Immune Monitoring In Patients With Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Treated With Frontline Nilotinib
2013
Imatinib and dasatinib modulate immune responses in vitro and in vivo . Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo . The ENEST1st study ([NCT01061177][1]) is focused on examining the role of firstline nilotinib therapy in CML-CP - this ENEST1st substudy involves a comprehensive immunological monitoring program.
To evaluate and characterize the immunomodulatory effects of nilotinib therapy in newly diagnosed CML-CP patients.
Peripheral blood was taken prior to treatment initiation and after 6 and12 months (mo) from 50 patients treated on the ENEST1st study. Samples were analyzed by nine color flow cytometry employing six panels of antibodies to determine various leukocyte populations including lymphocyte subsets (e.g. T cell subpopulations including Treg and NKT cells, NK cells, B cells), myeloid populations (e.g. monocytes, MDSC) and dendritic cell subsets (e.g. mDC, pDC), respectively. Changes in immune cell parameters were correlated to clinical endpoints and PK data.
55% of the patients included into this substudy achieved MMR at 6mo, 75% at 12mo and 79% at 12mo of therapy. MR4 was achieved by 21%, 31%, 50% of patients at 6, 12 and 24 mo of therapy, respectively. A high proportion of CD14+ monocytes with aberrant expression of CD56, present at baseline, dropped to undetectable levels at 6 and 12 mo of treatment. The most prominent immunological change from baseline to 12 mo was a dramatic increase of CD19+ B cells. The abundance of CD19+ B cells at baseline was negatively correlated with SOKAL score. Among T-cell subpopulations, the proportion of CD56+ NKT-cells decreased. Similarly, the proportion of CD8+ T cells significantly decreased concomitant with increasing CD4+ T cells during therapy. In parallel to a decrease of CD45RA+ expressing T cells among both CD8+ and CD4+ T cell subsets, the proportion of CD45R0+ memory cells increased. This increase was mainly due to an increase of the CD95+CD28+ central memory population. In contrast to our expectation, CD25high FoxP3+ Treg cells were even increased transiently 6 months after treatment initiation but at 12 months dropped back to levels seen at diagnosis. None of the immunological changes were associated with plasma levels of nilotinib or response to therapy.
Various immunological changes were detected during nilotinib therapy. However, most changes after therapy are most likely due to normalization of the peripheral blood compartment. Correlation of a specific immunological signature with response to nilotinib could not be identified. However the increased proportion of memory T cells during therapy suggests a potential contribution of the cellular immune response to the eradication of malignant cells. Molecular analyses of NKT-cells will show whether the increased proportion before therapy is due to aberrant expression of CD56 as in monocytes or a specific expansion of this subset.
Mustjoki: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Greil: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Thaler: Roche: Honoraria, Research Funding. Richter: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Verhoef: MedImmune: Research Funding. Mark: Novartis: Employment. Haenig: Novarts: Employment. Jurjonas: Novartis: Employment. Gastl: Novartis: Honoraria, Research Funding. Giles: Novartis: Consultancy, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Ossenkoppele: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Porkka: BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Wolf: Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Meyers Squibb: Honoraria.
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbloodjournal%2F122%2F21%2F2731.atom
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