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FAMILIAL B-CLL: REVIEW OF LITERATURE AND THE NCI FAMILIAL B-CLL REGISTRY   N CAPORASO, L FONTAINE, J WHITEHOUSE AND GE MARTI   INTRODUCTION  
    Of all the major hematological malignancies, CLL shows the highest familial incidence, suggesting a genetic component to the etiology (1-3). The study of families with multiple cases of CLL is important not only because family history is a prominent risk factor, but also because genetic susceptibility likely implies enhanced susceptibility to environmental co-factors. There have been several reports of familial CLL affecting two or more siblings in one generation and some reports of CLL occurring in two generations. Reports involving three generations are rare. Due to the late onset of CLL, the first generation is often not available for examination and the third generation is too young to be informative. Thus, in common with many adult-onset malignancies, identifying and studying kindreds with sufficient living members to permit informative genetic analyses is challenging.
  REVIEW OF THE LITERATURE  
    In an early 1937 report, Ardashnikov examined thirty three pedigrees with familial leukemia and noted an increase in lymphatic forms over other forms of leukemia (4). He concluded that heredity played a role in leukemia; that the mode of inheritance was a “conditionally dominant autosomal type.”  Ten years later, Videbaek summarized his observations on familial leukemia; he reported nineteen kindred with familial CLL (5). He concluded that a common leukemic gene was inherited via “irregular dominance.” He described several kindreds in which both CLL and chronic myelogenous leukemia (CML) occurred. Guasch reported twenty three families with CLL and noted both CML and acute leukemia (AL) in some families (6). In a much later comprehensive and landmark report, Guntz et al., in a study of 909 families clearly showed that CLL is increased 2.8-3.0 times in first degree relatives compared to that observed for solid tumors (1). They suggested the involvement of multiple genes or a polygenic mechanism rather than a simple Mendelian inheritance to explain increased predisposition to the disease.
 
    In addition to these large collected series, there are some individual case reports. These reports often describe only the affected members in terms of a nuclear family, lacking a fuller description of the complete kindred. A review of selected reports follows.  The earliest reported US family (H.S.) descended from two white Mississippi settlers born around 1840 described by McPhedren et al. (7) who reported six cases of CLL in the third generation whereas only 0.5 were estimated.  The duration of their disease from the time of diagnosis to death varied from five to seven years and one asymtomatic affected individual was discovered during the study.
 
    A Boston kindred is described in one of the earliest original reports (8) and is remarkable not only for the presence of CLL in two identical twins but also for their identical clinical course and blood lymphocyte morphology. The son of one of these twins also developed CLL. Both he and his wife died from CLL representing one of the earliest examples of conjugal CLL. In this early report, four other kindreds involving two siblings were also noted.
 
    In Germany, Schereschewsky reported a brother-sister sibship with CLL, giving details of the diagnosis and clinical course. He did not however provide a complete pedigree description (9). The case of Richards illustrates the death of a 16 year old daughter due to acute lymphoblastic leukemia followed five years later by the development of CLL in her 75 year old father; a complete pedigree was not given (10). Reily et al., (11) reported a California kindred with three affected male siblings; the onset of disease was at the age of 22 with death at the age of 36 for one of these three sibs. A family from Maryland described by Hornbaker is of interest because one of the sibs had CML while the two others had CLL (12). McGavran had reported a similar kindred earlier (13).
 
    Guntz and coworkers reported a kindred of 30 members with a consistent chromosomal abnormality (the Christchurch (CH') chromosome) in three siblings (14, 15). Their presentation and clinical course was variable. Undritz and Schnyder reported a Swiss kindred in which five siblings had CLL (16).  Schweitzer et al. (17) reported an isolated Dutch family in which five of eight siblings had CLL. Their clinical course was also variable. They examined several genetic markers and were unable to demonstrate any correlations with HLA, cytogenetics, or haptoglobin levels.
 
    Familial B-CLL: Review of Literature and The NCI Familial B-CLL Registry 175 Blattner et al., described a fifteen member family in which the father and three siblings had Waldenstom's macroglobulinemia (18). This lymphoma closely resembles CLL and is sometimes referred to as an immunocytoma.  The HLA haplotype A2, B8, Drw3 and the disease were linked in the Waldenstroms kindred with a lod score 4.86 (19). Potolsky et al., reported an Atlanta/Durham family of Russian Jewish extraction, studied extensively at the CDC and at Duke University Medical Center (19). In a sibship of twelve with ten members surviving to adulthood, five died with lymphorecticular neoplasms.  Abnormal immune function was noted in both the affected and some non affected members. In one sib, the immune abnormalities were predictive of a preleukemic or prelymphomatous state.
 
