Giné Soca, Eva, Cruz, Fátima de la, Jiménez Ubieto, Ana, López Jimenez, Javier, Martín García-Sancho, Alejandro, Terol, M. José, González Barca, Eva, Casanova, María, Fuente, Adolfo de la, Marín Niebla, Ana, Muntañola, Ana, González López, Tomás José, Aymerich Gregorio, Marta, Setoain, Xavier, Cortés Romera, Montserrat, Rotger, Amanda, Rodríguez, Sonia, Medina Herrera, Alejandro, García Sanz, Ramón, Nadeu, Ferran, Beà Bobet, Sílvia M., Campo Güerri, Elias, López Guillermo, Armando, The GELTAMO Group, Institut Català de la Salut, [Giné E] Hematology Department, Hospital Clínic of Barcelona, Barcelona, Spain. Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. Centro de Investigación Biomédica en Red, Cáncer (CIBERONC), Madrid, Spain. [de la Cruz F] Hematology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain. [Jiménez Ubieto A] Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. [López Jimenez J] Hematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. [Martín García-Sancho A] Centro de Investigación Biomédica en Red, Cáncer (CIBERONC), Madrid, Spain. Hematology Department, Hospital Clínico Universitario Salamanca, Salamanca, Spain. Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. [Terol MJ] Hematology Department, Hospital Clínico de Valencia, Valencia, Spain. Institut d’Investigació Sanitària (INCLIVA), Valencia, Spain. [Marín-Niebla A] Servei d’Hematologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Instituto de Salud Carlos III, Fundació La Marató de TV3, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), National Institutes of Health (US), European Commission, and Fundacion de la Sociedad Española de Hematología y Hemoterapia
[Puropose]: The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients., [Methods]: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m2. Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria., [Results]: Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia., [Conclusion]: Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases., The authors would like to thank the patients and their families, and study investigators and coordinators—among them, Carlos Grande, Lucia Palacios, and Silvia Ru´ız—for their contribution to the study. Partial support of biological and MRD studies was obtained from grants Instituto de Salud Carlos III (ISCIII) PI19/00887 (to A.L.-G. and E.G.) and PI17/ 01061 (to S.B.), Fundacio La Marat ´ o de TV3 grant 201904-30 (to S.B.), ´ Ministerio de Ciencia e Innovacion (MCI) RTI2018-094274-B-I00 (to ´E.C.), National Institutes of Health (NIH) 1P01CA229100 (to E.C.) and FEDER: European Regional Development Fund “Una manera de hacer Europa” (to E.C. and S.B.). A personal grant FEHH-Janssen 2021 to Alejandro Medina-Herrera from Fundacion Española de Hematología y Hemoterapia is acknowledged. E.C. is an ICREA Academia Researcher