Chronic Lymphocytic Leukemia in China
Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow, characterized by the accumulation of abnormal lymphocytes. While it is one of the most common types of leukemia in Western countries, particularly among individuals of European descent, its incidence in China is significantly lower. This article provides a comprehensive overview of CLL in China, exploring its epidemiology, genetic and environmental factors, clinical characteristics, and treatment landscape.
Epidemiology of CLL in China
The incidence of CLL in Han Chinese is markedly lower compared to individuals of European descent. Studies indicate that the incidence of CLL in China ranges from 0.2 to 0.6 cases per 100,000 population per year, whereas in Europe, the incidence is approximately 4.6 cases per 100,000 population per year. This 10- to 20-fold difference in incidence is not unique to China but is also observed in other Asian populations, including Japanese and Koreans. The reasons for this lower incidence remain unclear, but it is likely influenced by a combination of genetic, environmental, and surveillance factors.
Surveillance and Diagnosis
CLL is often asymptomatic in its early stages, and the diagnosis is frequently made incidentally during routine blood tests or evaluations for other medical conditions. In China, there is no population-based registry for CLL, which complicates the accurate assessment of its incidence and prevalence. Data from a registry covering 46 regions from 1986 to 1988 reported an age-adjusted incidence of 0.05 cases per 100,000 population, likely an underestimation due to the limited availability of advanced diagnostic techniques such as multi-parameter flow cytometry at the time.
However, more recent studies have reported a significant increase in the number of new CLL cases in China. A single-center retrospective study from 2011 to 2016 noted a dramatic rise in diagnoses, often based on abnormal complete blood counts (CBCs) conducted for unrelated medical conditions or routine health examinations. The median age at diagnosis in China is around 60 years, younger than the 65 to 70 years observed in Europe. This difference may be partly due to increased surveillance and more frequent CBCs in older individuals in China.
Genetic Factors
Genetic predisposition plays a crucial role in the development of CLL. Studies have shown that high-risk single-nucleotide variants associated with CLL in individuals of European descent are less common in Han Chinese and other Asian populations. Additionally, the familial risk of CLL observed in European populations has not been reported in Han Chinese, possibly due to surveillance biases.
Several genetic mutations are commonly associated with CLL, including deletions in chromosome 13q14 (del(13q14)), trisomy 12, and mutations in genes such as ATM, NOTCH1, TP53, BIRC3, and SF3B1. While del(13q14) is considered an initiating event in some cases of CLL, it is detected in only about half of Chinese and European patients with CLL. Chinese patients with CLL tend to have a lower frequency of SF3B1 mutations and an increased frequency of MYD88 and KMT2D mutations compared to Europeans.
The immunoglobulin heavy chain variable (IGHV) gene mutation status also differs between Chinese and European patients with CLL. Chinese patients are more likely to have mutated IGHV genes, and there are differences in the usage of specific IGHV genes and stereotyped B-cell receptors. For example, the frequency of subset eight stereotyped receptors is significantly higher in Chinese patients, while subset two is less common.
Environmental Factors
Environmental factors may also contribute to the lower incidence of CLL in China. Data from population-based cancer registries in Taiwan and Korea suggest that changes in lifestyle and environmental exposures may influence the incidence of CLL. A study in the United States found that Asians born in the U.S. had a higher incidence of CLL compared to those born in Asia, suggesting a possible environmental impact.
However, studies examining the association between environmental exposures such as ionizing radiation, UV exposure, obesity, pesticides, and herbicides have found little to no increased risk of CLL. For example, survivors of the atomic bombings in Japan had a marked increase in the risk of acute and chronic myeloid leukemias but only a slight increase in CLL, which was detected after 70 years.
Clinical Characteristics and Outcomes
CLL in Han Chinese shares many similarities with CLL in individuals of European descent, but there are some notable differences. Chinese patients with CLL tend to be younger at diagnosis and are more likely to present with advanced disease (Binet stage B or C). The median age at diagnosis in China is around 60 years, compared to 65 to 70 years in Europe. Additionally, Chinese patients may experience more rapid disease progression and worse outcomes.
These differences may be partly explained by surveillance biases, as more frequent CBCs in older individuals in China may lead to earlier diagnosis. However, the overall clinical course of CLL in Chinese patients is similar to that in Europeans, with comparable response rates to standard therapies such as fludarabine, cyclophosphamide, and rituximab (FCR).
Treatment Landscape
The treatment of CLL in China has evolved significantly over the past few decades. Chlorambucil was the only available therapy for many years, often used in combination with cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The introduction of purine analogs such as fludarabine in 2001 and monoclonal antibodies like rituximab in 2000 marked a significant advancement in CLL treatment.
More recently, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors have become available in China. Ibrutinib was approved in 2013, followed by zanubrutinib and orelabrutinib in 2020. Clinical trials of these agents in Chinese patients have shown safety and efficacy profiles similar to those observed in Europeans. For example, a study of ibrutinib in advanced CLL reported an overall response rate (ORR) of 61% and a 30-month progression-free survival (PFS) rate of 66%, comparable to European data.
However, there are some differences in treatment outcomes. For instance, the ORR may not be a reliable surrogate for PFS or overall survival in Chinese patients treated with ibrutinib. Additionally, Chinese patients with latent hepatitis B virus (HBV) infection may have a lower risk of HBV reactivation with ibrutinib compared to rituximab, highlighting the importance of screening for HBV before initiating therapy.
Despite these advancements, access to newer therapies remains a challenge in China. While ibrutinib and zanubrutinib are covered by public insurance, not all patients can afford these drugs, and therapy interruptions are associated with worse outcomes. There is growing interest in fixed-duration therapies, such as combining ibrutinib with FCR or bendamustine and rituximab, to improve access and outcomes.
Future Directions
Research efforts in China are focused on understanding the genetic and environmental factors that contribute to the lower incidence of CLL in Asian populations. Hypotheses include the possibility of an infectious agent present in Asia around 45,000 years ago that provided selective pressure against the development of CLL. Additionally, ongoing studies are exploring the efficacy of new therapies, including Bcl-2 inhibitors and chimeric antigen receptor (CAR) T-cell therapies, in Chinese patients with CLL.
In conclusion, CLL is significantly less common in Han Chinese compared to individuals of European descent, likely due to a combination of genetic and environmental factors. While the clinical characteristics and treatment outcomes of CLL in Chinese patients are similar to those in Europeans, there are some notable differences, including younger age at diagnosis and more advanced disease at presentation. Advances in targeted therapies have significantly improved outcomes for Chinese patients with CLL, but challenges remain in ensuring access to these treatments. Continued research is essential to further understand the unique aspects of CLL in Asian populations and to develop more effective therapies.
doi.org/10.1097/CM9.0000000000001811
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