Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy

Abstract

In a proportion of patients with chronic myeloid leukemia (CML) being treated with dasatinib, we recently observed large granular lymphocyte (LGL) expansions carrying clonal T-cell receptor (TCR) ␥/␦ gene rearrangements. To assess the prevalence and role of clonal lymphocytes in CML, we collected samples from patients (n ‫؍‬ 34) at the time of diagnosis and during imatinib and dasatinib therapies and analyzed lymphocyte clonality with a sensitive polymerase chain reaction-based method of TCR ␥ and ␦ genes. Surprisingly, at CML diagnosis, 15 of 18 patients (83%) had a sizeable clonal, BCR-ABL1 negative lymphocyte population, which was uncommon in healthy persons (1 of 12; 8%). The same clone persisted at low levels in most imatinibtreated patients. In contrast, in a distinct population of dasatinib-treated patients, the diagnostic phase clone markedly expanded, resulting in absolute lymphocytosis in blood. Most patients with LGL expansions (90%) had TCR ␦ rearrangements, which were uncommon in patients without an LGL expansion (

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

“…[32][33][34] Moreover, the mechanisms underlying the clinically relevant clonal lymphoproliferation in some patients under dasatinib are unresolved. [35][36][37][38] Thus, the in vivo immune effects of TKIs in CML deserve further study. Longitudinal analysis of lymphocyte sub-populations in CML patients on imatinib was subject to one previous report.…”

“…29 Importantly, despite the immunosuppressive activities reported for both drugs in vitro, functional T-cell responses were reported to develop in CML patients on imatinib, [32][33][34] and clonal lymphoproliferation was observed in some patients on dasatinib and was associated with favorable clinical responses. [35][36][37][38] Thus, further in vivo studies are needed to discern the effects of TKIs on immune effector cells.…”

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…15,17 Measurements of plasma CMV DNA viral load were performed on the basis of clinical indications using a quantitative polymerase chain reaction assay, with a detection limit of 250 copies/ml plasma. Dasatinib patients were grouped according to the presence or absence of LGL expansions, defined as an increased absolute lymphocyte count 43.6 Â 10 9 /l with morphological characteristics of LGLs.…”

“…15,16 The CD8 þ T-cell or NK-cell clones are present during the diagnostic phase of the disease and expand with dasatinib therapy, leading to a numerical and fractional lymphocytosis. 17 Thus, dasatinib does not induce these clones, but rather appears to promote their preferential expansion.…”

Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies

“…1,2 Although well described in the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, 3, the clinical and pathologic diagnosis often remains elusive, as patients can exhibit significant polyclonal or oligoclonal proliferations of LGLs in reactive conditions. [4][5][6] Because clonal T-cell receptor (TCR) gene rearrangements can be identified in patients without neoplastic conditions, 7 the detection of T-cell clonality is often not sufficient to predict whether an LGL proliferation is neoplastic or reactive. Therefore, predicting and defining patients with increased LGLs as a significant monoclonal, neoplastic proliferation remain difficult.…”