Secondary Cancer Risk Remains an Unresolved Issue in CLL

David Bond, MD

Patients with chronic lymphocytic leukemia (CLL) have an elevated risk of second primary neoplasia (SPN); however, the role of BTK inhibitors in second cancer development remains largely unexplored, according to David Bond, MD.

An analysis of 691 patients with CLL who were previously treated with either ibrutinib (Imbruvica) or acalabrutinib (Calquence) was conducted to investigate the incidence of SPN in relation to the general population, excluding those who developed Richter's transformation or nonmelanoma skin cancers.

"We found that in fact, second cancers were the second leading cause of death in our cohort of patients," said Bond. "Compared with the general population, the rates of second cancers remains significantly elevated in these patients receiving BTK inhibitors."

At a median follow-up of 44 months, results showed that 10% of patients developed SPN (standard incidence ratio, 2.4; 95% Cl, 1.9-3.0) including lung cancers (n = 13), melanoma (n = 9), prostate cancers (n = 9), bladder (n = 7), breast (n = 4), and kidney cancers (n = 3). Of the 179 patients who died after 3 years, 13% were caused by SPN, while 57% were caused by CLL/Richter's transformation.

In an interview with OncLive, Bond, an assistant professor at the Ohio State University Comprehensive Cancer Center, addressed the ongoing challenge of SPN in CLL.

OncLive: Could you discuss the impact that SPN has in CLL?

Bond: There is literature dating back to the 1970s showing that patients with CLL, both treated and untreated, are at an increased risk of second cancers. We know that certain past treatments, such as alkylating chemotherapy agents or purine nucleoside analogs, are immunosuppressive and pose a risk of acute myeloid leukemia. Now that we have novel oral agents such as BTK inhibitors, we were interested to see if the instances of second cancer remains elevated and how much this contributes to morbidity in this patient population.

Could you provide a brief overview of the findings of this study?

We identified 691 patients with CLL who were treated with BTK inhibitors. About 20% of patients were treated with acalabrutinib and 80% with ibrutinib. We cataloged second primary malignancies, excluding Richter's syndrome and non-melanoma skin cancers. Non-melanoma skin cancers are not included in cancer registries, and are generally more of a localized problem compared with other invasive second cancers.

Are there other classes of agents that are available in CLL that lead to SPN?

An important distinction is that we don't know what the relationship of the treatment is. We believe that the primary driver of secondary cancers in CLL is the immunosuppression from the CLL itself. We know that ibrutinib restores some immune function when patients are on it, but it also does not lead to complete response in the majority of cases. We aren't able to separate whether the risk is due exclusively to the immunosuppression of CLL, or if there could be some contribution from the BTK inhibitor.

With new CLL treatment approaches that have a greater depth of response, further studies to determine what the second cancer risk are needed. The literature that is published to date focuses on chemotherapeutic approaches, which are not used as widely today. As the treatment evolves, we need to understand what the risk of second cancers is because it appears to still be a major contributor to morbidity in this patient population.

What remaining questions do you have about these data? What other analyses should be done?

One question is, “Is there any contribution of therapy to SPN? [How can we] directly compare with other therapies?” We would be interested in looking at prospective data from clinical trials for patients who are receiving a BTK inhibitor as first treatment, then looking at the second malignancy rates compared with other treatment approaches. As studies go forward, it is important that the second cancers are cataloged, because this remains an important issue and something that is not necessarily emphasized. As we conduct prospective studies, we should understand what the risk of second cancers are with other treatment approaches. Could this be impacted with treatment approaches that, for instance, lead to a greater depth of response compared with the single-agent BTK inhibitors as seen in this cohort?

What else you would like to add regarding these data?

An interesting point that came out of this study was a correlation between two factors in the risk of second cancers. One of the strong predictors of second cancer risk was tobacco exposure. We know that tobacco leads to an increased risk of cancers, including lung cancer and bladder cancer, but that is an important point for counseling patients with CLL—whether they are receiving BTK inhibitors or otherwise.

Another point we saw was that a low CD8 count at baseline was associated with risk of developing second cancer. That is something that hasn't been demonstrated in CLL to date, but points to a close correlation between immune function and the risk for second cancer in this patient population. That is an intriguing finding that warrants further study as well.

What are some of your next steps going forward?

We plan to look at prospective data to [further investigate] second cancer rates. Then, we would be interested in future collaboration to look at risks for some of the particular second cancers in order to develop screening guidelines. For the most part, patients with CLL are subject to the same screening recommendations as the general population, but is that adequate given that we see significantly higher rates of second cancers in these patients compared with the general population?

Bond D, Huang Y, Fisher J, et al. Second cancer incidence in CLL patients receiving BTK inhibitors. Presented at: EHA Congress; June 13-16, 2019; Amsterdam, Netherlands, Abstract PS1149. https://bit.ly/2m2MFLY.