Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study.

Lymphoproliferative disease of granular lymphocytes (LDGL) is a recently recognized, relatively rare atypical lymphocytosis characterized by the presence of over 2000 lymphocytes with cytoplasmic azurophilic granules/mm3 in the peripheral blood. The clinical course is heterogeneous, varying from spontaneous regression to progressive, malignant disease. As a consequence, clinical intervention is not standardized. In a worldwide multicenter study, the authors observed 151 patients with LDGL for a mean follow-up time of 29 months. Forty-three patients were asymptomatic at the time of diagnosis. In the remaining cases, clinical symptoms included fever (41 cases), infections (58), neutropenia (47), anemia (17), and thrombocytopenia (12). In 69 cases, LDGL coexisted with an associated disease. Most patients had a nonprogressive clinical course despite the presence of severe symptoms. In 19 patients, death related to LDGL occurred within 48 months. The authors investigated which features at diagnosis were significantly associated with increased mortality. In the univariate analysis, lymph node and liver enlargement, fever at presentation, skin infiltration, a low (less than or equal to 5000/mm3) or high (greater than 20,000/mm3) peripheral leukocyte count, relatively low (less than or equal to 3000) or high (greater than 7000/mm3) absolute peripheral granular lymphocyte (GL) count, and a low (less than or equal to 15%) percentage of HNK-1-positive cells were found to be predictors of increased mortality. In the multivariate analysis, significant independent predictors were fever at diagnosis, a low (less than or equal to 15%) percentage of HNK-1-positive peripheral blood mononuclear cells (PBMC) and a relatively low (less than or equal to 3000) GL count. These results showed that about 25% of the patients with LDGL were diagnosed after a routine blood count and had no clinical symptoms. The remaining patients were symptomatic, with some experiencing a fatal clinical course. The author's analysis of the significant prognostic features of LDGL may help in understanding the heterogeneous nature of this syndrom

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies

The risk of venous thromboembolism associated with peripherally inserted central catheters in ambulant cancer patients

Background Deep vein thrombosis (DVT) is a common complication of peripherally inserted central catheters (PICCs). PICCs are increasingly utilised in the management of cancer patients, a group which carries both additional risks for vascular thromboembolism as well as for complex morbidity. We analysed a cohort of cancer patients subjected to PICC insertion in a single cancer centre for the incidence of all-type vascular thromboembolism (VTE) and investigated relative risk factors. Methods In this clinical audit, the records of patients referred for PICC insertion in our centre in the period between 1/1/2011 and 1/4/2014 were retrospectively reviewed. The primary outcomes investigated were a) PICC-related deep vein thrombosis (PRDVT) and b) distant VTE (lower limb DVT and pulmonary embolism). 4Fr single lumen PICCs were placed in all patients. The Kaplan Meier method was used to study time from PICC insertion to PRDVT/VTE. Survival curves were compared using the log rank method. Logistic and Cox regression analyses were used to assess local, distant and combined endpoints. Results Four hundred ninety patients were included in the analysis of which 27 (5.5%) developed a PRDVT. Statistically significant risk factors for developing PRDVT in multivariate analysis included more than one attempt for insertion (OR 2.61, 95%CI: 1.12–6.05) and the use of fluoropyrimidine containing chemotherapy (OR 4.27, 95%CI 1.3–14.07). Twenty-six patients developed a distant VTE. Male gender was the only significant risk factor for distant VTE. When all-type VTE were considered together fluoropyrimidine containing chemotherapy (OR 4.54, 95% CI 1.63–12.61), male gender (OR 2.03, 95% CI 1.04–3.93) and white cell count (OR 1.12, 95% CI 1.00–1.26) were statistically significant as risk factors in this analysis. Conclusions This is a large study of VTE following PICC insertion in cancer patients which also looks at the rate of distant VTE. The observed PRDVT incidence is comparable with available literature. Fluoropyrimidine containing chemotherapy and more than one attempt for PICC insertion were independent predictors of PICC-associated VTE whilst the former remained an independent predictor of all-type VTE. Anticoagulation did not prevent thrombotic events in this cohort

Cyclophosphamide as a first-line therapy in LGL leukemia.

Cyclophosphamide as a first-line therapy in LGL leukemi