EHA Education session: The role of the immune system in maintaining remission after stopping CML treatment
Lessons learned from treatment discontinuation studies are that nearly half of patients who have achieved deep molecular response at least for two years are able to discontinue TKI therapy. After discontinuation, residual CML on a very low, fluctuating PCR level has been detected in many patients. Similar issues have been observed with Interferon treatment in the 1990s where most patients had molecular evidence of residual disease despite successful discontinuation. Patients who had achieved good response on Interferon and have been able to stop therapy had increased levels of “natural killer immune cells” (NK-cells), lower levels of specific T-cells or a unique cytokine profile compared to those patients who failed stopping treatment. The immune mechanisms were also observed e.g. in the single-center study in Mannheim from 2001 where patients received imatinib and Peg-Interferon combination therapy and then subsequently stopped imatinib or both drugs.
In the STIM (France), DADI (Japan), EUROSKI (Europe), ISAV (Italy and Germany), TRAD (Canada) and STOP (Scandinavia) therapy-free remission studies, immunological sub-studies are currently being conducted with patients in those STOP trials to evaluate immunological factors, e.g. measuring lymphocyte subsets, dendritic cells or immunoglobuline receptors. For example, the EUROSKI immunology sub-study has already observed that higher individual levels of NK cells reduced the risk of relapse. When looking at timepoints of relapses after stopping treatment, especially those patients who relapsed early (within the first 6 months after stopping) had a lower proportion and number of NK-cells compared to non-relapsing patients.
It is currently not clear whether the immune-specific factors influencing the success of stopping treatment are specific to the individual patient (e.g. characteristics of receptors, HLA type, genetic factors) or are disease-specific (e.g. biology of the disease, immunosuppressive mechanisms by the CML itself, or antigen profile of CML cells). It is also not clear whether these factors can be influenced with drugs (e.g. Interferon, TKIs, vaccines, cytokines, targeted immunoagonists or immunoantagonists, NK-cell activating agents).
In summary, it is clear that patients who stay in remission have residual leukemia cells left in their body, which suggests that immune surveillance may play an important role when CML therapy is being stopped. Several studies have associated increased proportion and absolute number of NK cells in individual patients with better probability to discontinue TKI treatment. NK cells may function together with other cells of the immune system to prevent relapse. The role of the immune system will be further analysed in the ongoing studies and in larger patient cohorts, which may give the chance to find biomarkers for successful TKI discontinuation. Immuno-modulating treatments may have a role in the future therapy of CML to increase the number of patients successfully stopping TKI treatment.
--- Jan Geissler, 10 June 2016