Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.
Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.
Mustjoki
S
S
Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Ekblom
M
M
Arstila
T P
TP
Dybedal
I
I
Epling-Burnette
P K
PK
Guilhot
F
F
Hjorth-Hansen
H
H
Höglund
M
M
Kovanen
P
P
Laurinolli
T
T
Liesveld
J
J
Paquette
R
R
Pinilla-Ibarz
J
J
Rauhala
A
A
Shah
N
N
Simonsson
B
B
Sinisalo
M
M
Steegmann
J L
JL
Stenke
L
L
Porkka
K
K
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D015331:Cohort Studies; D003092:Colitis / Q000139:chemically induced; D000069439:Dasatinib; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D008218:Lymphocytosis / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D010998:Pleurisy / Q000139:chemically induced; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib