Frontline immunotherapy: Treating older adults with acute lymphoblastic leukaemia

Q: How has the availability of immunotherapies changed your frontline approach to adult ALL, particularly in older or unfit patients?
It’s difficult to overstate how much immunotherapies have changed the landscape of therapeutic options in adult ALL, especially in older and unfit patients. Our arsenal of approved immunotherapies in ALL includes blinatumomab (a CD3–CD19 BiTE), inotuzumab (a CD22 antibody–drug conjugate), and three different CD19-directed CAR-T cell options. Based on the E1910 data, almost every patient with Ph-negative B-cell ALL is receiving blinatumomab in upfront consolidation if MRD-negative, and chemotherapy-free regimens using blinatumomab plus TKIs have completely changed the way we treat Ph-positive B-ALL.

In older or unfit patients with Ph-negative disease, there are now multiple approaches aiming to improve on the toxicity and historically mediocre outcomes of chemotherapy-only regimens. Reduced-intensity backbones, such as mini-CVD plus inotuzumab with or without blinatumomab, are significantly more tolerable and have shown promising outcomes in phase II studies. The Alliance A042001 trial is attempting to confirm these data in a randomized setting, while Alliance A041703 tested a chemotherapy-free approach using inotuzumab induction followed by blinatumomab consolidation in patients older than 60 years, with high remission rates and favorable event-free survival.

More recently, early studies from City of Hope and China have explored upfront CAR-T consolidation following modified chemotherapy induction, providing proof of concept that CAR-T therapy may eventually move into the frontline setting and further reduce reliance on chemotherapy and transplant.

Q: What are the key toxicity considerations that influence your choice, particularly in older adults?
Traditional ALL regimens include several agents that are difficult for older adults to tolerate, including anthracyclines in patients with compromised cardiac function, vincristine in those with baseline neuropathy, and steroids, which can be particularly challenging in this population. Induction mortality with intensive regimens such as HyperCVAD can be as high as 10% in older adults.

Although pediatric-inspired regimens have produced excellent outcomes in AYA patients and can be dose-adjusted for selected older patients, tolerability declines with age, and many clinicians are hesitant to use PEG-asparaginase in older adults, particularly those with obesity, metabolic syndrome, or steatohepatitis. For these reasons, attenuated chemotherapy backbones combined with upfront immunotherapy are very appealing. That said, we still have much to learn about how best to integrate chemotherapy and immunotherapy without compromising efficacy, and how to manage immunotherapy-specific toxicities in older adults.

Q: In your practice, when do you consider immunotherapy-based regimens over traditional multi-agent chemotherapy?
We now integrate immunotherapy into the treatment of almost all patients, provided their disease expresses CD19 and/or CD22. Blinatumomab is standard of care in consolidation, and inotuzumab is incorporated into reduced-intensity regimens such as mini-CVD plus inotuzumab. In rare cases of CD19- and CD22-negative disease, we are left without immunotherapeutic options, representing a clear unmet need.

Another group that has not yet benefited fully from the immunotherapy revolution is patients with T-ALL, although there is emerging promise with ongoing trials of both autologous and allogeneic CD7-directed CAR-T products.

Q: How do you balance efficacy with tolerability and quality of life in older or unfit patients?
This requires highly individualized decision-making and candid discussions with patients about their goals and values. While some patients are too frail to tolerate CAR-T therapy, many ambulatory older adults with adequate organ function can safely receive it. With newer CAR-T products associated with lower rates of CRS and ICANS, and improved management of these toxicities, the potential survival benefit is often worth the risk.