Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

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Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 μg/week and it increased to 25 μg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

Phenotypically and functionally distinct progenitors and developmental pathways have been proposed to exist for fetally derived B-1 and conventional B-2 cells. Although IL-7 appears to be the primary cytokine regulator of fetal and adult B lymphopoiesis in mice, considerable fetal B lymphopoiesis and postnatal B cells are sustained in the absence of IL-7; in humans, B-cell generation is suggested to be largely IL-7-independent, as severe combined immune-deficient patients with IL-7 deficiency appear to have normal B-cell numbers. However, the role of other cytokines in IL-7-independent B lymphopoiesis remains to be established. Although thymic stromal lymphopoietin (TSLP) has been proposed to be the main factor driving IL-7-independent B lymphopoiesis and to distinguish fetal from adult B-cell progenitor development in mice, recent studies failed to support a primary role of TSLP in IL-7-independent fetal B-cell development. However, the role of TSLP in IL-7-independent adult B lymphopoiesis and in particular in regulation of B-1 cells remains to be established. Here we demonstrate that, rather than TSLP, IL-7 and FLT3 ligand are combined responsible for all B-cell generation in mice, including recently identified B-1-specified cell progenitors. Thus, the same IL-7-and FLT3 ligand-mediated signaling regulates alternative pathways of fetal and adult B-1 and B-2 lymphopoiesis. IntroductionHuman immunodeficiencies have uncovered the key role of cytokine signaling pathways in T lymphocyte development, facilitating development of cell replacement and gene therapies. 1,2 In contrast, little is known about the cytokine pathways that might be perturbed in immunodeficiencies with a B-cell phenotype.In mice, fetal and adult B-cell development has been suggested to be regulated by overlapping yet largely distinct cytokine ligands and receptors. [3][4][5][6][7][8][9] Specifically, whereas conventional B-2 B lymphopoiesis in the adult bone marrow (BM) is lost in the absence of only interleukin-7 (IL-7), fetal and early postnatal B lymphopoiesis, in particular B-1 B-cell genesis, seems to be largely driven by IL-7-independent mechanisms. 10-12 Importantly, such IL-7-independent B lymphopoiesis is sufficient to sustain a pool of peripheral B cells and normal immunoglobulin levels through life. 3,13 Notably, also human B-cell development appears to be largely or entirely IL-7-independent, as X-linked severe combined immunodeficiency caused by a loss of function mutation in the IL-2 receptor gamma chain (IL-2Rg), as well as IL-7 receptor alpha chain (IL-7R␣) deficiency, are accompanied by severely defective T lymphopoiesis but apparently normal B-cell numbers. 14-16 Thus, it could have considerable clinical implications to establish which alternative cytokines might be involved in regulating IL-7-independent B lymphopoiesis.Several previous lines of evidence strongly implicated thymic stromal lymphopoietin (TSLP) as a primary regulator of IL-7-independent fetal B lymphopoiesis. 8,9 TSLP shares with IL-7 the IL-7R␣ as a ligand-b...