What Are the Most Common Secondary Cancers With CLL?

Skin cancers, particularly non-melanoma types like squamous cell carcinoma and basal cell carcinoma, top the list of secondary malignancies in people living with chronic lymphocytic leukemia (CLL). After skin cancers, the most frequently seen second primaries include prostate cancer, breast cancer, melanoma, and lung cancer. Population studies consistently find that CLL patients face roughly 60 to 120 percent higher overall risk of developing another cancer compared to the general population, and that risk stays elevated for a decade or more after diagnosis.

How Much Higher Is the Overall Risk?

Several large registry-based studies have tried to pin down just how much extra cancer risk CLL confers. A Dutch population study covering three decades found that the overall risk of a second primary malignancy was about 63 percent higher than expected, with elevated risk for both solid tumors and blood cancers.¹ A large Australian analysis put the figure even higher, finding the risk was roughly doubled.² And a study of over 2,000 CLL patients at the MD Anderson Cancer Center reported that about 11 percent developed another malignancy during follow-up, with the observed risk 2.2 times higher than expected.³ The numbers vary depending on the population studied and the follow-up period, but the pattern is consistent: CLL patients get second cancers at a meaningfully higher rate.

One detail that sometimes surprises patients is that this elevated risk does not fade over time. Registry data from Scandinavia showed that the risk of a second cancer remained about 80 percent above expected even more than ten years after CLL diagnosis.⁴ This suggests the underlying factors driving second cancers are not just a temporary blip around the time of diagnosis or initial treatment.

Skin Cancers Are Disproportionately Common

Non-melanoma skin cancer, primarily squamous cell carcinoma and basal cell carcinoma, is by far the most frequently reported second malignancy in CLL. A recent large study found that roughly 9 percent of CLL patients developed basal cell carcinoma and about 5 percent developed squamous cell carcinoma, compared with roughly 5 percent and 1.4 percent in matched controls.⁵ Multiple international studies confirm that non-melanoma skin cancer is the single most common second cancer in CLL patients regardless of whether they have received treatment.⁶

What makes this especially concerning is that skin cancers in CLL patients tend to behave more aggressively. CLL patients have a higher rate of skin cancer metastasis and skin cancer-specific death compared with people who have the same skin cancers but no CLL.⁵ Squamous cell carcinoma, which in healthy individuals is usually straightforward to treat, can become a real clinical problem in someone whose immune system has been weakened by CLL.

Melanoma risk is also sharply elevated. The Australian population study found that melanoma risk was nearly eight times higher than in the general population, the largest increase of any individual cancer type in that analysis.² A U.S. SEER-based study of nearly 49,000 CLL cases found the melanoma risk was about twice that of the general population, with the increase most pronounced in white men between ages 45 and 64 and within the first five years of CLL diagnosis.⁷ The difference in magnitude between those studies likely reflects differences in the background melanoma rate in Australia versus the U.S., but the direction of the finding is the same everywhere.

One practical difficulty with skin cancer in CLL patients is that the dense infiltration of CLL cells in the skin can make it harder for surgeons to read tissue margins during removal procedures. When a CLL patient has squamous cell carcinoma removed using Mohs surgery, the surrounding CLL cell infiltrate can mimic or obscure the boundary of the tumor, complicating the interpretation of frozen sections.⁸

Other Solid Tumors That Appear More Often

Beyond skin cancers, prostate cancer and lung cancer are among the most common solid-tumor second primaries. A large European multicenter study conducted through the ERIC research initiative confirmed that after non-melanoma skin cancer, prostate cancer was the next most frequent solid tumor in CLL patients.⁹ CLL-directed treatment was associated with a higher odds of developing prostate cancer in that study.

Lung cancer is particularly notable because when CLL patients develop it, it tends to determine their prognosis. A review at Memorial Sloan Kettering found that among CLL patients who also developed lung cancer, the lung cancer was what killed them, not the CLL.¹⁰ The Scandinavian registry study found lung cancer risk was about 60 percent higher than expected in CLL patients, with the elevation strongest in younger age groups and for adenocarcinoma specifically.⁴

Breast cancer also appears on the list, though it has an interesting pattern. In the ERIC multicenter study, breast cancers were actually more frequent among CLL patients who had not yet received treatment, while non-melanoma skin cancer and prostate cancer were more common in those who had been treated.⁹ This hints that not all second cancers in CLL are driven by the same mechanisms, and that treatment itself plays a role for some cancer types but not others.

