In the United States, chronic lymphocytic leukemia (CLL) accounts for about one of every four new cases of leukemia.1 In China, though, a country with more than three times as many citizens, incidence of CLL is about 10 to 20 times less than it is in the U.S. The rate of new cases in the U.S. is about 4.9 per 100,000 per year; in China, that number is about 0.27 per 100,000.2 It is similarly uncommon in Japan, other Asian countries, and amongst Asians living in North America and Europe.3
“Incidence of CLL is not only lower, but follicular lymphoma has a lower incidence in Asians as well,” said Shenmiao Yang, MD, of Peking University People’s Hospital in Beijing. “On the contrary, the incidence of natural killer– or T-cell lymphoma, which is associated with Epstein-Barr virus, is much higher in this area. The incidence of other cancers does not show a significant difference.”
The reason for the disparity in incidence of CLL is unknown.
“A number of people have studied this trend over the last 50 years to try to understand the difference in CLL and I don’t think we have a satisfactory explanation,” said Robert Peter Gale, MD, PhD, visiting professor of hematology at Imperial College London. “We have made some progress though.”
Begin at the Beginning
To better understand the differences between incidence of CLL in patients of Asian descent and other ethnic groups, one must look back a bit in history, according to Dr. Gale, who has devoted a significant portion of his career to studying this enigma.
After the U.S. detonated two nuclear weapons in Hiroshima and Nagasaki in 1945, the American-Japanese partnership now known as Radiation Effects Research Foundation (RERF) was established to study the effects of radiation on survivors. RERF’s Life Span Study encompasses about 94,000 survivors and 26,000 unexposed individuals as a control group.4
“These people have been followed since the 1950s and, not too long after the atomic bomb explosion, the researchers noted markedly increased rates of acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia, but no increase in CLL,” Dr. Gale said. “That lack of increase in CLL has fundamentally persisted until today.”
Dr. Gale said that when considering the lack of increase in CLL, there are two obvious potential answers. First, CLL is not a radiogenic tumor. The second explanation relates to the control group of the Life Span Study.
“There was also no CLL in controls or unexposed persons,” Dr. Gale said. “This is the most common leukemia in Europeans. How can there be no CLL in the controls?”
Low CLL Rates Across Borders
In his research looking at the differences in CLL among Asian populations, Dr. Gale and colleagues also conducted research of CLL in Asians living in the U.S., looking at age-adjusted incidence rates of CLL diagnosed from 1972 to 1995 among Asian, non-Hispanic white, Hispanic white, and Black people residing in Los Angeles County. Asian groups studied included people of Chinese, Japanese, Filipino, and Korean descent.5
“We found a five- to 10-fold deficit in CLL in Asians compared with age- and sex-matched non-Hispanic whites,” Dr. Gale said.
The outcomes were not linked to birthplace or socioeconomic status, suggesting a possible genetic influence. Dr. Gale said that similar trends were seen in San Francisco and in a study conducted in Hawaii. These findings contrast with geographic trends of other cancers that are increased in Asian countries.
“For example, breast cancer rates in Japan and China are low, while levels are intermediate in Asians living in Hawaii. In California, levels are almost up to the breast cancer rates among women of European descent,” Dr. Gale said. “It is the opposite for gastric cancer. China and Japan have very high incidences of gastric cancer, Asians residing in Hawaii have intermediate incidences, and in California, incidence in Asian people all but went away.”
Also, he noted, CLL incidence remains low in Asians in all these locations. “This all supports the notion that the deficit is predominantly genetic,” Dr. Gale said.
CLL Similarities, Differences
When CLL does occur in Asian people, research has identified some differences in the features of the disease.
“Histologically, atypical CLL accounts for 20% or more of CLL in Japan, which tends to be higher than that of Western European countries, where it is about 10%,” said Jun Takizawa, MD, PhD, associate professor in the department of hematology at the Niigata University School of Medicine in Japan. “Furthermore, in Japan, more than one-fourth of cases have a histology and clinical course that are the same as CLL, but the immune phenotypes, such as CD5(-) and CD23(-), are different.”
