Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia

Ilander, Mette; Olsson‐Strömberg, Ulla; Schlums, Heinrich; Guilhot, Joëlle; Brück, Oscar; Lähteenmäki, Hanna; Kasanen, Tiina; Koskenvesa, Perttu; Söderlund, Stina; Höglund, Martin; Markevärn, Berit; Själander, Anders; Lotfi, Kourosh; Dreimane, Arta; Lübking, Anna; Holm, Elena; Björeman, Mats; Lehmann, Sören; Stenke, Leif; Ohm, Lotta; Gedde‐Dahl, Tobias; Majeed, Waleed; Ehrencrona, Hans; Koskela, Satu; Saußele, Susanne; Fx, Mahon; Porkka, Kimmo; Hjorth‐Hansen, Henrik; Bryceson, Yenan T.; Richter, Johan; Mustjoki, Satu

doi:10.1038/leu.2016.360

Cited by 207 publications

(233 citation statements)

References 42 publications

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“…NKG2D represented the only differentially expressed receptor, decreased in MolR patients when compared to TFR at all three time points assessed. The functional degranulation response of CD3 − CD56 dim NK cells following target cell stimulation does not appear to be different between TFR and MolR (18, 136, 142). In further analysis by EURO-SKI, TFR patients had more NK cells that had downregulated CD16 (CD16 − ) upon K562 stimulation, suggesting an increased activity of these cells.…”

Section: Role Of the Immune System For Successful Tfrmentioning

confidence: 88%

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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Section: Role Of the Immune System For Successful Tfrmentioning

confidence: 88%

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

2017

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“…This unique lymphocyte changes could predict successful discontinuation. In another study by Ilander et al, patients with a higher number of NK cells and a mature NK cell subtype were more likely to stay in remission[38]. …”

Section: Who Is Eligible To Discontinue Therapy?mentioning

confidence: 99%

Chronic Myeloid Leukemia—the Promise of Tyrosine Kinase Inhibitor Discontinuation

Narra

Flynn

Atallah

2017

Curr Hematol Malig Rep

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Some believe that tyrosine kinase inhibitor (TKI) therapy is as close to perfect as it gets in oncologic therapy. Patients diagnosed with chronic myeloid leukemia (CML) are treated with a daily oral therapy, through which most achieve remission. TKI therapy is not associated with classic chemotherapy side effects, and most patients are able to resume their normal activities of daily living. Moreover, recent data has demonstrated that CML does not affect the life expectancy of patients whose disease is well-controlled with a TKI. However, TKI therapy is actually not that perfect. Patients need to stay on therapy forever. They have to remember to take their medications daily. TKIs are expensive, and the financial burden to patient and society cannot be overstated. Most patient’s health-related quality of life is affected; common side effects include fatigue, muscle cramps, pain, edema, skin problems, and gastrointestinal symptoms. In addition, concerns about long-term side effects remain. Recently several studies have shown the feasibility and safety of discontinuation in a select group of patients. Herein, we will review the currently available data on stopping TKIs in CML.

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“…[14] Immunologic predictive factors of TFR maintenance have also been identified in substudies from STIM1 and the European Stop TKI (EURO-SKI) trial. [58][59][60] These findings suggest that immunogenic effects of treatment may affect the probability of TFR success. Other factors associated with successful TFR include achievement of UMRD 9 months after switching from IFN to imatinib, [7] duration of imatinib 62 months, [15] imatinib withdrawal syndrome (i.e.…”

Section: Introductionmentioning

confidence: 99%

Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia

Caldemeyer

Akard

2016

Leukemia & Lymphoma

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With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses. With many patients achieving deep molecular responses to TKI therapy, there is growing interest in whether such patients can achieve TFR. In addition, adverse events (AEs) with long-term TKI therapy, including both the potential for later-emerging AEs and chronic, low-grade AEs, represent a major motivator for oncologists and their patients to investigate the feasibility of TFR. In this review, we provide an overview of data from TFR clinical trials, discuss the importance of achieving a deep molecular response to TKI treatment, and consider potential reasons for investigating TFR following TKI therapy. ARTICLE HISTORY

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Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia

Cited by 207 publications

References 42 publications

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

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

Chronic Myeloid Leukemia—the Promise of Tyrosine Kinase Inhibitor Discontinuation

Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia

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