    Fraumeni et al., (20) reported a West Virginian family of Welch descent with second cousin consanguinity involving two male and one female sibling with CLL. There was considerable variation in lymphadenopathy, splenomegaly and the magnitude of blood lymphocytosis. A fourth sib without CLL in this kindred was found to have a selective deficiency of serum IgM and IgG and significant impairment of mitogen induced lymphocyte transformation.
 
    The longest studied kindred consists of four siblings and a parent with documented blood and marrow lymphocytosis spanning a 25 year period consistent with B-CLL (21-24). As noted above in other familial cases with CLL, there was in this family, remarkable variability in the clinical course, cytogenetic and molecular findings of each affected member. Marrow, blood, lymph node and spleen involvement were variable as was the progression of their clinical course and response to chemotherapy. Linkage analysis in this family suggested no linkage between either ABO, HLA (A, B and DR) loci, and Rh loci and disease with lod scores of less than -2.0 (24).
 
    The most recent reported series is by Cuttner (25). She noted that seven of ten B-CLL patients with a positive (first degree relative) family history of hematologic neoplasia were from Eastern Europe and of Jewish descent (EEJD). She also described one patient with an identical male twin with B-CLL and two patients who had spouses with a lymphoid malignancy.
  NCI FAMILIAL B-CLL REGISTRY  
    This registry is contained within the larger Familial Cancer Registry. An attempt is made to examine and follow all affected individuals and their first degree relatives. The amount of information obtained varies depending on geographic factors, degree of association of family members, interest and willingness to participate and allow consent to obtain medical records and information, and inevitable family members lost to follow-up. Ideally, for each member of a kindred we obtain a detailed personal and family history, medical history and physical examination. Additional medical and clinical information is obtained from private physicians, hospital records and death certificates.  All malignancies are histologically confirmed and documentation of diagnoses from original pathology materials is sought in cases not originally identified at NIH. When appropriate, immunoperoxidase studies are added.  Complete blood counts, automated chemistries, quantitative serum immunoglobulins, urine analysis, chest x-ray, and electrocardiogram are obtained on all individuals at the initial clinic visit. More recently, flow cytometric lymphocyte subset analyses are also carried out on both affected and unaffected individuals. We store red cells, serum, cryopreserved lymphocytes, and leukemic cells on affected individuals and in some cases skin biopsies on members of a given kindred. We are now exploring the use of buccal smears as a source of non-tumor DNA. Archival biopsies have become important with the advent of molecular methods. Institutional approval of this protocol was obtained and signed informed consent is required of all participants.
 
    The NCI-CLL Family Registry currently contains 26 kindreds with two or more affected members. Seventeen of the 26 kindreds involve sibships, including one set of twins; fourteen involve a parent-child relationship and seven kindreds involve both sibships and parent-child relationships. Only one family involves three generations (proband, her father and her son). There is evidence that second degree relatives are involved in five families. Consanguinity is observed in at least three kindreds. Six of the kindred are of Eastern European origin and of Jewish descent (EEJD). Overall there are 70 affected individuals within the 26 families. In addition, there are 14 family members with other hematological malignancies (CML-3, HD-4, AML-4, MM-1, hairy cell-1, and NHL-1). There is a 4:3 ratio of men to women, compared to a 2:1 ratio among patients with common B-CLL. There are no cases of CLL observed in the non-blood line subjects (ie, among spouses) in the kindred under discussion; however, in separate investigations, we have observed a few cases of both connubial CLL and connubial non-Hodgkin’s lymphoma.
 
    The longest follow-up for a B-CLL proband is currently almost 25 years.  She has splenomegalic B-CLL and has received several cycles of chlorambucil and prednisone. Recently she survived multitrauma (fractures, respiratory complications and pneumonia, and a large subcapsular hematoma of her spleen) from a motor vehicle accident, but has recovered completely. Subsequently, she underwent splenectomy for massive splenomegaly and secondary hypersplenism.
 
