A 20 Year Clinical and Laboratory Study of Familial B-Chronic Lymphocytic Leukemia in a Single Kindred

Abstract

Four siblings and a parent in a single kindred had documented blood and marrow lymphocytosis during the past 18 to 20 years consistent with chronic lymphocytic leukemia (CLL). Of the four siblings, one developed a spontaneous remission; one died secondary to subepiglotitis with sepsis; one died with prolymphocytoid transformation and one remains alive with splenomegalic CLL. Lymphadenopathy and splenomegaly were variable as was the clinical response to chemotherapy. Bone marrow morphology was initially nodular but progessed to diffuse patterns in both deceased siblings. Blood lymphocyte morphology was extremely variable as were cell doubling times and cytogenetic studies. ABO and HLA typing revealed no evidence of linkage. Immunophenotypic analysis of the B lymphocytes demonstrated a CD19 +, CD20-, CD5 +, Leu8-, Kappa + and a CD19 +, CD20 +, CD5 +, Leu8 +, Kappa + monoclonal lymphocytosis in two affected members. An unaffected sibling showed a CD4 lymphocytosis. VHV and VHII gene sequences were previously described in this kindred (PNAS 84: 8563, '87). We speculate that a CD5 B cell and CD4 T cell lymphocytosis may arise early in this disease followed by the development of a pleomorphic, monoclonal lymphocytosis. The subsequent oligomorphic, monoclonal lymphocytosis shows genotypic, immunophenotypic and some morphological heterogeneity consistent with ongoing differentiation. The longitudinal investigation of familial CLL offers a unique opportunity to study the sequence of events related to the natural history of B-CLL.

Diagnostic criteria for monoclonal B‐cell lymphocytosis

“…Epidemiological studies have shown that the risk of CLL in relatives of patients with CLL is increased and it is likely that a subset of the disease is caused by a genetic susceptibility (Fraumeni et al, 1969;Neuland et al, 1983;Blattner et al, 1987;Caporaso et al, 1991Caporaso et al, , 1997Goldin et al, 1999;Yuille et al, 2000;Ishibe et al, 2001Ishibe et al, , 2002a. As CD5 + 23 + MBL may be a precursor of CLL, it has been postulated that MBL might be overrepresented in apparently healthy relatives of familial CLL cases.…”

Immunophenotypic features distinguishing familial chronic lymphocytic leukemia from sporadic chronic lymphocytic leukemia

“…CLL is the most common adult leukemia and familial CLL exhibits the most frequent familial aggregation among hematological malignancies (1–3). Familial and sporadic chronic lymphocytic leukemia have been extensively studied and the clinical presentation, molecular and cytogenetic properties compared (7, 14). Clinical anticipation (earlier age of onset and/or increased severity in successive generations) is well characterized in familial CLL (6, 8).…”

“…Familial aggregation of chronic lymphocytic leukemia (familial CLL) has been observed more frequently than familial aggregation in any other hematological malignancies. Familial CLL families provide the unique opportunity to identify susceptibility genes and other factors that contribute in the etiology of CLL (3–10). Familial CLL and sporadic CLL have been studied with regard to their clinical presentation, anticipation, genetics, and molecular abnormalities; however, no study has been conducted to evaluate and compare patterns of cell surface antigen expression.…”

Bioethical considerations of monoclonal B‐cell lymphocytosis: donor transfer after haematopoietic stem cell transplantation

“…B‐cell CLL exhibits a high degree of familial clustering (Gunz et al , 1975; Caporaso et al , 1991; Ishibe et al , 2001), and for over 25 years, the National Cancer Institute (NCI) of the National Institutes of Health (NIH, Bethesda, MD, USA) has studied kindreds with two or more affected family members. Members of the kindreds are invited to visit the NIH Clinical Center and participate in studies that seek to identify genetic and environmental factors that contribute to disease in their families.…”