title: A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study.
abstract: 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-ABL1p190patients showed a significantly faster molecular response than BCR-ABL1p210patients (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).
authors: Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University of Rome, Italy rfoa@bce.uniroma1.it chiaretti@bce.uniroma1.it.
authors: Sabina
authors: S
authors: Chiaretti
authors: Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University of Rome, Italy.
authors: Antonella
authors: A
authors: Vitale
authors: GIMEMA Data Center, Rome, Italy.
authors: Marco
authors: M
authors: Vignetti
authors: GIMEMA Data Center, Rome, Italy.
authors: Alfonso
authors: A
authors: Piciocchi
authors: GIMEMA Data Center, Rome, Italy.
authors: Paola
authors: P
authors: Fazi
authors: Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University of Rome, Italy.
authors: Loredana
authors: L
authors: Elia
authors: Institute of Hematology, University of Perugia, Italy.
authors: Brunangelo
authors: B
authors: Falini
authors: Hematology Unit, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy.
authors: Francesca
authors: F
authors: Ronco
authors: Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Naples, Italy.
authors: Felicetto
authors: F
authors: Ferrara
authors: Hematology Unit and Department of Pharmacy Services, Sant'Eugenio Hospital, Rome, Italy.
authors: Paolo
authors: P
authors: De Fabritiis
authors: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Mario
authors: M
authors: Luppi
authors: Hematology Unit, Department of Medical Sciences, University of Cagliari, Italy.
authors: Giorgio
authors: G
authors: La Nasa
authors: Department of Oncology/Hematology, Niguarda Cancer Center, Niguarda Ca' Granda Hospital, Milano, Italy.
authors: Alessandra
authors: A
authors: Tedeschi
authors: Oncohematology Unit A. Tortora Hospital, Pagani, Salerno, Italy.
authors: Catello
authors: C
authors: Califano
authors: Division of Hematology and Bone Marrow Transplantation, University Hospital, Udine, Italy.
authors: Renato
authors: R
authors: Fanin
authors: Department of Biomedical Sciences, University of Sassari, Italy.
authors: Fausto
authors: F
authors: Dore
authors: GIMEMA Data Center, Rome, Italy.
authors: Franco
authors: F
authors: Mandelli
authors: Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University of Rome, Italy.
authors: Giovanna
authors: G
authors: Meloni
authors: Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University of Rome, Italy rfoa@bce.uniroma1.it chiaretti@bce.uniroma1.it.
authors: Robin
authors: R
authors: Foà
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000175:diagnosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl