Nilotinib‐induced bone marrow CD34+/lin‐Ph+ cells early clearance in newly diagnosed CP‐Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study

• Published in: European journal of haematology Vol. 107; no. 4; pp. 436 - 448
• Main Authors: Pungolino, Ester, D'adda, Mariella, De Canal, Gabriella, Trojani, Alessandra, Perego, Alessandra, Elena, Chiara, Lunghi, Francesca, Turrini, Mauro, Borin, Lorenza, Iurlo, Alessandra, Latargia, Maria Luisa, Carraro, Maria Cristina, Spina, Francesco, Artale, Salvatore, Anghilieri, Michela, Molteni, Alfredo, Caramella, Marianna, Baruzzo, Giacomo, Nichelatti, Michele, Di Camillo, Barbara, Cairoli, Roberto
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2021; John Wiley and Sons Inc
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; BCR-ABL protein; Biomarkers, Pharmacological; Bone marrow; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Case-Control Studies; CD34 antigen; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromosomes; Chronic Myeloid Leukemia; Diagnosis; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; GEP; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte Colony-Stimulating Factor - metabolism; Humans; Imatinib; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - diagnosis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Middle Aged; Myeloid leukemia; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-KappaB Inhibitor alpha - genetics; NF-KappaB Inhibitor alpha - metabolism; NFKBIA; nilotinib; Original; Patients; Philadelphia Chromosome; Prospective Studies; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - therapeutic use; Recurrence; Signal transduction; Stem cells; NFKBIA; stem cells; Chronic Myeloid Leukemia; GEP; nilotinib
• ISSN: 0902-4441; 1600-0609; 1600-0609
• DOI: 10.1111/ejh.13680

Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph‐chromosome and the BCR‐ABL tyrosine‐kinase (TK). Target‐therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second‐generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin−Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in‐vivo activity and timecourse of first‐line Nilotinib therapy on BM CD34+/lin−Ph+ cells clearance. Eighty‐seven CP‐CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin− cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per‐Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin− cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK‐STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.