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.

No abstract

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...

No abstract

Objectives As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care. Methods We used the population‐based Swedish ALL Registry to evaluate characteristics, treatment and long‐term outcome in 933 patients with diagnosis between 1997 and 2015. Results The median age was 53 years. The frequency of Philadelphia (Ph)‐positive leukaemia was 34% of examined B‐ALL with a peak incidence at 50‐59 years. Five‐year overall survival (OS) improved between 1997‐2006 and 2007‐2015; in patients 18‐45 years from 50% (95% CI 43‐57) to 65% (95% CI 58‐72), 46‐65 years from 25% (95% CI 18‐32) to 46% (95% CI 37‐55) and >65 years from 7% (95% CI 2.6‐11) to 11% (95% CI 5.9‐16) (P < 0.05). Men with Ph‐neg B‐ALL 46‐65 years had inferior OS compared with women (P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0‐6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph‐positive disease was not associated with impaired prognosis but with lower risk of death in 2007‐2015. Conclusions In a population‐based cohort, OS has improved in adult ALL, especially for Ph‐positive disease but for middle‐aged men with Ph‐negative B‐ALL outcome was poor. Cure without late toxicity or relapse is still desired.

Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor ␣ (IL-7R␣) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7R␣, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7-independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l Ϫ/Ϫ mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in IntroductionGrowth factor dependent hematopoietic cell lines can on overexpression of the antiapoptotic regulator B-cell lymphoma-2 (BCL2) become independent of cytokines of the hematopoietin family. 1 In vivo studies demonstrating that defective thymopoiesis in interleukin-7 (IL-7)-and IL-7R␣-deficient (Il7 Ϫ/Ϫ and Il7r Ϫ/Ϫ ) mice can be rescued on overexpression of BCL2 2-4 or by deleting the proapoptotic regulator Bax, 5 further support the hypothesis that hematopoietin family cytokine receptors play a permissive role in thymopoiesis. Hematopoiesis is also regulated by a distinct family of cytokines acting through tyrosine kinase receptors, such as KIT oncogene (KIT) and FMS-like tyrosine kinase 3 (FLT3). 6 Notably, although KIT, like IL-7R␣, is critically involved in the regulation of thymopoiesis, BCL2 overexpression failed to rescue the impaired T lymphopoiesis in This implies that at least some members of this family of cytokine receptors and ligands, unlike the hematopoietin family, might not promote hematopoiesis through permissive actions.More recently, FLT3 ligand (FLT3L) has emerged as a key regulator of T lymphopoiesis, including of IL-7R␣-independent thymopoiesis, 8-12 but it has not been investigated to what degree FLT3 might act through permissive actions. Furthermore, as both IL-7 and thymic stromal lymphopoietin (TSLP) share the IL-7R␣, it is unclear to what degree the almost completely arrested T lymphopoiesis in adult Flt3l Ϫ/Ϫ Il7r Ϫ/Ϫ mice 8 reflects a role of FLT3L in conjunction with IL-7 and/or TSLP. TSLP also depends on and acts through a second IL-2R gamma chain (IL-2R␥)-like TSLP receptor (TSLPR) subunit 13 and has been shown to modulate immunologic responses by activating T cells through regulation of dendritic cells. 14 TSLP has also been implicated to play an important role in IL-7-independent B lymphopoiesis, as Il7r Ϫ/Ϫ mice have ...

No abstract