Mohamed El Missiry1, Shady Adnan Awad1, Hanna L Rajala1, Ahmed Al-Samadi2, Marja Ekblom3, Berit Markevän4, Ingbritt Åstrand-Grundström3, Maren Wold5, Ellen Rabben Svedahl5, Birgitte Ravn Juhl6, Ole Weis Bjerrum7, Inger Haulin8, Kimmo Porkka1, Ulla Olsson-Strömberg9,10, Henrik Hjorth-Hansen5, Satu Mustjoki11,12. 1. Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland. 2. Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland. 3. Skåne University Hospital, Lund, Sweden. 4. Department of Hematology, Umeå University Hospital, Umeå, Sweden. 5. Department of Hematology, St Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. 6. Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 7. Department of Hematology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. 8. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. 9. Department of Hematology, Uppsala University Hospital, Uppsala, Sweden. 10. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. 11. Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland. satu.mustjoki@helsinki.fi. 12. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi.
Abstract
PURPOSE: Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. METHODS: BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. RESULTS: Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 <10 % showed higher lymphocyte counts than patients with BCR-ABL1 >10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. CONCLUSIONS: Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.
PURPOSE: Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. METHODS: BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. RESULTS: Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 <10 % showed higher lymphocyte counts than patients with BCR-ABL1 >10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinibpatients. CONCLUSIONS: Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.
Entities:
Keywords:
Bone marrow; CML; Lymphocyte; Therapy response; Tyrosine kinase inhibitor
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