Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line

Abstract

Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naïve and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

Long‐term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome–positive leukemia resistant or intolerant to prior therapy

“…22 The mechanism of action for bosutinib is unclear; however, major TA B L E 7 Management of cardiac, vascular, hypertension, and effusion TEAEs immunological changes during treatment do not seem to be the predominant factor. 23 Although nilotinib treatment has been associated with fluid-retention AEs, such as peripheral edema, the incidence of pleural effusion is relatively low (~1-2%). 24 This study determined age ≥ 65 years, ECOG PS > 0, a history of hyperlipidemia, and a history of cardiac disorders were prognostic risk factors of cardiac AEs and history of vascular disorders to be prognostic of vascular AEs with bosutinib treatment.…”

“…The mechanism of action with dasatinib has been associated with increase of lymphocytes, specifically natural killer cells 22 . The mechanism of action for bosutinib is unclear; however, major immunological changes during treatment do not seem to be the predominant factor 23 . Although nilotinib treatment has been associated with fluid‐retention AEs, such as peripheral edema, the incidence of pleural effusion is relatively low (~1‐2%) 24 …”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“… 77 , 81 , 82 Conversely, immune suppressor cells such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) expand during disease progression or relapse and are reduced following TKI therapy. 77 , 80 Other immunological factors, such as dendritic cells (DCs), 83 plasmacytoid dendritic cells (pDCs), 84 CD8 + cytotoxic T-cells (CTLs), 85 leukemia-associated antigens (LAAs), 86 and B-cells, 87 also play a pivotal role in contributing to CML; however, further investigation should be launched to explore their impact on therapy responses. Additionally, studies have also indicated that imatinib and dasatinib treatment generates a more active immune system, and changes were not observed during bosutinib treatment.…”

Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

“…Furthermore, imatinib and dasatinib impair CD8+ CTLs specifically directed against LAA function in vitro [ 19 , 20 ], and dasatinib also inhibits NK cell function [ 21 ]. In contrast to the in vitro results, clinical data showed that imatinib or dasatinib treated patients exhibit expansion of CD8+ CTLs or NK cells which are associated with an improved response to therapy [ 22 – 24 ]. Furthermore, dasatinib may induce a reversible state of aberrant immune reactivity, leading to large granular lymphocytic lymphocytosis, which is associated with a favorable clinical response [ 22 ].…”