    There is one kindred of Italian descent with three affected members with CLL and one with hairy cell leukemia. In our one three generation family, the father developed CLL at the age of 79 and died at the age of 98. His daughter developed lung cancer at the age of 64, basal cell carcinoma at the age of 72 Familial B-CLL: Review of Literature and The NCI Familial B-CLL Registry 177 and CLL at the age of 74 and is still alive. Her son developed CLL at age 55 and died approximately two years later.
 
    In another kindred, the proband and her mother and her brother are remarkable for early age of onset (<40 years). The one set of identical male twins in the registry developed the onset of disease within one year of each other.
 
    Affected individuals are characterized by a variable clinical course, which is typical of this disease in the general population as well. We are currently planning a formal study to examine and define the characteristics of familial versus sporadic or common B-CLL. Formal segregation analysis is precluded in this series because the mode of ascertainment is mixed. In general, the evidence from this series and the literature appear to favor a dominant mode of inheritance.
  CLINICAL ISSUES IN THE CONTEXT OF FAMILY STUDIES  
    Even though the increased incidence of familial CLL compared to other lymphoproliferative cancers has been confirmed and is appreciated in the community, familial aggregations can easily go unrecognized. A careful and repeated history is required in this older patient populations to detect and confirm other cases within a given family (personal communication, C. Lockard Conley, MD). The earliest descriptions of CLL suggested familial clustering, in contradistinction to acute leukemias and CML where a familial excess exists but is more modest. However, there is no evidence that familial B-CLL and common (sporadic) B-CLL have any obvious distinctive clinical or laboratory features or follow an atypical clinical course.
 
    To the best of our knowledge, this summary of the NCI Familial B-CLL registry represents one of the largest compilations of pedigrees described.  These families exemplify many of the clinical findings from previous case studies. These features include the coexistence of CLL with either AML or ALL in the same kindred. We have also observed the coexistence of CLL with Hodgkin’s disease, myeloma, and hairy cell leukemia in different familial B-CLL kindreds. The presence of other lymphoid neoplasms was not unexpected.  In fact, familial lymphoproliferative disease might be a better term for these kindreds.
 
    The inheritance patterns are varied and complex. Affected sibships; combined first, second generation and even affected members in the third generation; and identical male twins. The associated lymphoid neoplasms are varied and solid tumor involvement is at least as high or higher than in common B-CLL.  Autoimmune disease is also as prevalent as in common or sporadic B-CLL.  At least six of our kindred are of EEJD and two of these kindred have a history of consanguinity. The general pattern of familial inheritance in the literature suggests autosomal dominance as the mode of inheritance, while occasional reports of consanguinity are consistent with a recessive mechanism.  This suggests a minimum of two genes which is consistent with an NZB murine model for B-CLL that suggests five to eight genes for the manifestion of disease in the NZB mouse (26).
 
    Families are referred to the NCI Family Studies clinic for various reasons.  The major motivation is the concern about the potential for disease in their offspring once the familial pattern is recognized. Patients generally have an altruistic motivation as well and are very willing to support the long term research involved. This is fortunate since the present state of knowledge does not permit the identification of high risk family members either through clinical findings (eg, as in dysplastic nevi in melanoma kindreds) or distinctive genetic findings (ie, as in BRCA1 in breast-ovary families).
 
    The options for therapy in B-CLL are numerous and the decisions concerning therapy are difficult for patients. A watch and wait approach versus aggressive chemotherapy with and without stem cell storage is a difficult decision for practicing clinicians even in the best of medical centers. The role of autologous bone marrow transplantation is not yet as well defined as in other hematological malignancy but appears to be promising. Obviously therapy has to be tailored to each individual patient. To that end we attempt to inform these patients of the various clinical protocols available in the US. We are pursuing the possibility of setting up a newsletter and patient discussion group for familial B-CLL. Future plans include a detailed formal analysis of the families seen to date to determine age of onset, stage adjusted survival, gender ratio, prospective occurrence of other malignancies and autoimmune disease within kindred. We have initiated a genetic linkage analysis of a F1 backcross of the above mentioned NZB mouse. We would like to apply this methodological approach to a loss of heterozygosity (LOH) assay in familial B-CLL, and the evaluation of candidate loci in the families. Future studies will combine epidemiology, the clinic and genetics to further our understanding of this lymphoproliferative disorder. We are grateful to the patients and their families and health professionals who have participated in our studies and welcome any and all future referrals.
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