Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.
// Alessandro Broccoli 1 , Beatrice Casadei 1 , Alice Morigi 1 , Federico Sottotetti 2 , Manuel Gotti 3 , Michele Spina 4 , Stefano Volpetti 5 , Simone Ferrero 6 , Francesco Spina 7 , Francesco Pisani 8 , Michele Merli 9 , Carlo Visco 10 , Rossella Paolini 11 , Vittorio Ruggero Zilioli 12 , Luca Baldini 13 , Nicola Di Renzo 14 , Patrizia Tosi 15 , Nicola Cascavilla 16 , Stefano Molica 17 , Fiorella Ilariucci 18 , Gian Matteo Rigolin 19 , Francesco D'Alò 20 , Anna Vanazzi 21 , Elisa Santambrogio 22 , Roberto Marasca 23 , Lucia Mastrullo 24 , Claudia Castellino 25 , Giovanni Desabbata 26 , Ilaria Scortechini 27 , Livio Trentin 28 , Lucia Morello 29 , Lisa Argnani 1 and Pier Luigi Zinzani 1 1 Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy 2 Operative Unit of Medical Oncology, IRCCS Fondazione Maugeri, Pavia, Italy 3 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 4 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy 5 Department of Hematology, DISM, Azienda Sanitaria Universitaria Integrata, Udine, Italy 6 Division of Hematology, Department of Molecular Biotechnologies and Scienze for Health, University Torino, Torino, Italy 7 Unit of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 8 Hematology and Transplantation Unit, Regina Elena National Cancer Institute, Roma, Italy 9 Unit of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy 10 Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy 11 Hematology Service, Medicine Department, Rovigo Hospital, Rovigo, Italy 12 Division of Hematology, Niguarda Ca' Granda Hospital, Milano, Italy 13 OncoHematology Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy 14 Unit of Hematology, Vito Fazzi Hospital, Lecce, Italy 15 Hematology Unit, Infermi Hospital Rimini, Rimini, Italy 16 IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 17 Unit of Oncology/Hematology, Azienda Ospedaliera "Pugliese-Ciaccio", Catanzaro, Italy 18 Unit of Hematology, Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia, Italy 19 Unit of Hematology, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy 20 Institute of Hematology, Università Cattolica del Sacro Cuore, Roma, Italy 21 Hemato-Oncology Division, European Institute of Oncology, Milano, Italy 22 Unit of Hematology, University-Hospital Città della Salute e della Scienza di Torino, Torino, Italy 23 Department of Medical Sciences, Hematology Unit, University of Modena and Reggio Emilia, Modena, Italy 24 Unit of Hematology, Ospedale San Gennaro di Napoli, Napoli, Italy 25 Unit of Hematology, Ospedale Santa Croce E Carle, Cuneo, Italy 26 Ematologia Clinica, Ospedale Maggiore, Trieste, Italy 27 Clinica di Ematologia Ospedali Riuniti, Ancona, Italy 28 Unit of Hematology, University of Padova, Padova, Italy 29 Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy Correspondence to: Pier Luigi Zinzani, email: pierluigi.zinzani@unibo.it Keywords: ibrutinib; mantle cell lymphoma; relapsed; refractory; real life Received: January 30, 2018 Accepted: April 07, 2018 Published: May 04, 2018 ABSTRACT Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.
Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.
