Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML

Schütz, C.; Inselmann, Sabrina; Saußele, Susanne; Dietz, Christian; Müller, Martin C.; Eigendorff, Ekkehard; Brendel, Cornelia; Metzelder, Stephan; Brümmendorf, Tim H.; Waller, Christiane; Dengler, Jolanta; Goebeler, Matthias; Herbst, Regina; Freunek, G.; Hanzel, Stefan; Illmer, Thomas; Wang, Y.; Lange, Thoralf; Finkernagel, Florian; Hehlmann, Rüdiger; Huber, Magdalena; Neubauer, Andreas; Hochhaus, Andreas; Guilhot, Joëlle; Fx, Mahon; Pfirrmann, Markus; Burchert, Andreas

doi:10.1038/leu.2017.9

Cited by 82 publications

(73 citation statements)

References 53 publications

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“…Some studies have recently indicated that an increased proportion of mature natural killer cells and expression of the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) ligand CD86 on plasmacytoid dendritic cells are associated with the risk of relapse after TKI discontinuation. Therefore, immunologic factors may be linked with molecular relapse-free survival, [30][31][32] as also suggested by the higher rates of successful TFR associated with prior treatment with recombinant interferon, an immunomodulatory agent. 20 In this context, the differences in transcript immunogenicity may help to explain the differences observed in TFR in the current study between subgroups with the e13a2 and e14a2 transcripts.…”

Section: Discussionmentioning

confidence: 99%

The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

D’Adda

Farina

Schieppati

et al. 2019

Cancer

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Background Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment‐free remission (TFR). Methods The potential predictive role of BCR‐ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors’ center. Results Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second‐generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second‐generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. Conclusions The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.

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Section: Discussionmentioning

confidence: 99%

The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

D’Adda

Farina

Schieppati

et al. 2019

Cancer

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“…In addition, the TNF-α/IFN-γ cytokine secretion by these activated CD56 dim CD16 − NK cells correlated with TFR success (18). A separate sub-study of 122 EURO-SKI patients has recently reported that increased CD86 + pDCs, which mediate immune tolerance are found in MolR patients at the time of TKI cessation, and thus low CD86 + pDC might be predictive of TFR (19). This study also found that higher numbers of pDCs correlated with increased PD-1-expression on PR3-specific CD8 + CTLs, suggesting immune exhaustion contributes to relapse risk.…”

Section: Role Of the Immune System For Successful Tfrmentioning

confidence: 99%

“…Very recently, an increased proportion of mature, adaptive-like CD56 dim NK cells have been observed in CML patients who successfully discontinued imatinib (18). Other immunologic mediators such as plasmacytoid dendritic cells (pDCs), which may serve as promising prognostic factors for successful TFR, are also currently under investigation (19). TKIs also exert significant off-target multikinase inhibitory effects, albeit with differing potencies.…”

Section: Introductionmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

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“…Immunological biomarkers at the time of TKI discontinuation are linked to the likelihood of continuous TFR, including increased natural killer (NK) cells [10,11] and CD86-positive plasmacytoid dendritic cells (pDC) [12] numbers and function, the latter being also linked to a T cell exhaustion phenotype with high PD-1 expression potentially also at least in part explaining limited anti-leukemic potency of leukemia antigen(LAA)-specific cytotoxic T lymphocytes. The latter study also suggested that the number of CD86-positive pDC overrules the time effect of previous therapy on TFR likelihood, as in patients with high CD86 pDC numbers (>95/µl) the effect of previous TKI therapy duration does not at all impact TFR rates, whereas in patients with low CD86 pDC numbers, long-term TKI pretreated patients have a 90% success rate of being continuously TKI free.…”

Section: Which Biomarkers Predict Successful Treatmentfree Remission?mentioning

confidence: 99%

My burning issues in TKI therapy and treatment-free remission in CML

Wolf

2017

memo

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Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML

Cited by 82 publications

References 53 publications

The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

My burning issues in TKI therapy and treatment-free remission in CML

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