This month, Kanti R. Rai, MD, discusses familial chronic lymphocytic leukemia.
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I have a patient with a strong family history of chronic lymphocytic leukemia (CLL) who was recently diagnosed with CLL. Her mother and brother have CLL as well. What is the status of familial CLL? Has a gene been identified yet?
Virtually all clinicians who treat chronic lymphocytic leukemia (CLL) have observed that family members of patients with this disease are also found to have CLL in greater frequency than can be expected in the general population. Your patient, who was recently diagnosed with CLL, reports that her mother and brother have CLL. Such family occurrences of CLL or any other lymphoproliferative disorders (LPDs) have been reported in 18 percent of patients with CLL. This high incidence is clearly suggestive of a strong inherited genetic component in the causation or development of CLL.1 However, an oncogene associated with family occurrence of CLL has not been discovered.
Several investigators have found a few CLL susceptibility loci, but a clearly heritable risk factor remains unidentified. A meta-analysis of six genomewide association studies provided single-nucleotide polymorphism genotypes and nine risk loci (which map to areas of B-cell development). These are very exciting observations but account for only a fraction of cases of familial CLL.2
Using a combination of data from a Norwegian cancer registry and a questionnaire, Geir E. Tjønnfjord, MD, PhD, and co-authors found a sixfold increased risk of CLL among family members of persons known to have CLL.3 Another comprehensive study using data from the Swedish Cancer Registry reported an 8.5-fold increased risk of CLL (and 1.9-fold increased risk of LPDs) in first-degree relatives of patients with CLL.4
We also should include an additional public health-related condition called monoclonal B-cell lymphocytosis, a pre-CLL state somewhat analogous to monoclonal gammopathy of unknown significance and multiple myeloma, which also occurs more frequently in family members of persons known to have CLL. With the current rapid pace of investigations, I am optimistic that we will soon have a definitive answer to your question.
- Slager SL, Caporaso NE, de Sanjose S, Goldin LR. Genetic susceptibility to chronic lymphocytic leukemia. Semin Hematol. 2013;50:296-302.
- Law PJ, Berndt JI, Speedy HE, et al. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Comm. 2017;8:14175.
- Tjønnfjord GE. Familial occurrence of chronic lymphocytic leukaemia in Norway. J Norw Med Assoc. 2012;132:2060-3.
- Goldin LR, Björkholm M, Kristinsson SY, et al. Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin’s lymphomas among relatives of patients with chronic lymphocytic leukemia. Haematologica. 2009;94:647-53.
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NEXT MONTH'S CLINICAL DILEMMA
I have a 36-year-old male Samoan patient with glucose-6-phosphate-dehydrogenase (G6PD) deficiency (World Health Organization class III), chronic tophaceous gouty arthropathy, and chronic renal insufficiency secondary to prolonged nonsteroidal anti-inflammatory drug use. His baseline creatinine is 2.67 mg/dL and his glomerular filtration rate is 27. He has a white blood count of 13.8, hemoglobin level of 11.6 g/dL, hematocrit level of 35.1 percent, and a platelet count of 438×109/L. He is experiencing extreme pain and difficulty walking due to gouty arthropathy and has been disabled for eight years.
His rheumatologist would like to institute pegloticase, a pegylated uric acid–specific enzyme, which is a known cause of hemolysis in patients with G6PD deficiency. The patient wants to try this agent to reduce his extensive, painful tophi. I am looking for other opinions about the possibility of administering pegloticase in a hospital setting with transfusion support if brisk hemolysis should occur.
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