The treatment of younger patients is an unmet clinical need in chronic lymphocytic leukemia (CLL), given the concern that this population is not currently able to achieve a normal life span because they eventually run out of treatments if they have intermediate- or high-risk disease. As patients with CLL continue to live longer, more research on novel treatment regimens and their sequencing is needed to provide younger patients with better outcomes.

The majority of people with CLL do not die due to their CLL, they die from something else. However, with younger patients, we start to worry that, even with the outstanding therapies that we have today, they might die from their CLL rather than with it—even if their disease is not high risk. It is very important to think about not only the first few therapeutic choices but also the potential for several lines of treatment. Limiting side effects and determining appropriate sequencing takes on an extra layer of importance when treating younger patients with CLL.

The median age of patients at diagnosis is between 65 and 74 years, so most people with CLL are older. When we talk about younger patients, we are usually referring to people in their 40s, 50s, or early 60s and not people in their 20s or 30s. In many cases, we are expecting patients in their 50s to live for 3 or more decades. However, although the median progression-free survival (PFS) for most of our first-line therapies for CLL is longer than 5 years, when we add up that initial response followed by the length of PFS that is provided by subsequent therapies, we are still not looking at 30 years.

Treating younger patients with high-risk disease is particularly challenging in that sense, and outcomes for those whose CLL becomes resistant to both BTK inhibitors and venetoclax are particularly poor. In these patients, I think that there is a role for the consideration of options such as allogeneic stem cell transplant, the recently approved CAR T-cell therapy lisocabtagene maraleucel, and clinical trials with other CAR T-cell therapies or bispecific antibodies. It is very important to counsel patients who are younger and fitter—especially if they have high-risk disease—about their eventual need for clinical trial participation and cellular therapies.

There are very good data with fludarabine, cyclophosphamide, and rituximab (FCR), our most effective chemoimmunotherapy regimen, showing that it might cure some patients with IGHV-mutated disease. While using this regimen is tempting, the randomized E1912 trial comparing FCR with ibrutinib plus rituximab in younger patients with CLL showed that ibrutinib and rituximab still have improved PFS. Additionally, FCR has a clinically significant rate of secondary acute myeloid leukemia and myelodysplastic syndromes, so, even if it is exciting to think that we might cure someone with CLL by using FCR, it is not in their best interest in the long-term.

It is also worth considering whether younger patients could be treated with fixed-duration combination therapy such as venetoclax plus obinutuzumab and be able to have time off treatment. Knowing that their life span is expected to be very long, the intervals off therapy between treatments may become a little more important. I see a lot of patients in their 70s, 80s, and 90s experiencing first-line treatment for CLL. If they have low- or intermediate-risk CLL, one treatment might be enough for the rest of their natural life span. But this is really not the case for younger people, especially if they have intermediate- or high-risk disease. It is important to talk this through with patients when selecting therapy. For example, treatment with a BTK inhibitor may be indefinite, so, if a patient receives a BTK inhibitor in the first line, most of their life will involve treatments unless they undergo a successful cellular therapy. Alternatively, they could choose something with a fixed duration first, including clinical trial participation. These conversations become markedly more important when treating younger patients.