Relative increase in lymphocytes from as early as 1 month predicts improved response to dasatinib in chronic-phase chronic myelogenous leukemia

Abstract

Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts >150 % at 1 month or >200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P < 0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells >200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.

Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation

“…We previously reported that a relative increase in the levels of NK cells with initial dasatinib was associated with higher DMR achievement. Increased levels of NK cells may function to exclude CML cells before achieving DMR . Such patients with increased levels of NK cells could achieve DMR and enter a cessation‐study such as the D‐STOP.…”

“…During the dasatinib‐consolidation phase, real‐time quantitative RT‐PCR (RQ‐PCR) analyses were performed every 3 months in the central laboratory (Bio Medical Laboratories [BML], Tokyo, Japan) to measure molecular responses according to the BCR‐ABL1 International Scale (IS) and the laboratory's conversion factor, as previously described . In summary, ABL1 was used as an internal control, and the cut‐off corresponded to BCR‐ABL1 of 0.0069% IS or molecular response of 4.0 (detectable disease with a BCR‐ABL1 <0.01% IS or undetectable disease in cDNA with >10 000 ABL1 transcripts) .…”

“…Peripheral white blood cell counts were measured using an automated cell count analyzer. The flow cytometry methods have been previously described . In brief, the lymphocyte fraction was determined using forward‐scatter vs side‐scatter gating (Figure ), and immunophenotypic examinations were performed using two‐color or three‐color flow cytometry on a FACSCalibur system with CellQuest software, version 3.3 (Becton Dickinson, Franklin Lakes, NJ, USA).…”

“…All antibodies used in this study were purchased from Becton Dickinson. The defined lymphocyte subsets comprised NK cells (CD3 − CD56 + and CD16 + CD56 + cells), NK‐cell LGL (NK‐LGL, CD56 + CD57 + ), helper T cells (CD4 + CD8 − ), cytotoxic T cells (CD4 − CD8 + ), T‐cell LGL (T‐LGL) (CD3 + CD57 + ) and regulatory T cells (Tregs) (CD4 + CD25 + CD127 dim/− ) (Figure ).…”

Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group

“…Studies have shown that dasatinib increases the number of lymphocytes, particularly natural killer cells and/or cytotoxic T lymphocytes, in the circulation [20][21][22]. These lymphocytes exhibit a large granular lymphocyte morphology and a differentiated immune phenotype [20][21][22][23].…”