Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

Abstract

Key Points• TKIs impair B-cell immune responses in CML through off-target inhibition of kinases important for B-cell signaling.• Our results call for close monitoring of patients on TKI to assess the long-term impact of impaired B-cell function.Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P 5 .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-g2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML. (Blood. 2013;122(2):227-238)

Emerging EPO and EPO receptor regulators and signal transducers

“…85 In oncology contexts, promising inhibitors of SRC are being developed that additionally can affect Plc-g1 and/or RAS circuits. 86,87 For these agents, potential compromising effects on erythropoiesis should also be considered.…”

Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans

“…The cells in each tube were then stained with anti-CD56 BV605 (IgG1, clone HCD56), anti-CD3 APC-cyanin 7 (Cy7 (IgG1, SK7) and anti-NKG2C FITC (IgG1, clone 134591). The cells were then lysed, permeabilized and stained with anti-IFN-g VG-450 (IgG1, clone B27), as described previously [38]. The anti-CD3, anti-CD107a and anti-IFN-g antibodies were purchased from BD Biosciences; the anti-CD56 antibody from Biolegend (San Diego, CA, USA); and the anti-NKG2C antibody from R&D Systems.…”

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

“…Although it will be important to gather more data in prospective studies, we recommend that pediatric patients who are treated with TKIs off protocol are at least monitored for height, weight, and Tanner stage on every visit, in addition to periodic bone age and dual-energy x-ray absorptiometry scans, and that an endocrinology consultation is pursued if there are abnormal patterns (Table 3). 3 TKIs appear to cause immune dysfunction to some degree, 70 which interferes with routine immunizations in children. Live vaccines are not recommended.…”