematology Department. Hospital General Universitario Dr. Balmis, Alicante, Spain
19 Hematology Department. Hospital Universitario Virgen de la Victoria, Málaga, Spain
20 Hematology Department. Hospital Universitario de Salamanca, Salamanca, Spain
21 Hematology Department. ICO-Hospital Universitari Joan XXIII, Tarragona, Spain
22 Hematology Department. Hospital Universitario Central de Asturias, Oviedo, Spain
23 Hematology Department. Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Universidad de Valencia, Valencia, Spain
24 Hematology Department. Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
25 Hematology Department. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
26 Hematology Department. Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
27 Hematology Department. Hospital Universitario 12 de Octubre, Madrid, Spain
28 Hematology Department. Hospital Universitario Marqués de Valdecilla, Santander, Spain
29 Hematology Department. Hospital General Universitario Gregorio Marañón, Madrid, Spain
30 Centro de Investigación del Cáncer (IBMCC-CSIC/USAL-IBSAL); Servicio de Citometría (NUCLEUS), Departamento de Medicina, Universidad de Salamanca, Salamanca; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC), Instituto de Salud Carlos II, Madrid, Spain
31 Centro de Investigación del Cáncer (IBMCC-CSIC/USAL-IBSAL); Servicio de Citometría (NUCLEUS), Departamento de Medicina, Universidad de Salamanca, Salamanca; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC), Instituto de Salud Carlos II, Madrid, Spain
32 Hematology Department. Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain
33 Hematology Department. Hospital Universitario Jerez de la Frontera, Jerez de la Frontera, Spain
34 Hematology Department. Hospital Universitario Reina Sofia, IMIBIC, Córdoba, Spain
35 Hematology Department. Hospital Puerta del Mar, Cádiz, Spain
36 Hematology Department. Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
37 Hematology Department. Hospital Universitario de Cruces, Barakaldo, Spain
38 Hematology Department. Hospital Universitario Puerta de Hierro, Mahadaonda, Spain
39 Hematology Department. Hospital del Mar, Barcelona, Spain
40 Hematology Department. Hospital Universitario Juan Ramón Jiménez, Huelva, Spain
41 Hematology Department. Hospital Universitario de Badajoz, Badajoz, Spain
42 Hematology Department. Hospital Universitario HM Sanchinarro, Madrid, Spain
43 Hematology Department. Hospital Regional Universitario de Málaga, Málaga, Spain
44 Hematology Department. Hospital Universitari Mútua Terrassa, Terrassa, Spain
45 Hematology Department. Complejo Hospitalario Universitario de Albacete, Albacete, Spain
46 Hematology Department. Complejo Hospitalario Pontevedra, Pontevedra, Spain
47 Hematology Department. Hospital General Universitario de Castellón, Castellón de la Plana, Spain
48 Hematology Department. Hospital Son Llàtzer, Palma, Spain
49 Hematology Department. Hospital San Pedro de Alcántara, Cáceres, Spain
50 Cancer Center Clínica Universitaria de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, CIBER-ONC, CB16/12/00369 and CB16/12/00489, Pamplona, Spain
51 Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
52 Departamento de Medicina, Hospital Universitario de Salamanca, IBSAL, Centro de Investigación del Cáncer, IBMCC, CSIC, Universidad de Salamanca, Salamanca, Spain
53 Centro de Investigación del Cáncer (IBMCC-CSIC/USAL-IBSAL); Servicio de Citometría (NUCLEUS), Departamento de Medicina, Universidad de Salamanca, Salamanca; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC), Instituto de Salud Carlos II, Madrid, Spain
54 Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
ABSTRACT
Background
In adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-neg ALL), the combination of measurable residual disease (MRD) and genetic risk identifies patients with standard-risk (SR) ALL who may not require allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission. The PETHEMA LAL19 trial (NCT04179929) demonstrated good outcomes in this SR population; however, approximately one-third of these patients still relapse, highlighting the need to further refine risk stratification. This analysis aimed to identify risk factors for relapse among SR patients with Ph-neg ALL included in the PETHEMA LAL19 trial.
