title: Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180-270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation.
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Nira
authors.initials: N
authors.lastname: Varda-Bloom
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Ivetta
authors.initials: I
authors.lastname: Danylesko
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.|Dr. Pinchas Bornstein Talpiot Medical Leadership Program, Sheba Medical Center, Israel.|Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Shouval
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Eldror
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.|Pediatric Immunology Service, Jeffrey Modell Foundation, USA.|Edmond and Lily Safra Children's Hospital, Israel.
authors.forename: Atar
authors.initials: A
authors.lastname: Lev
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Davidson
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Rosenthal
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Volchek
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Noga
authors.initials: N
authors.lastname: Shem-Tov
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Yerushalmi
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Avichai
authors.initials: A
authors.lastname: Shimoni
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.|Pediatric Immunology Service, Jeffrey Modell Foundation, USA.|Edmond and Lily Safra Children's Hospital, Israel.
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
authors.affiliation: Sheba Medical Center, Ramat-Gan, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004270:DNA, Circular; D005260:Female; D005500:Follow-Up Studies; D019672:Genes, T-Cell Receptor / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D000074243:Immune Reconstitution; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy*; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004270:DNA, Circular; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C498826:nilotinib
keywords: immune reconstitution; mitogens; nilotinib; stem cell transplantation; thymic activity