According to Dr. Yang, more patients in China have immunoglobulin heavy-chain variable (IGHV)-mutated disease.
Dr. Yang noted that, in research from her group presented at the 2019 International Workshop on Chronic Lymphocytic Leukemia, investigators reached the consensus that there is no “atypical CLL.” “Atypical CLL is believed to be a type of mature B-cell lymphoma, such as marginal zone lymphoma [MZL] or lymphoplasmacytic lymphoma,” she said. “We can do detailed flow cytometric examination, IGHV detection, cytogenetics, and next-generation sequencing to differentiate between them.”
The exact diagnosis is important, she added, and has implication for treatment. “We can use Bruton tyrosine kinase (BTK) inhibitors as the treatment for patients with CLL and achieve a 90% response rate,” Dr. Yang said. “When we use the drug to treat MZL, the response rate will be about 50 to 60%.”
“IGHV 1-69 is often seen in [CLL patients of] European descent, but this subtype is rarely seen in China,” Dr. Yang said. Dr. Takizawa added that IGHV 1-69 is also extremely rare in Japan.
“Stereotype use is also different,” Dr. Yang said. “Subset 8 is most often seen in China, whereas subset 2 is rare.”
In 2019, Shuhua Yi, MD, of the Institute of Hematology and Blood Diseases Hospital at the Chinese Academy of Medical Sciences in Tianjin, and colleagues conducted a study assessing 96 CLL-mutated genes associated with cases of CLL in Western countries in a group of CLL samples from Chinese people. They found high frequency in mutations of KMT2D and MYD88 that correlated with specific IGHV repertoire in the Chinese CLL population, suggesting the pathogenesis of CLL may be different between these populations.6
CLL in Asian patients also seems to be associated with young age, advanced stage, rapid progression, and poor risk, Dr. Yang said. However, there may be biases influencing these factors.
“In China, the average age of the population is younger in most areas,” Dr. Yang said. “Delayed ascertainment could contribute to advanced stage, more symptomatic disease, and poorer risk.”
According to Dr. Gale, about half of the people diagnosed with CLL in the U.S. and Europe are diagnosed as the result of a routine blood test done for other purposes.
In areas of Asia, where routine blood testing is less common, “you tend to get later stages at diagnoses and more advanced disease,” Dr. Gale said. “This is a surveillance bias.”
Drs. Gale, Yang, and colleagues observed an increasing frequency of new cases of CLL beginning in 2011, prompting them to initiate a study interrogating the causes of this increase. The increase, they determined, reflected ascertainment bias.7
“Chinese are getting rich, changing jobs, and getting health insurance,” Dr. Gale said of the recently observed trend. “Two-thirds of people we see in Beijing are diagnosed because they present for things completely unrelated to CLL. They had a physical or a heart attack and wound up in the hospital where they had some bloodwork leading to the CLL diagnosis.”
Differences in CLL Treatment and Prognosis
Similar chromosomal abnormalities and mutations are prognostic for time from diagnosis to first treatment and therapy efficacy, according to Dr. Yang.
For example, hepatitis B virus (HBV) and Epstein-Barr virus infections are both associated with a short interval from diagnosis to first therapy in Chinese patients with CLL, Dr. Yang said. Notably, there is a high prevalence of HBV in China.
As another example, in general, CLL has poor prognosis for people with TP53 abnormalities.
“The frequency of TP53 deletion using FISH analysis in untreated CLL in Japan is about 5%, which is the same as in Europe and the U.S.,” Dr. Takizawa said, and these mutations result in similarly poor outcomes.
However, there may be some key differences. Among patients with CLL treated with fludarabine, cyclophosphamide, and rituximab, those without IGHV mutations are known to have a poor prognosis as well.