Methods
The pediatric-inspired PETHEMA LAL19 trial was a multicenter study enrolling adults with newly diagnosed Ph-neg ALL (B and T-lineage) across 94 centers in Spain. Patients with MRD ≥0.01% after induction-1 and/or high-risk (HR) genetic features were classified in the HR group and received consolidation followed by allo-HSCT. HR genetic features included KMT2A rearrangements, low hypodiploidy in patients >35 years, biallelic TP53 alterations (mutations and/or deletions), or concurrent IKZF1 and CDKN2A/B deletions (B-ALL) as well as absence of?NOTCH1/FBXW7?mutations and/or mutations in?K/NRAS?or?PTEN (T-ALL). Patients without HR genetics and MRD <0.01% after induction-1 were classified as SR and received consolidation, reinduction and maintenance without allo-HCT and represent the study population.
The primary endpoint of the study was the cumulative incidence of relapse (CIR) and was analyzed using competing-risk methods (cumulative incidence functions and Gray's test). Overall survival (OS) and leukemia free survival (LFS) were estimated using the Kaplan–Meier method and compared by log-rank test. Relapse risk factors were evaluated by univariable and multivariable Fine–Gray regression analyses.
Results
Between December 2019 and August 2024, 436 adults with newly diagnosed Ph-neg ALL were included. The median age was 39 years (range, 18–60), 56% were male, and 76% had B-ALL. Extramedullary disease was present in 26% of patients. After induction, 157/400 patients (39%) (B-ALL=126 [80%] and T-ALL=31 [20%]) met the predefined SR criteria, whereas 243/400 (61%) were classified as HR. Compared with HR patients, those classified as SR were younger (median age, 37 vs 40 years), had lower presenting white blood cell (WBC) counts (8.9 vs 14.8×10?/L), and were enriched for high hyperdiploidy, TCF3::PBX1, and PAX5 P80R genetic subtypes (p<0.05).
In the SR cohort and after a median follow-up of 2.6 years (95%CI, 0.4 - 5) months, the estimated 3-year overall survival (OS), leukemia-free survival (LFS), and cumulative incidence of relapse (CIR) were 82% (95%CI, 74–88%), 68% (95%CI, 58–75%), and 30% (95%CI, 22–38%), respectively. In the univariable analyses, higher WBC (HR 1.60, 95%CI 1.05-2.43, p=0.03) at diagnosis and detectable MRD (0.001-0.01%) after induction (HR 2.20, 95%CI 1.12-4.32, p=0.02) were associated with an increased CIR. In the multivariable analysis, both variables retained similar effect size but did not reach statistical significance (WBC: HR 1.49, 95%CI 0.92-2.42, p=0.10; MRD: HR 1.99, 95%CI 0.94-4.20, p=0.07). Mid-induction MRD level (day +14) was not associated with lower CIR (p=0.36).
Combining WBC at diagnosis and post-induction MRD further discriminated relapse risk, with the lowest 3-year CIR observed in patients with low WBC count and MRD level <0.001% (18%, 95%CI 8-30) and the highest in those with elevated WBC and MRD ≥0.001% (50%, 95%CI 19-73).
Finally, we explored whether favorable genetic subtypes in B-ALL could further refine risk stratification in this SR population, defined as high hyperdiploidy, PAX5 P80R, ZNF384-rearranged, or ETV6::RUNX1 alterations. Patients harboring favorable genetic profile had a significantly lower 3-year CIR than the remaining SR genetic subtypes (7% vs 40%; p=0.024). OS probability was also numerically higher in SR patients with favorable genetic profile (92% vs 82%, p=0.12).
Conclusions
Patients with SR Ph-neg ALL have globally a favorable prognosis without consolidative allo-HCT, although there is significant variability in the relapse risk within this group. Further risk discrimination using clinical variables or deeper MRD responses appears limited, whereas refined molecular classification may identify an ultra-low-risk B-ALL subgroup that could support future treatment de-escalation strategies.