Aggressive lymphomas on CART-ace-ous threads: to each its own protocol

During CAR T-cell therapy, patients’ T cells are collected and genetically modified to express a chimeric antigen receptor that helps target and kill lymphoma cells. These modified T cells are then infused back into the patient. CART therapy is a relatively new treatment for non-Hodgkin lymphoma (NHL), so there’s a need for more information on how and when to use it instead of other treatment options and which patients it might benefit most. While the therapy is initially highly effective in patients whose NHL has relapsed or resisted other treatments, most eventually relapse again. Knowing how to identify those patients early on could help providers move on to other therapies more quickly.

Measuring the lymphocytes in a patient’s blood can be used to predict outcomes in non-Hodgkin lymphoma patients who receive CAR T-cell therapy, according to research from physicians at Fox Chase Cancer Center and Temple Health. The study, which was presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, found that a higher absolute lymphocyte count, or ALC, and a faster rate of ALC increase after therapy, were linked with better outcomes, including progression-free survival, overall survival, and complete response. A high concentration of lymphocytes in the blood indicates a strong immune response.

For the new study, researchers looked at the link between absolute lymphocyte count and treatment outcomes in patients with relapsed or resistant NHL who received a type of CAR T therapy called axicabtagene ciloleucel, which is also known by its brand name, Yescarta. Scientists found that higher baseline ALC meant better survival: patients whose ALC was above-median at the start of treatment had significantly longer progression-free survival and higher overall survival. A faster ALC increase meant stronger response: patients whose ALC increased the fastest in the first 10 days post-treatment had a greater complete response rate and longer progression-free survival.

Finally, an early peak was meaning favorable prognosis: the patients whose ALC peaked sooner had better survival outcomes. It’s an important finding, because it could help providers quickly assess how patients are responding to therapy and guide treatment decisions. Researchers hope to study ALC trends in other patient populations, including patients receiving lisocabtagene maraleucel, a different type of CART therapy. Another novelty comes from a new research from Sylvester Comprehensive Cancer Center at the University of Miami. Most patients with a rare and aggressive form of large B-cell lymphoma can safely receive a less toxic treatment than the intensive chemotherapy.

The study’s findings could help standardize treatment for T-cell/histocyte-rich large B-cell lymphoma (THRLBCL). Previous research has suggested that patients with THRLBCL benefit from intensive chemotherapy regimens. However, this approach comes with a significant downside: frequent and considerable side effects. To determine if R-CHOP drug protocol could offer similar benefits without these drawbacks, the researchers compared results in THRLBCL to those of a cohort of patients with diffuse large B cell lymphoma (DLBCL), the most common large B cell lymphoma.

The R-CHOP protocol combines three chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine), a steroid (prednisone) and the monoclonal antibody rituximab, which latches onto the CD20 protein on B cells. R-CHOP has proven highly effective in treating DLBCL. About 60% of these patients see their cancer disappear after completing the six cycles of R-CHOP. Of the 140 patients with THRLBCL, 106 received R-CHOP. Four years following treatment, 80% of these patients were still alive and 70% had not had their cancer return or experienced complications. The nearly 6,100 patients they included with diffuse large B cell lymphoma had similar outcomes.

This means that there’s no need to choose more aggressive protocols for a cancer that has similar response with regular protocols used to less aggressive lymphomas. Another new research findings presented at the 67th American Society of Hematology (ASH) Annual Meeting by scientists from the Abramson Cancer Center of the University of Pennsylvania and Penn’s Perelman School of Medicine, declares that serious side effects, including neurotoxicity and intestinal inflammation, that appear weeks or months after patients receive CAR T cell therapy for multiple myeloma share a common immune root cause and thaty can be avoided.

Since B cell maturation-directed (BCMA) CAR T cell therapies for relapsed or refractory multiple myeloma have become commercially available in recent years, physicians have reported different adverse events. These included delayed cranial nerve palsies, Parkinson’s disease-like symptoms and enterocolitis, which can be deadly in those with compromised immune systems. These reactions can happen weeks or even months after treatment. The research team collectively defined these complications as CAR T-associated immune-related adverse events (CirAE). The team analyzed data from a cohort of 198 patients who received either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) for multiple myeloma, between June 2021 and December 2024 at Penn Medicine.

Researchers found that the incidence of any CirAE was 13.6% and significantly higher with cilta-cel (20%) compared to ide-cel (2.7%). Non-relapse mortality-meaning death from a cause other than cancer relapse-at one year after the CAR T infusion was significantly higher (17 vs 2.7%) in patients who experienced CirAE. Infection accounted for 60 percent of non-relapse mortality deaths in the patients with CirAE, compared to 14.3% in patients without CirAE, which the researchers attribute to a seven-fold higher cumulative steroid exposure in the CirAE group. Patients who developed CirAE had higher proportion of circulating CD4⁺ versus CD8⁺ T-cells post-infusion compared to those without CirAE.

The team found additional common clinical features among patients with CirAE and significantly higher peak absolute lymphocyte count within 14 days post-infusion, which correlated with greater CAR T expansion. Patients treated with cilta-cel who have an unexpectedly high absolute lymphocyte count are considered high-risk and given a brief course of steroids (DEX) to curb excessive CD4+ CAR T expansion. Ideally, a strategy that doesn’t involve steroids would be even less toxic and better for patients, so the research team took a closer look at what was causing the high CD4+ CAR T expansion. They found a specific circuit (IL‑15–CCL5–CCR5) was driving the proliferation and demonstrated in preclinical tests that blocking CCR5 safely restrained BCMA-CAR T cell expansion to optimal levels, while preserving their ability to attack the cancer cells.

These findings suggest that a CCR5-directed targeted strategy would be worth exploring to protect against CirAE. Overall, lymphoma world is not shrinking but exapnding with newer and better opportunities for precision medicine.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Galarza Fortuna GM et al. Blood Adv. 2025; 9(23):6009.

Leick MB, Maus MV.Mol Ther. 2025; 33(12):5916-5917.

Watanabe T. Current Gastroenterol Rep. 2025; 27(1):75.

Luttwak E et al. Hemasphere. 2025 Nov; 9(11):e70248.