CCR4-Directed Strategy Achieves Durable Response in T-Cell Lymphoma Following Treatment with Anti-BCMA CAR T-Cell Therapy

CAR T-cell therapy has demonstrated durable efficacy across hematologic malignancies; however, rare secondary malignancies following CAR T-cell therapy have emerged as a clinical concern. Through a multidisciplinary approach, investigators identified CCR4 expression on the lymphoma cells and successfully repurposed the anti-CCR4 antibody mogamulizumab (Poteligeo) in combination with chemotherapy, leading to durable remission.

In an interview with OncLive®, study investigator Samir Parekh, MBBS, discussed the clinical presentation, diagnostic workup, and therapeutic strategy used to manage a patient who develops a secondary malignancy, as well as the broader implications for monitoring, drug repurposing, and precision medicine approaches in rare post–CAR T-cell complications.

Parekh currently serves as the director of the Center of Excellence for Multiple Myeloma and section head of Multiple Myeloma in the Division of Hematology and Medical Oncology, and is co-leader of the Cancer Clinical Investigation program and a professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City.

OncLive: How would you characterize the current role of CAR T-cell therapy in hematologic malignancies?

Parekh: [CAR T-cell] therapy has emerged as a very exciting and successful treatment for hematological malignancies, including leukemias, lymphomas, and multiple myeloma. Thousands of patients have been treated with this, and more and more patients are being treated. In fact, in the case of multiple myeloma, treatments are now moving earlier and earlier in the treatment paradigm, which is really exciting.

Earlier this year, in fact, [a] multi-institutional report led by one of my colleagues at Mount Sinai showed that 1/3 of patients treated with [CAR T-cell therapy] actually get cured, even with advanced-stage disease. So [it is] really an exciting time to be in this field. However, one of the unfortunate and rare [adverse] effects that has been noted with the use of [CAR T-cell therapy] is the development of secondary neoplasms.

What is currently known about the risk of secondary cancers emerging after treatment with CAR T-cell therapy?

[The development of secondary malignancies] indeed extremely rare, and there have been 2 or 3 large studies that have been published on this [topic]. One was published by the Stanford group last year, led by Ash Alizadeh, MD, PhD, and it showed an incidence of around 5% to 6%. Another, more recently [published study] led by [investigators at] Memorial [Sloan Kettering], looked at [an] even larger number of patients, and showed a similar number, just around 5%. Therefore, [it is] really quite rare, looking at all secondary neoplasms.

In fact, the T-cell lymphomas in those patients were only a handful. With the BCMA-directed CAR T-cell therapies, there have been fewer than half a dozen patients who have been described so far. Our patient was probably the fourth or fifth patient that was described in the literature. Therefore, this is extremely rare, considering hundreds or possibly even [a] larger number of patients that have been treated with anti-BCMA CAR T-cell therapy by now.

Nevertheless, it warrants some interest and monitoring because even the FDA, as of 2024, issued a warning to the community to look out for these, and a pathway is now in place for reporting these to the FDA.

What were the key clinical features of this patient’s case, and how did they help guide your team’s treatment approach?

This was a patient who was young. He was a 50-year-old who had [relapsed] multiple myeloma and then received an anti-BCMA CAR T-cell therapy and actually went successfully [into] remission after the CAR T-cell therapy.

Like most patients, he had mild CRS after the CAR T-cell therapy and a couple of mild viral infections, including [COVID-19]. As he was [recovering from] COVID-19, about 3 months after [CAR T-cell therapy] we noticed when he came to clinic that he had a little bit of [a] rash [on his] face, and we sent him to the dermatologist.

The dermatologist gave him a skin cream [and asked] him to come back, and when he came back, the rash had not gotten better; it had gotten worse. We [then] sent him [back] to the dermatologist [with a request] to biopsy [the rash], and unfortunately, the biopsy showed [a] T-cell lymphoma, [with] an unusual phenotype. Usually, T-cell lymphomas have [a] signature of CD4 or CD8 cells. [The lymphoma] lacked both CD4 and CD8 cells; therefore, it was [dedifferentiated]. By this time, the patient had also shown signs that this lymphoma was spreading aggressively in the blood as well as the lymph nodes. When we checked his blood, he had a high lymphocyte count. We did [flow] cytometry and saw exactly the same phenotype in the blood and bone marrow, and [a] PET scan showed lymph node [involvement], which we also biopsied and found this identical phenotype. We knew the lymphoma was spreading, and week after week, we saw the counts rising, so this was quite aggressive.

We therefore reached out to the other physicians around the world that had treated this rare complication, and found that similar rare patients that had been diagnosed with T-cell lymphoma after BCMA-directed CAR T-cell therapy had received [a] variety of different treatments, some even very aggressive, including allogeneic [CAR T-cell therapy], and failed them, which was to our dismay, perplexing, because we had to come up with a successful treatment for this patient.

After exhausting initial treatment options, how did you and your colleagues decide to proceed with treatment?

We decided to take a [different plan of action]. What we did was [consulted] both lymphoma colleagues within our institution and expert dermatologists [and] immunology scientists, and we all put our heads together and came up with a strategy where we would actually screen the patient's lymphoma cells against a very broad array of FDA-approved [treatments] and rank order the compounds that would kill lymphoma cells while sparing the normal T cells.

This was important because post [CAR T-cell therapy,] patients are generally immunocompromised, and we didn't want the patient [to risk] having more sepsis because of the treatment. In this manner, we were able to actually identify several compounds that we could make a treatment [from] that was intelligently directed at the lymphoma, and at the same time, in parallel, using our immunology strengths at the institution, we were able to do phenotyping of a large number of surface markers on the lymphoma cells.

To our surprise, we found a surface marker called CCR4, which has a monoclonal antibody that's been used in another kind of T-cell lymphoma called HTLV-associated adult T-cell lymphoma.

This is usually seen in [the] Japanese and Caribbean population and is linked to the HTLV-1 virus—a different disease entirely. However, it is approved, and we were able to reposition this drug along with the top hit from the drug screen that we had, which was an anthracycline. We used these two [agents] along with gemcitabine, which is commonly used in lymphomas. Within days, the patient's skin lesions, lymph nodes, and [the] abnormal lymphocytes started resolving. Within 1 or 2 cycles, the patient went into remission, and I'm happy to report he's still in remission more than [a] year and [a] half later. In fact, recently [he] told me that over the summer, he went to the Yosemite National Park in California with his family and had a wonderful vacation. I am really grateful that he is doing well, both from the lymphoma and the myeloma point of view.

References

1. Mount Sinai researchers pioneer first targeted therapy for rare T-cell lymphoma after CAR T treatment. News Release. Mount Sinai. Updated August 21, 2025. Accessed September 30, 2025. https://www.mountsinai.org/about/newsroom/2025/mount-sinai-researchers-pioneer-first-targeted-therapy-for-rare-t-cell-lymphoma-after-car-t-treatment
2. Aleman A, Oekelen OV, Melnekoff DT, et al. Targeted Therapy of CAR+ T-Cell Lymphoma after Anti-BCMA CAR T-Cell Therapy. N Engl J Med. 2025;393(8):823-825. doi:10.1056/NEJMc2504588