Richter Transformation and Other Blood Cancers

CLL can also give rise to second hematologic malignancies. The most well-known is Richter transformation, in which the slow-growing CLL transforms into a much more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This is not technically a “second primary” cancer in the traditional sense since it arises from the same disease, but clinically it behaves like a new and far more dangerous diagnosis. Research into the genetic underpinnings of this transformation has revealed complex molecular changes, with multiple pathogenic variants detected in the transformed lymphoma cells.¹¹

Hodgkin lymphoma arising in CLL patients is less common than DLBCL transformation but well documented. A large multicenter study identified 94 CLL patients who developed Hodgkin lymphoma, with a median time from CLL diagnosis to the Hodgkin diagnosis of about five and a half years. These patients were predominantly older men, and the majority had advanced-stage disease at diagnosis. Notably, over half of evaluable cases were positive for Epstein-Barr virus, suggesting the virus may play a role in driving this transformation in an immune-compromised setting. The encouraging finding was that patients who received standard chemotherapy had a median overall survival of over 13 years after their Hodgkin diagnosis.¹²

Treatment-Related Myeloid Cancers

One category of second cancer that deserves special attention is therapy-related myelodysplastic syndrome and acute myeloid leukemia (commonly abbreviated tMDS/AML). These are cancers of the bone marrow that can arise as a direct consequence of certain chemotherapy drugs. CLL had one of the highest risks of tMDS/AML among all lymphoid cancers studied in a recent population-level analysis, with the risk roughly nine times higher than expected.¹³

The drugs historically most associated with this risk are alkylating agents and purine nucleoside analogues, both of which were staples of CLL treatment for decades. Survival for patients who develop tMDS/AML after CLL treatment has historically been measured in months.¹⁴ Worryingly, the risk of tMDS/AML after CLL treatment appeared to increase over time in calendar-year analyses, more than doubling from the early 2000s to the mid-2010s.¹³ This rise likely reflects the broader use of intensive chemoimmunotherapy regimens like FCR during that period.

There is a meaningful silver lining here. Newer targeted therapies, particularly BTK inhibitors like ibrutinib and BCL-2 inhibitors like venetoclax, are rapidly replacing chemotherapy as frontline CLL treatment. Early data suggest these agents do not carry the same second-cancer risk. The ERIC multicenter study found that patients treated with targeted therapies or monoclonal antibodies alone did not have a significantly higher risk of other cancers compared with those on active surveillance. A separate U.S. real-world data analysis found that a significantly lower percentage of patients who received targeted therapy developed a second primary malignancy compared with those treated with traditional chemoimmunotherapy.¹⁵ This is still relatively early evidence, and longer follow-up is needed, but the trend is reassuring.

Why CLL Raises the Risk of Other Cancers

The immune dysfunction caused by CLL itself is probably the most important driver. CLL is not just a cancer of B lymphocytes; it progressively undermines the entire immune system. The killer T cells that normally patrol for abnormal cells become exhausted and less effective. Research has shown that CD8+ cytotoxic T cells in CLL patients are replaced by dysfunctional, worn-out versions that express high levels of inhibitory surface receptors.¹⁶ This T-cell exhaustion reduces the body’s ability to detect and destroy early cancerous cells before they become established tumors.¹⁷

But immune suppression does not fully explain the pattern, especially for skin cancers. Researchers have identified shared genetic susceptibility between CLL and non-melanoma skin cancer. A gene called IRF4, which regulates immune cell development and also plays a role in skin-cell biology, has variants that independently raise the risk of both CLL and squamous cell carcinoma of the skin. The same polymorphism that reduces IRF4 activity in lymphocytes, making CLL more likely, also appears to impair the skin’s immune defenses against abnormal keratinocytes.¹⁸ In other words, some of the same genetic wiring that makes a person susceptible to CLL in the first place also makes them more prone to skin cancer, independent of any treatment or immune changes caused by the leukemia.

