Geographical diversity in CLL

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, however, the global incidence varies. These patterns persist in migrants to other countries, reaching into subsequent generations. This lack of association between place of birth and the CLL incidence indicates a genetic basis for the geographic variations in CLL. This was a hot topic at the International Workshop on CLL 2019, and is reported in this article by Astrid Pavlovsky.

Geographic incidence

Previous research suggests that CLL accounts for approximately 30% of leukemias in Western countries, under 7% among Mexican Mestizos, and under 5% in the Far East. As migrant groups retain their innate CLL risk in their new geographic location, the implication is that genetic, rather than socioeconomic or environmental, factors are more likely to explain differences in the incidence of the disease.¹

CLL is uncommon in Asia —including Korea, Singapore, the Philippines, Taiwan, and India — and particularly rare in Japan and China. The incidence of CLL does not appear to increase with migration to the US.¹

Lower CLL incidence rates have also been documented in Spain, South America, among individuals of Spanish origin in New Mexico, and in many parts of Africa.¹

Those from former USSR countries have been reported to have a higher incidence of CLL, especially in Latvia.¹

Israel, being a country with a mixed population of immigrants with both European and Middle Eastern ancestry and a smaller population of indigenous people, has a high incidence of CLL, particularly among Ashkenazi Jews.¹

Demographic differences

In the US, CLL is typically diagnosed at a median age of 72 and is more common in males. However, globally, age at diagnosis is demonstrably lower and the gender ratio highly variable, as can be seen in Table 1.

Cytogenetics and prognosis

Chromosomal aberrations were detected in up to 82% of Western patients with CLL using fluorescence in situ hybridization (FISH), most frequently 13q deletion, 11q deletion, trisomy 12q, 17p deletion, and 6q deletion.  These chromosomal aberrations have prognostic significance, ranging from 13q deletion, associated with favorable prognosis, trisomy 12, associated with intermediate prognosis, to 17p and 11q deletions, which are associated with a worse prognosis. As can be seen in Table 2, the frequencies of these chromosomal aberrations reportedly vary in Asian populations, however most studies are small and variable patient selection renders comparison problematic. ¹

Immunoglobulin (Ig) gene rearrangement is an essential process of normal B-cell maturation, as this process creates a unique B-cell receptor (BCR) on each lymphocyte. For the heavy Ig chain, selection and recombination takes place for each of 51 VH genes, 27 D genes, and 6 JH genes. ¹

The mutational status of rearranged Ig HV (IGHV) genes is a strong prognostic factor to stratify patients in clinical trials. In particular, patients with 2%, or greater, mutations in IGHV genes have a better prognosis than patients with less than 2% mutations.³ Biased usage of IGHV gene repertoire in CLL has been noted with differences in gene frequencies used in BCR rearrangements demonstrated across Europe. In cohorts from the South of France, IGHV gene frequencies were similar to those described in the Mediterranean and North-eastern region of Italy, but differed from the North of Europe, which may reflect a geographical-dependent CLL repertoire.⁴ A higher proportion of patients with CLL in East Asia were reported to have mutated IGHV — 69% of patients in China and 88.5% in Japan — whereas in Ukraine, mutated cases accounted for only 31.7% of cases. ¹

Non-random use of IGHV genes was seen in Chinese patients with CLL who demonstrate IGHV3 > IGHV4 > IGHV1 order of subgroup frequency, significantly different from Italian CLL patients, who showed a IGHV3 > IGHV1 > IGHV4 distribution. In Chinese CLL patients, IGHV4-34 was the most common gene, whereas IGHV1-69 and IGHV1-2 genes were significantly under-represented.⁵

Specific studies of the IGHV3-21 gene also suggest a geographical pattern of Ig rearrangement in CLL, with a difference between the Mediterranean and Scandinavian populations. The IGHV3-21 gene, frequently found in the North of Europe, has a gene frequency three times lower in studies from the Mediterranean area (France, Greece, Italy, and Spain). In Britain and Scandinavia, where IGHV3-21 mutation is more common, mutated IGHV3-21 has a negative effect on overall survival. ⁴

Conclusions

Determining the influence of ethnicity on biological and genetic characteristics of CLL is problematic as it depends on patient selection and access to available health care, and the usual limitations of the lack of comparative studies involving consistently managed CLL cohorts. As CLL diagnosis/prognosis moves further towards the molecular level, global clinical implementation is likely to be hampered by access to the specialist services needed to carry out the analysis. In many countries, access to molecular diagnostics may be restricted to the private sector, making treatment decisions difficult outside this setting.

Studies involving large cohorts of patients with CLL from diverse ethnic backgrounds and regions are needed to verify the association of geography, IGVH structure, and possible environmental factors which could modify the biology and prognosis of CLL.