Combination of genetics at baseline and clearance of MRD to assign the post-remission treatment of patients with Philadelphia-negative ACUTE lymphoblastic leukemia. FINAL results 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 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.
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