A comprehensive analysis of second malignancy patterns across different lymphoma subtypes concluded that the varied patterns of second cancers reflect a mix of immunologic disruption, treatment effects (especially from alkylating agents), shared genetic susceptibilities, viral infections, and modifiable risk factors like tobacco use.¹⁹ No single explanation accounts for all the excess risk.

How CLL Affects Outcomes When a Second Cancer Strikes

Having CLL does not just make second cancers more likely; it makes them harder to survive. A large SEER database study compared outcomes for people with breast, colon, kidney, prostate, and lung cancers who did or did not have a pre-existing CLL diagnosis. After adjusting for age, sex, race, and disease stage, patients with CLL had worse overall survival across all five cancer types. For breast and colorectal cancer specifically, even cancer-specific survival was worse, meaning CLL patients were more likely to die of those cancers themselves, not just of competing causes.²⁰

Among patients treated with the FCR chemoimmunotherapy regimen who then developed second cancers, the five-year overall survival was roughly 48 percent, compared with 92 percent for FCR-treated patients who had no history of any other cancer.²¹ Half of the patients who developed a second cancer after FCR died during the study period. These numbers underscore why second-cancer prevention and early detection matter so much in CLL care.

What Screening Looks Like for CLL Patients

Given the breadth of second-cancer risk, current guidance emphasizes that CLL patients should stay current with all age-appropriate cancer screenings and, for skin cancer specifically, should be more vigilant than the general population. A 2025 review in the journal Cancers outlined evidence-based strategies for preventive care in CLL, including routine cancer screenings, immunizations, and lifestyle modifications.²²

For skin specifically, many CLL specialists recommend annual or even more frequent full-body skin exams by a dermatologist, especially for patients who are fair-skinned or have a history of significant sun exposure. Any new or changing skin lesion should be evaluated promptly rather than watched. The combination of higher incidence, more aggressive behavior, and diagnostic challenges with skin cancers in CLL makes a proactive approach particularly worthwhile.

For other cancers, the approach is generally the same as for the general population — routine mammograms, colonoscopies, low-dose CT scans for lung cancer in eligible patients, and PSA discussions for prostate cancer — but with a heightened awareness that CLL patients sit in a higher-risk category. Smoking cessation is especially relevant given the elevated lung cancer risk, and sun protection is not optional. These are modifiable factors that CLL patients can act on immediately. The immune system may already be compromised, but reducing the carcinogenic burden the body has to cope with still makes a measurable difference.

Epstein-Barr Virus and Its Role in CLL-Associated Lymphomas

The finding that over half of Hodgkin lymphoma cases arising in CLL patients tested positive for Epstein-Barr virus (EBV) is worth a closer look.¹² In the general population, EBV is found in a smaller proportion of Hodgkin cases. The high EBV positivity rate in CLL-related Hodgkin lymphoma mirrors what is seen in other immunocompromised populations, such as organ transplant recipients and people with HIV. Most adults carry latent EBV without issue, but when the immune system is sufficiently weakened, the virus can drive lymphocyte proliferation that tips into malignancy.

This observation has practical implications. Researchers are exploring whether monitoring EBV viral load in CLL patients could serve as an early warning signal for lymphomatous transformation. It also raises the question of whether antiviral strategies could someday play a preventive role, though no such intervention has been validated for this purpose in CLL patients. For now, the EBV connection mostly reinforces the central theme: the immune dysfunction inherent to CLL creates fertile ground for cancers that a healthy immune system would ordinarily keep in check.

1
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2
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3
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4
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6
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8
PubMed. Squamous cell carcinoma in a patient with chronic lymphocytic leukemia. An intraoperative diagnostic challenge for the Mohs surgeon
9
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10
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11
PubMed Central. Genetic background of Richter transformation of atypical chronic lymphocytic leukemia to diffuse large B-cell lymphoma – a case study
12
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13
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14
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15
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16
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17
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19
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20
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21
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22
PubMed Central. Best Supportive Care for Patients with Chronic Lymphocytic Leukemia: Relevance of Cancer Screening and Immunizations