Immune modulation in chronic myeloid leukaemia patients treated with nilotinib and interferon‐alpha

Abstract

SummaryThe addition of interferon to tyrosine kinase inhibitors (TKIs), to improve deep molecular response (DMR) and potentially treatment‐free remission (TFR) rates in chronic‐phase chronic myeloid leukaemia (CP‐CML) patients is under active investigation. However, the immunobiology of this combination is poorly understood. We performed a comprehensive longitudinal assessment of immunological changes in CML patients treated with nilotinib and interferon‐alpha (IFN‐α) within the ALLG CML11 trial (n = 12) or nilotinib alone (n = 17). We demonstrate that nilotinib+IFN transiently reduced absolute counts of natural killer (NK) cells, compared with nilotinib alone. Furthermore, CD16+‐cytolytic and CD57+CD62L−‐mature NK cells were transiently reduced during IFN therapy, without affecting NK‐cell function. IFN transiently increased cytotoxic T‐lymphocyte (CTL) responses to leukaemia‐associated antigens (LAAs) proteinase‐3, BMI‐1 and PRAME; and had no effect on regulatory T cells, or myeloid‐derived suppressor cells. Patients on nilotinib+IFN who achieved MR4.5 by 12 months had a significantly higher proportion of NK cells expressing NKp46, NKp30 and NKG2D compared with patients not achieving this milestone. This difference was not observed in the nilotinib‐alone group. The addition of IFN to nilotinib drives an increase in NK‐activating receptors, CTLs responding to LAAs and results in transient immune modulation, which may influence earlier DMR, and its effect on long‐term outcomes warrants further investigation.

Interferon in chronic myeloid leukaemia: Is it useful for treatment‐free remission?

“…In their paper the authors performed a very exhaustive prospective study to detect the effects of nilotinib plus IFNα in newly diagnosed CML patients enrolled in the PINNACLE trial. 11 The study included evaluation of NK cells, T and Bcells, T-regs and monocytic myeloid-derived suppressor cells (MDSCs) and assessment was performed in a dynamic way at different time points (earlier if <5 months from the start, and later if assessed after the first 5 months of treatment). The results showed a behaviour of NK cells changing with time: a transient reduction in the early time point was followed by a reduction of cytolytic and mature NK cells, without affecting the functionality, in the later time points in patients treated with IFNα + nilotinib.…”