Effectiveness of Gilteritinib Beyond Second‐Line Therapy in Relapsed/Refractory <scp> <i>FLT3</i> </scp> ‐Mutated Acute Myeloid Leukemia: A Real‐World Multicenter Study of 171 Patients

Gilteritinib is a selective FLT3 inhibitor approved for the treatment of relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) following ≥ 1 prior line of therapy. However, data on its effectiveness in later-line settings is limited. We conducted a multicenter, retrospective study including 171 adult patients with R/R FLT3-mutated AML who received gilteritinib as third-line or beyond between August 2017 and March 2024 across centers in Italy, Spain, the United Kingdom, and Turkey. The primary endpoint was overall survival (OS). Secondary endpoints included overall response rate (ORR), composite complete remission (cCR), duration of response. Among the 171 patients, 84% carried FLT3-ITD mutations and 26% had received ≥ 3 prior lines of therapy. The cCR rate was 28%, and ORR was 47%. Patients who were younger and presented with relapsed (vs. refractory) disease had better outcomes. Prior exposure to venetoclax or allogeneic hematopoietic stem cell transplantation (HSCT) was associated with inferior response. Gilteritinib enabled HSCT in 12% of patients. Median OS was 7.1 months (95% CI, 5.9-10.1), and in Cox-regression analysis was significantly improved among responders and those who underwent HSCT (median OS: 21.5 months; 95% CI, 12.8-NR). Prior venetoclax exposure was associated with shorter survival (5.7 months; 95% CI, 5.1-8.8). On multivariate analysis, previous exposure to venetoclax and FLT3 inhibitors was the strongest predictor of reduced response rates. Despite heavy pretreatment, gilteritinib retained clinically relevant activity in later-line R/R FLT3-mutated AML. Its use beyond second-line may serve as a bridge to HSCT in selected patients. Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.

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Journal
American Journal of Hematology
Published
2025-11-22
DOI
https://doi.org/10.1002/ajh.70142
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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article

Effectiveness of Gilteritinib Beyond Second‐Line Therapy in Relapsed/Refractory FLT3 ‐Mutated Acute Myeloid Leukemia: A Real‐World Multicenter Study of 171 Patients

Richard Dillon, Pau Montesinos, Gaetano Cimino, Alessandra Serrao et al.
American Journal of Hematology
Acute Myeloid Leukemia Research
article

Effectiveness of Gilteritinib Beyond Second‐Line Therapy in Relapsed/Refractory FLT3 ‐Mutated Acute Myeloid Leukemia: A Real‐World Multicenter Study of 171 Patients

Richard Dillon, Pau Montesinos, Gaetano Cimino, Alessandra Serrao, Matteo Molica, Ferran Vall‐Llovera Calmet, Giulia Ciotti, Jenny O’Nions, Victoria Campbell, Mario Annunziata, Calogero Vetro, Giuseppe Sucato, Cristina Gil, Cristina Papayannidis, Jad Othman, Anjum Bashir Khan, Amaia Balerdi, María Teresa Olave Rubio, Laura De Fazio, Marina Aurora Urbano, Juan Bergua, Haşim Atakan Erol, Andrea Corbingi, Gema Miralles, Anna Lina Piccioni, Gerardo Musuraca, Salvatore Perrone, Marco Rossi, Susana Vives, Maria Paola Martelli, Carla Mazzone, İstemi Serin, Antonino Mulè, Denis Cetin, Sabrina Mariani, Fanny Erika Palumbo, Vincenzo Federico, Faisal Basheer, Omur Gokmen Sevindik, Yasa Mutlu Gulu, Mariana Norata, Jackeline Sanchez‐Tovar
article en

Abstract

Gilteritinib is a selective FLT3 inhibitor approved for the treatment of relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) following ≥ 1 prior line of therapy. However, data on its effectiveness in later-line settings is limited. We conducted a multicenter, retrospective study including 171 adult patients with R/R FLT3-mutated AML who received gilteritinib as third-line or beyond between August 2017 and March 2024 across centers in Italy, Spain, the United Kingdom, and Turkey. The primary endpoint was overall survival (OS). Secondary endpoints included overall response rate (ORR), composite complete remission (cCR), duration of response. Among the 171 patients, 84% carried FLT3-ITD mutations and 26% had received ≥ 3 prior lines of therapy. The cCR rate was 28%, and ORR was 47%. Patients who were younger and presented with relapsed (vs. refractory) disease had better outcomes. Prior exposure to venetoclax or allogeneic hematopoietic stem cell transplantation (HSCT) was associated with inferior response. Gilteritinib enabled HSCT in 12% of patients. Median OS was 7.1 months (95% CI, 5.9-10.1), and in Cox-regression analysis was significantly improved among responders and those who underwent HSCT (median OS: 21.5 months; 95% CI, 12.8-NR). Prior venetoclax exposure was associated with shorter survival (5.7 months; 95% CI, 5.1-8.8). On multivariate analysis, previous exposure to venetoclax and FLT3 inhibitors was the strongest predictor of reduced response rates. Despite heavy pretreatment, gilteritinib retained clinically relevant activity in later-line R/R FLT3-mutated AML. Its use beyond second-line may serve as a bridge to HSCT in selected patients. Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.

American Journal of HematologyVol. 101(1)
University College London Hospitals NHS Foundation Trust (GB), King's College London (GB), University of Perugia (IT), Azienda Ospedaliera San Giovanni Addolorata (IT), Leeds Teaching Hospitals NHS Trust (GB), Western General Hospital (GB), Hospital Universitari i Politècnic La Fe (ES), Ege University (TR), Azienda Ospedaliera di Perugia (IT), Ospedale di Bolzano (IT), Gaziantep Children's Hospital (TR), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Ospedale Vincenzo Cervello (IT), Istanbul Florence Nightingale Hospital (TR), Ospedale A. Perrino (IT), Fatebenefratelli Hospital (IT), Istituto Oncologico Veneto (IT), Hospital San Pedro de Alcántara (ES), Hospital Rio Carrion (ES), Hospital General Universitario de Elche (ES), Istituto di Ematologia di Bologna (IT), Azienda Ospedaliera Sant'Andrea (IT), Policlinico Universitario di Catania (IT), Mútua Terrassa (ES), IRCCS San Camillo Hospital (IT), Hospital Clínico Universitario Lozano Blesa (ES), Hospital de Cruces (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Istanbul Eye Hospital (TR), Ospedale Santa Maria Goretti (IT), St. Eugenio Hospital (IT), Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" di Palermo (IT), Ospedale Vito Fazzi (IT), Hospital Universitari Germans Trias i Pujol (ES), Addenbrooke's Hospital (GB), Complejo Asistencial Universitario de Palencia (ES), University College London (GB), Kocaeli Üniversitesi (TR)
University College London, Kocaeli Üniversitesi, Sapienza Università di Roma, Associazione Italiana per la Ricerca sul Cancro, Istituto Oncologico Veneto, Paracelsus Medizinische Privatuniversität
Openalex Percentile: Top 53%
Acute Myeloid Leukemia Research
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