High BCR-ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses.Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABL transcripts at diagnosis with the outcome-defined by the 2013 European LeukemiaNet recommendations-of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR-ABL/GUSIS and BCR-ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings," 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates.Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189-98. ©2017 AACR.

A population-based study of chronic myeloid leukemia patients treated with imatinib in first line.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

Flow cytometric immunophenotyping analysis of patterns of antigen expression in non-Hodgkin's B cell lymphoma in samples obtained from different anatomic sites.

Multiparametric clinical flow cytometry has evolved from two-parameter quantitative assessment of lymphocytes to assessment of many qualitative parameters of suspensions obtained from bone marrow, peripheral blood, and lymph nodes for hematopathology. Nowadays, lymphoma immunophenotyping is a necessary complement to morphology and molecular parameters in the diagnosis and monitoring of human hematopoietic malignancies. The aim of the present study was to determine whether immunophenotypic differences could be used to distinguish between non-Hodgkin's B cell lymphoma (NHL-B) and the normal B cell subpopulation by assessing the variability in the patterns of expression of some lymphoid antigens (CD5, CD19, FMC7, CD23, CD20, CD79b, CD38, CD22, CD10, sIgkappa, sIglambda, mIgA, mIgG, mIgM, and mIgD) in specimens obtained from patients with NHL-B. We have studied peripheral blood samples, lymph node suspensions, and bone marrow specimens from 20 patients with malignant lymphoma and from controls without oncohematologic disease. Some patients showed stable patterns of antigen expression that remained unchanged over time and were consistent from one specimen to another. Other patients showed more variability in the pattern of antigen expression from different specimens. The two-way cluster analysis of antigens revealed three patterns of expression: (1) most cells in most cases positive (CD5, CD19, CD20, CD23, CD45); (2) most cells in most cases negative (CD10, mIgG, CD22, CD23,CD38); and (3) a mixed pattern with a variable number of positive cases and a variable percentage of positive cells in individual cases (CD22, CD38, CD79b, FMC7, mIgD, mIgM, mIgA, mIgG, sIgkappa, sIglambda). The expression of several antigens was strongly interdependent, even when antigens belonged to entirely different gene families. Such antigen pairs were CD19/CD45; CD19/CD79b; CD23/Igkappa; and CD45/CD79b. Our results suggest that different factors may determine the stability or the variability of such multiantigen expression, particularly the biology and function of the different antigens and the mechanisms of disease dissemination and progression.