A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study
Sabina Chiaretti,
Antonella Vitale,
Marco Vignetti,
Alfonso Piciocchi,
Paola Fazi,
Loredana Elia,
Brunangelo Falini,
Francesca Ronco,
Felicetto Ferrara,
Paolo De Fabritiis,
Mario Luppi,
Giorgio La Nasa,
Alessandra Tedeschi,
Catello Califano,
Renato Fanin,
Fausto Dore,
Franco Mandelli,
Giovanna Meloni,
Robin Foà
Affiliations
Sabina Chiaretti
Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, “Sapienza” University of Rome, Italy
Antonella Vitale
Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, “Sapienza” University of Rome, Italy
Marco Vignetti
GIMEMA Data Center, Rome, Italy
Alfonso Piciocchi
GIMEMA Data Center, Rome, Italy
Paola Fazi
GIMEMA Data Center, Rome, Italy
Loredana Elia
Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, “Sapienza” University of Rome, Italy
Brunangelo Falini
Institute of Hematology, University of Perugia, Italy
Francesca Ronco
Hematology Unit, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy
Felicetto Ferrara
Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Naples, Italy
Paolo De Fabritiis
Hematology Unit and Department of Pharmacy Services, Sant’Eugenio Hospital, Rome, Italy
Mario Luppi
Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
Giorgio La Nasa
Hematology Unit, Department of Medical Sciences, University of Cagliari, Italy
Alessandra Tedeschi
Department of Oncology/Hematology, Niguarda Cancer Center, Niguarda Ca’ Granda Hospital, Milano, Italy
Catello Califano
Oncohematology Unit A. Tortora Hospital, Pagani, Salerno, Italy
Renato Fanin
Division of Hematology and Bone Marrow Transplantation, University Hospital, Udine, Italy
Fausto Dore
Department of Biomedical Sciences, University of Sassari, Italy
Franco Mandelli
GIMEMA Data Center, Rome, Italy
Giovanna Meloni
Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, “Sapienza” University of Rome, Italy
Robin Foà
Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, “Sapienza” University of Rome, Italy
In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0–79.3 vs. 20%, 95%CI: 5.8–69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3–82.6 vs. 20%, 95%CI: 5.8–69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2–38.6 vs. 60.0%, 95%CI: 21.6–84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1p190 patients showed a significantly faster molecular response than BCR-ABL1p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).