“In Europe and the U.S., about two-thirds of people with CLL have IGHV-mutated disease and a poor prognosis,” Dr. Takizawa said. “However, according to the CLLRSG-01 study, 80% of Japanese [people] with untreated CLL have IGHV-mutated disease, and only 20% of the IGHV-unmutated cohort has poor prognosis.”8
Treatment options – whether BTK inhibitors or conventional chemoimmunotherapy – also affect this risk, Dr. Yang commented, as IGHV status does not appear to affect prognosis in patients receiving BTK inhibitors.
Treatment of CLL also differs slightly in Japan and China compared with the U.S. and Europe. “In Japan, effective drugs for CLL, such as ibrutinib and venetoclax, have been approved in recent years,” Dr. Takizawa said. “Previously, efficacy of CLL therapies was worse in Japan than in Europe and the U.S., but it has recently equalized.”
However, according to Dr. Yang, in China, clinical practice is largely impacted by the local policy of public insurance. She said there are three BTK inhibitors approved in mainland China, including zanubrutinib and orelabrutinib, neither of which is approved for the treatment of CLL in Europe or North America. Meanwhile, the U.S. Food and Drug Administration (FDA)-approved obinutuzumab just launched in China, venetoclax is not yet approved for CLL, and acalabrutinib is only available in clinical trials.
“Clinical trials including new drugs and cell therapy are active in China,” Dr. Yang said.
The Mystery Continues
Even as CLL therapy continues to improve, more research is needed to explain the lower incidence of CLL in Asians. Environmental factors such as radiation, environmental pollution, or tobacco have little effect on CLL risk, as evidenced by the similarly low rates observed among Asian people residing in North America and Europe.
Dr. Gale and colleagues are now studying single nucleotide variants (SNVs) in four cohorts: Europeans with CLL, healthy Europeans, Chinese with CLL, and healthy Chinese. He said that studies have revealed several SNVs associated with risk of developing CLL.
“It is very unlikely that someone is going to find a gene that explains all of this,” Dr. Gale said. “It is more likely that someone finds a group of genes acting in concert to decrease susceptibility, confer resistance, or both.”
Dr. Yang said research is also needed for the true age-adjusted incidence rate of CLL in Black people of African descent. It is not possible to determine whether modern Europeans have acquired susceptibility to CLL or these other populations have lost susceptibility or developed resistance to CLL.
Drs. Gale and Yang hypothesize that an infectious agent in Asia about 45,000 years ago acted as a selective pressure for resistance to or decreased susceptibility to developing CLL.
Even if the mystery is uncovered, Dr. Gale said it will not have wide therapeutic implications, given the already-rare incidence.
“We are not going to do gene manipulation in a million people to prevent 50 cases of CLL,” Dr. Gale said. “It is more about answering the scientific question.” —By Leah Lawrence
References
- American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia. Accessed November 4, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html.
- National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). Accessed November 4, 2021. https://seer.cancer.gov/statfacts/html/clyl.html.
- Yang SM, Li JY, Gale RP, Huang XJ. The mystery of chronic lymphocytic leukemia (CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology? Blood Rev. 2015;29(3):205-13.
- Radiation Effects Research Foundation. About RERF. Accessed November 4, 2021. https://www.rerf.or.jp/en/.
- Gale RP, Cozen W, Goodman MT, et al. Decreased chronic lymphocytic leukemia incidence in Asians in Los Angeles County. Leuk Res. 2000;24:665-669.
- Yi S, Yan Y, Jin M, et al. High frequency mutations of MYD88 and KMT2D in Chinese chronic lymphocytic leukemia. Blood. 2019;134(Supplement_1):2761.
- Yang S, Gale RP, Shi H, et al. Is there an epidemic of chronic lymphocytic leukemia (CLL) in China? Leuk Res. 2018;73:16-20.
- Takizawa J, Gruber M, Suzuki R, et al. Comparative analysis of Japanese and European typical CLL patients. Blood. 2016;128:5564-5564.
