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
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.
Article Details
Authors (50)
Anna Torrent
Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
Mireia Morgades
Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
Susana Barrera
4Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC – University of Salamanca); Cytometry Service, NUCLEUS;, Department of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain
Jordi Ribera
Josep Carreras Leukemia Research Institute (IJC), Badalona, Spain
Eulalia Genesca
Josep Carreras Leukemia Research Institute (IJC), Badalona, Spain
José González-Campos
Hematology Department. Hospital Universitario Virgen del Rocío. Instituto de Biomedicina de Sevilla (IBIS)/CSIC/CIBERONC. Universidad de Sevilla, Sevilla, Spain
Nuria Martínez-Cibrian
Hematology Department. Hospital Clínic, Barcelona, Spain
Pau Montesinos
Hospital Universitari i Politecnic La Fe, Valencia, Spain
Alberto Hernández-Sánchez
Pere Barba
Hematology Department. Hospital Universitari Vall d'Hebron, Barcelona, Spain
Edgar Zapico
Biochemical Department. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Ricardo Sánchez
Hematology Department. Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (i+12) Madrid, Spain
Marta Sitges Arriaga
12ICO-Hospital Universitari Doctor Josep Trueta, Girona, Spain., Hematology Department, Girona, Spain
Clara Maluquer Artigal
Hematology Department. ICO-Duran i Reynals, L'Hospitalet de Llobregat, Spain
Esperanza Such
Laboratory of Cytogenetics and Molecular Biology. Hospital Universitari i Politècnic La Fe, Valencia, Spain
Carmen Botella
Hematology Department. Hospital General Universitario Dr. Balmis, Alicante, Spain
Maria Queipo De Llano
15Hospital Universitario Virgen de la Victoria, Málaga, Spain, Hematology Department, Málaga, Spain
Mónica Cabrero Calvo
8Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain., Hematology Department, Salamanca, Spain
Ana Maria Vicent Castelló
16ICO-Hospital Universitari Joan XXIII, Tarragona, Spain., Hematology Department, Tarragona, Spain
Paula Lopez de Ugarriza
Hematology Department. Hospital Universitario Central de Asturias, Oviedo, Spain
Mar Tormo
Hospital Clinico Universitary. INCLIVA Research Institute, Valencia 46010, Spain
Bernardo Gonzalez Gonzalez
19Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain., Hematology Department, Santa Cruz de Tenerife, Spain
Irene Garcia-Cadenas
Hematology Department. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Carlos Rodriguez Medina
21Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain., Hematology Department, Las Palmas de Gran Canaria, Spain
Pilar Martínez-Sánchez
22Hospital Universitario 12 de Octubre, Madrid, Spain., Hematology Department, Madrid, Spain
Arancha Bermúdez
Hematology Department. Hospital Universitario Marqués de Valdecilla, Santander, Spain
Ignacio Gómez-Centurión
Hematology Department. Hospital General Universitario Gregorio Marañón, Madrid, Spain
María Herrero García
8Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain., Hematology Department, Salamanca, Spain
Juana Ciudad
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 III, Madrid, Spain
María Hermosín-Ramos
25Hospital Universitario Jerez de la Frontera, Jerez de la Frontera, Spain., Hematology Department, Jerez de la Frontera, Spain
Josefina Serrano
University Hospital Reina Sofia. IMIBIC. UCO, Cordoba, Spain
Jose Angel Raposo Puglia
27Hospital Universitario Puerta del Mar, Cádiz., Cádiz, Spain
Laura Solán Blanco
28Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain., Hematology Department, Madrid, Spain
Verónica Roldán Galiacho
29Hospital Universitario de Cruces, Barakaldo (Vizcaya), Spain., Hematology Department, Barakaldo, Spain
María Almudena De Laiglesia Lorenzo
30Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain., Hematology Department, Madrid, Spain
Lucía Gómez Pérez
31Hospital del Mar, Barcelona, Spain., Hematology Department, Barcelona, Spain
María Solé Rodriguez
32Hospital Universitario Juan Ramón Jiménez, Huelva, Spain., Hematology Department, Huelva, Spain
Mará Sol Casado Calderón
33Hospital Universitario de Badajoz, Badajoz, Spain., Hematology Department, Badajoz, Spain
Laura Llorente Gonzalez
Hematology Department. Hospital Universitario HM Sanchinarro, Madrid, Spain
Daniel Barrios Decoud
Hematology Department. Hospital Regional Universitario de Málaga, Málaga, Spain
Ferran Vall-Llovera Calmet
36Hospital Universitari Mútua Terrassa, Terrassa, Spain., Hematology Department, Terrassa, Spain
Lorenzo Algarra
37Complejo Hospitalario Universitario de Albacete, Albacete, Spain., Hematology Department, Albacete, Spain
María Lourdes Amador Barciela
38Complejo Hospitalario Pontevedra, Pontevedra, Spain., Hematology Department, Pontevedra, Spain
Raimundo Garcia
39Hospital General Universitario de Castellón, Castellón de la Plana, Spain., Hematology Department, Castellón de la Plana, Spain
Antonia Cladera Serra
40Hospital Son Llàtzer, Palma de Mallorca, Spain., Hematology Department, Palma de Mallorca, Spain
Juan Miguel Bergua Burgues
Hospital San Pedro de Alcántara. Cáceres, Caceres, Spain
Isabel Granada
Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
Jesus Maria Hernandez Rivas
8Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain., Hematology Department, Salamanca, Spain
Alberto Orfao
Josep-Maria Ribera
Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain