Advancements in Treating Richter Transformation: CAR T-Cell Therapy or Allo-SCT?

Following presentations focused on the treatment of sickle cell disease using gene therapy or haploidentical transplant, panelists Nirav N Shah, MD, associate professor of medicine at the Medical College of Wisconsin in Milwaukee, and Issa F Khouri, MD, oncologist at the MD Anderson Cancer Center in Houston, debated on the preferred therapy for Richter transformation at the Society of Hematologic Oncology 2024 Summit. They presented clinical findings supporting their stance on the use of CD19 chimeric antigen receptor (CAR) T-cell therapy or allogenic stem cell transplantation (Allo-SCT), respectively. The debate covers various aspects of these treatments, as well as the potential advantages and disadvantages of each therapy.¹

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Richter transformation, or Richter syndrome (RS), represents the transformation of underlying chronic lymphocytic leukemia (CLL) to a more aggressive histology, typically diffuse large B-cell lymphoma. Patients with Richter transformation have poor prognoses with a median overall survival of only 12 to 13 months. Standard of care treatment recommendations are clinical trials, combination of chemotherapy and immunotherapy, or transplantation, such as Allo-SCT. Historically, Allo-SCT is considered a potential curative option; however, it is associated with high non-relapse mortality rates around 25%.

“About a third of them had progressive disease at the time of transplant, and so the 3-year relapse free survival was only 27%,” said Shah. “But the cumulative incidence of non-relapse mortality was 26%, which means that 1 out of 4 patients ends up dying of a transplant-related complication. These historical therapies are dangerous and risky, and I would suggest that they're no better than bloodletting, which we also have moved on from.”

Allo-SCT is associated with various possible lifelong complications including graft-versus-host disease (GVHD), as well as increased risk of infection due to long-term immunosuppression. It historically has better outcomes in chemo-sensitive patients, which limits the pool of eligibility and leaves other populations with few alternative options. Additionally, hospitals and care centers require extensive experience in treating patients with CLL experiencing RS, further reducing access to this treatment for many patients. As a result of these treatment barriers, Shah suggests the use of CD19 CAR T-cell therapy as an alternative with fewer short- and long-term complications.

Referencing a study conducted at Ohio State University, Shah presents CAR T-cell therapy as an efficacious option for treating RS. According to the study findings, the treatment had an overall response rate of 63% and a 46% complete response rate with a median 28-month duration of response. Common toxicities associated with CAR T, such as cytokine release syndrome, neurotoxicity, and infections, were observed; however, the risk of GVHD was eliminated.²

"It's not that these patients that CAR T was being used as a bridge to an Allo transplant,” he said. “It was a standalone therapy that [led] to durable outcomes in patients with hard-to-treat [RS].”

Shah emphasized the precise, targeted capabilities of CAR T-cell therapy and spoke to the continued improvement of this treatment for patients with RS. According to his presentation, CAR T is an effective treatment pathway for active disease that has lower toxicity risks for patients. Looking forward, he plans to help lead a multicenter study evaluating CD20 and CD19 CAR T-cell therapy in patients with RS.

“We are getting better. There are dual targeted CARs, there are armored CARs, there's allogeneic CARs, and so this therapy stands to have significant improvement over the next decade, leading to improved efficacy and reducing the toxicities associated,” Shah concluded.

However, Shah’s debate opponent, Khouri, argued in favor of Allo-SCT as a curative option for Richter's transformation, citing that CAR T-cell therapy is not curative and needs further research. Using registry data, Khouri showed the improved outcomes with Allo-SCT observed in recent studies, with patients achieving a 3-year progression-free survival of 48% and 1-year relapse rate of 29%. Treatment advancements from recent years has resulted in the development of newer approaches such as post-transplant cyclophosphamide to decrease the risk of GVHD. Additionally, when engrafting patients after Allo-SCT, they achieve 100% donor chimerism, which may help mitigate the risk of myeloid neoplasms.

According to Khouri, while CAR T-cell therapy can be an effective palliative therapy, it is not curative, and the durability of responses is uncertain. He states that the lack of clinical evidence, cost, and secondary cancer risks may outweigh the benefits of CAR T for patients with RS.

“This is a treatment that costs $500,000 per treatment for a progressive fee, survival of 4.7 months,” Khouri said. “The curves of patients who receive the CR is not stable, [it] continues to dip down. [Additionally,] there are secondary cancers coming up to be of importance after CAR T. Many are focused on what the FDA is saying about T-cell malignancy, but there is also mild malignancy.”

The decision to use CAR T-cell therapy or Allo-SCT for Richter transformation is reliant on several factors including patient eligibility, disease progression, and treatment availability. While CAR T-cell therapy offers a promising option with fewer immediate complications, it still faces questions regarding long-term durability and cost-effectiveness. Conversely, Allo-SCT is potentially curative, but comes with significant risks. As research in both therapies continues to evolve, clinicians hope more personalized and effective treatment pathways will become available for patients with RS.

REFERENCES

1. Khouri I, Kassim A, Boelens J, et al. Cellular Therapy. Society of Hematologic Oncology 2024 Summit. September 7, 2024. Houston, TX

2. Kittai AS, Bond D, Huang Y, et al. Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study. J Clin Oncol. March 29, 2024. doi:10.1200/JCO.24.00033