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Both I RUNX1 i and I TP53 i mutations were already present in the PB DNA of patient II.5 at least one year before diagnosis, although the 5q deletion present at diagnosis was not detected. Additionally, we sequenced a posttransplant sample from patient II.5 in CR with positive MRD and detected the same mutations as in the diagnostic sample, but at lower allele frequencies: 2.7% I RUNX1 i p.L56S and 2% I TP53 i p.G245D. Although the reason why the second mutation occurred in I TP53 i in both patients is unknown, previous studies have demonstrated a cooperation between I RUNX1 i and I TP53 i . In addition, findings from this family add to the existing evidence that I RUNX1 i is a highly penetrant leukemia predisposing gene and that I TP53 i mutations are the final leukemia-causing event. [Extracted from the article]

Prognostic factors in Hodgkin lymphoma (HL) still fail to accurately identify high-risk patients. Tumor microenvironment in HL is a current focus of research for risk definition but few studies have focused on infiltrating lymphocytes. Here, we analyzed the number of tumor infiltrating lymphocytes by flow cytometry in diagnostic biopsies from 96 HL homogeneously treated patients with ABVD with or without radiotherapy. Most lymph node cells were lymphocytes (90 ± 17), with a median T/B/NK distribution of 74%/26%/0.7%, and CD4+T-cell predominance. The amount of CD19+B cells, and NK cells did not show association with disease features. However, high numbers of CD8+and CD4+cells were associated with better and poorer outcomes, respectively. Patients with ≥15% cytotoxic CD8+cells among the total cell population had a longer 10-year freedom from treatment failure (FFTF) (93% vs. 73%,p=.04). In turn, cases with ≥75% of CD4+infiltrating cells showed a significantly decreased FFTF (73% vs. 96%,p=.021). Consequently, CD4/CD8 ratio ≥5 associated with a poorer 10-year FFTF (69.5% vs. 94%,p=.02). This deleterious effect was particularly prominent in advanced disease (n = 58,p=.01). In multivariate analysis, a CD4/CD8 ratio ≥5 was the only independent variable to predict for treatment failure (HR = 4.5, 95% confidence interval, 1.2–16.8). In conclusion, our study shows that high CD4+and low CD8+T-cells infiltrates of tumor specimens associate with poor prognosis in HL patients, and CD4/CD8 ratio might be potentially useful for tailoring therapy. [ABSTRACT FROM PUBLISHER]

The International Prognostic Score (IPS) is the most widely used system to date for identifying risk groups for the outcome of patients with advanced Hodgkin lymphoma, although important limitations have been recognized. We analyzed the value of the IPS in a series of 311 patients with advanced classical Hodgkin lymphoma (cHL) (Ann Arbor stage III, IV or stage II with B symptoms and/or bulky masses) treated with first-line chemotherapy including adriamycin (adriamycin, bleomycin, vinblastine, dacarbazine [ABVD] or equivalent variants). In univariate and multivariate analyses, stage IV disease and age ≥ 45 years were the only factors with independent predictive significance for overall survival (OS) ( p == 0.002 and p < 0.001, respectively). Stage IV was still significant for freedom from progression (FFP) ( p == 0.001) and age ≥ 45 years was borderline significant ( p == 0.058). IPS separates prognostic groups, as in the original publication, but this is mainly due to the high statistical significance of stage IV and age ≥ 45 years. Moreover, the combination of these two factors enables a simpler system to be constructed that separates groups with different FFP and OS. In conclusion, in our series, stage IV and age ≥ 45 years are the key prognostic factors for the outcome of advanced cHL. [ABSTRACT FROM AUTHOR]

Our study revealed a new familial acute myeloblastic leukemia (AML) case with inherited I RUNX1 i mutations, detected in four of the six siblings analyzed, two of whom acquired mutations in I TP53 i and developed an AML. Pre-donor evaluation of an HLA matched sibling identifies a novel inherited RUNX1 mutation encoding a missense mutation found outside of the RUNT domain in familial platelet disorder. [Extracted from the article]