Immunomodulatory Influence by Interferon alpha and Imatinib Mesylate in Chronic Myeloid Leukemia.
Authors: Yokoyama Kazuaki , Nagamura-Inoue Tokiko , Nakayama Shin , Ishige Ikuo , Ohno Nobuhiro , Takahashi Satoshi , Uchimaru Kaoru , Iseki Toru , Tojo Arinobu 
Published: October 2019

Objectives: Imatinib mesylate (STI) is the first-line therapy for chronic myeloid leukemia in the chronic phase (CML-CP). However, STI as well as interferonα (IFN) has been reported to inhibit both T-cell activation and B cell function. To clarify the immunological differences by the type of therapy, we compared immunological parameters between CML patients in very good CyR to either STI or IFN as well as normal volunteers. We also studied the in vitro effects of STI on immune cell function.

Patients and Methods: Each group comprised 14 subjects. The median treatment dose and duration were 6 MIU/week and 174 months for IFN, and 400 mg/day and 54 months for STI, respectively. Peripheral blood sample was used and subjected to multi-color flow cytometry (FCM) acquisition and analysis. For analysing TCR-mediated activation of T cells, we stained MNC with CFSE and stimulated those with anti-CD3/CD28 antibodies in the presence of STI at various concentrations for 4 days, followed by FCM.

Results: The summary is shown in Table. WBC counts were well controlled at moderately lower levels than in the control group of normal volunteers: Hb levels were significantly reduced in the STI-group compared to the other two groups (P<0.0001), while platelet counts were lower in the IFN-group than in the control group (P<0.01). The number of T cells was significantly lower in both patient groups (P=0.0006), while the NK cell number was comparable among the three groups. Not only the absolute numbers of monocytes and B cells but also serum IgG and IgA titers were significantly lower in the STI- than IFN-group (P<0.0001). For T-cell subsets, the ratio of CD4/8 T cells was significantly lower, but that of CD26highCD4+ T cells was significantly higher in the IFN- than STI-group. TCR-triggered T cell proliferation was suppressed by STI in a dose dependent manner. Intriguingly, we also found that STI treatment resulted in significant down-regulation of CD4+CD26high T cell population which is considered as a subset of effector T cells. Collectively, our data imply that the two therapeutic agents induce a distinct immunological status in CML patients, and also raise the possibility that immunological surveillance of residual Ph clone may be somewhat defective in patients receiving STI for prolonged periods. In addition, STI revealed the inhibitory effect on TCR-mediated T cell activation in vitro. Finally, the periodic monitoring of immunological parameters is recommended for these patients.

Control IFN STI No.of Subjects 14 14 14 Median age (range) 41 (30–63) 50 (39–73) 54 (29–65) Immune parameters Mean (SD) p value WBC (10^9/L) 5.50 (1.21) 4.81 (1.36) 3.95 (0.89) .0056 T cells (10^9/L) 1.02 (0.22) 0.63 (0.28) 0.59 (0.28) .0006 CD26high/CD4+T cells (%) 9.12 (5.19) 12.08 (5.01) 7.92 (3.65) .0407 Monocytes (10^8/L) 2.81 (0.53) 3.56 (1.52) 1.87 (1.10) .0003 B cells (10^8/L) 2.67 (1.34) 2.61 (1.67) 1.38 (0.94) .0201 Serum IgG (g/L) 15.63 (3.95) 10.32 (2.10) <.0001 Serum IgA (g/L) 3.70 (0.24) 2.32 (0.24) .0013