Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richter's transformation and 1 Hodgkin's disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84-4.55) for second malignancy and 2.69 (95% CI 1.62-4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).

Telomerase RNA deficiency in peripheral blood mononuclear cells in X-linked dyskeratosis congenita.

Compromised renewal and eventual failure of the hematopoietic system in dyskeratosis congenita (DC) have been proposed to arise from a deficiency in telomerase function. Previously, cultured cell lines from patients with X-linked DC were shown to accumulate less telomerase RNA than cell lines from unaffected family members. Here, we report that telomerase RNA deficiency is also present in the circulating lymphocytes of DC patients. We have compared the accumulation levels of telomerase RNA and a panel of other small RNAs in peripheral blood mononuclear cells from an X-linked DC patient and an unaffected maternal carrier and similarly analyzed cultured lymphoblasts from an X-linked DC patient and maternal carrier in a second family. The DC-patient lymphoid cells show a specific defect in telomerase RNA accumulation with or without cell culture. Our findings support the clinical significance of telomerase deficiency and encourage the use of telomerase activation as a disease therapy.

Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by an acquired immune defect that can cause autoimmune complications, including anemia and thrombocytopenia. We conducted an observational study of the epidemiology, clinical presentation and significance of autoimmune complications of CLL/SLL in 132 patients from a large population (>45,000 veterans), in which at least 90% of patients with CLL/SLL have been previously identified. Over a period of 12.5 years, 12 patients (9.1%) had autoimmune complications; of these, 6 (4.5%) had autoimmune hemolytic anemia (AIHA), 5 (3.8%) had immune thrombocytopenia (ITP), and 1 (0.8%) had pure red blood cell aplasia (PRBA). All 6 cases of AIHA had a positive direct immunoglobulin test for IgG and C3d. In 6 patients, CLL/SLL was an incidental finding at the time of presentation with autoimmune cytopenia. Nine out of 10 patients responded to immunosuppressive therapy, which was complicated by serious infection in 7 cases, one of which was fatal. The major cause of mortality in patients with autoimmune complications of CLL/SLL was secondary malignancy. Survival of patients with immune cytopenia was not significantly different from CLL/SLL patients without immune cytopenia. Among patients with anemia or thrombocytopenia, mortality was significantly higher in those with bone marrow failure compared to an autoimmune etiology. We show that in a non-referred population with a high incidence of CLL/SLL, autoimmune cytopenia can occur early in the natural history of the disease. These data suggest that the Rai and Binet classifications for CLL need to be modified for patients with autoimmune cytopenia. .