ABSTRACT
Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Fusion Proteins, bcr-abl/genetics , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic useABSTRACT
PURPOSE: To report a case of atypical corneal lesions presumably induced by trastuzumab emtansine, an antibody-drug conjugate that is designed to selectively deliver cytotoxic agents to human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. CASE: A 64-year-old Japanese woman developed bilateral corneal epithelial abnormalities that originated from the limbus. The corneal lesions covered the superior area in the right eye and both superior and inferior areas including the visual axis in the left eye. The patient had advanced ductal carcinoma of the left breast and had been receiving anticancer treatment with trastuzumab emtansine for 15 months. After switching the chemotherapy from trastuzumab emtansine monotherapy to the combination of docetaxel, trastuzumab, and pertuzumab, the abnormal corneal lesions showed gradual improvement. CONCLUSIONS: As corneal epithelial cells express human epidermal growth factor receptor 2 under normal conditions, such cells may also be targeted by trastuzumab emtansine and lead to corneal epithelial lesions.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Corneal Diseases/chemically induced , Epithelium, Corneal/drug effects , Maytansine/analogs & derivatives , Ado-Trastuzumab Emtansine , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Corneal Diseases/diagnosis , Corneal Diseases/physiopathology , Drug Substitution , Epithelium, Corneal/metabolism , Epithelium, Corneal/pathology , Female , Humans , Maytansine/adverse effects , Middle Aged , Receptor, ErbB-2/metabolism , Trastuzumab , Visual AcuityABSTRACT
PURPOSE: In a recent study to purify adult T-cell leukemia-lymphoma (ATL) cells from acute-type patients by flow cytometry, three subpopulations were observed in a CD3 versus CD7 plot (H: CD3(high)CD7(high); D: CD3(dim)CD7(dim); L: CD3(dim)CD7(low)). The majority of leukemia cells were enriched in the L subpopulation and the same clone was included in the D and L subpopulations, suggesting clonal evolution. In this study, we analyzed patients with indolent-type ATL and human T-cell leukemia virus type I (HTLV-I) asymptomatic carriers (ACs) to see whether the CD3 versus CD7 profile reflected progression in the properties of HTLV-I-infected cells. EXPERIMENTAL DESIGN: Using peripheral blood mononuclear cells from patient samples, we performed multi-color flow cytometry. Cells that underwent fluorescence-activated cell sorting were subjected to molecular analyses, including inverse long PCR. RESULTS: In the D(%) versus L(%) plot, patient data could largely be categorized into three groups (Group 1: AC; Group 2: smoldering- and chronic-type ATL; and Group 3: acute-type ATL). Some exceptions, however, were noted (e.g., ACs in Group 2). In the follow-up of some patients, clinical disease progression correlated well with the CD3 versus CD7 profile. In clonality analysis, we clearly detected a major clone in the D and L subpopulations in ATL cases and, intriguingly, in some ACs in Group 2. CONCLUSION: We propose that the CD3 versus CD7 plot reflects progression of disease stage in patients infected with HTLV-I. The CD3 versus CD7 profile will be a new indicator, along with high proviral load, for HTLV-I ACs in forecasting disease progression.
Subject(s)
Antigens, CD7/metabolism , CD3 Complex/metabolism , Disease Progression , Flow Cytometry , Human T-lymphotropic virus 1/physiology , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/virology , Adult , Aged , Antigens, CD7/chemistry , Asymptomatic Infections , CD3 Complex/chemistry , Color , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathology , Male , Middle Aged , Prognosis , Protein Multimerization , Protein Structure, Quaternary , Risk Factors , Viral LoadABSTRACT
The morphological discrimination of leukemic from non-leukemic T cells is often difficult in adult T-cell leukemia (ATL) as ATL cells show morphological diversity, with the exception of typical "flower cells." Because defects in the expression of CD3 as well as CD7 are common in ATL cells, we applied multi-color flow cytometry to detect a putative leukemia-specific cell population in the peripheral blood from ATL patients. CD4(+) CD14(-) cells subjected to two-color analysis based on a CD3 vs CD7 plot clearly demonstrated the presence of a CD3(dim) CD7(low) subpopulation in each of nine patients with acute-type ATL. The majority of sorted cells from this fraction showed a flower cell-like morphology and carried a high proviral load for the human T-cell leukemia virus type 1 (HTLV-I). Genomic integration site analysis (inverse long-range PCR) and analysis of the T cell receptor Vß repertoire by flow cytometry indicated that the majority of leukemia cells were included in the CD3(dim) CD7(low) subpopulation. These results suggest that leukemic T cells are specifically enriched in a unique CD3(dim) CD7(low) subpopulation of CD4(+) T cells in acute-type ATL.
