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Nilotinib‐induced bone marrow CD34+/lin‐Ph+ cells early clearance in newly diagnosed CP‐Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study
Author(s) -
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
Publication year - 2021
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13680
Subject(s) - nilotinib , medicine , myeloid leukemia , imatinib , cd34 , discontinuation , bone marrow , minimal residual disease , cancer research , haematopoiesis , stem cell , oncology , tyrosine kinase inhibitor , immunology , gastroenterology , biology , cancer , genetics
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.