CD19-targeted CAR-T therapy in patients with Richter transformation (RT) results in a high overall response rate and similar PFS rates as those seen in pivotal trials of patients with de novo LBCL.

An international study, reviewing 69 patients from 12 centres including in Australia, found CAR-T led to an overall response rate of 63% and 1-year and 2-year PFS rates of 35.7% and 28.9% respectively.

The treated cohort had a median age of 64 years at CAR-T infusion and had been diagnosed with RT at a median of 6 years from CLL diagnosis. Patients had received a median of four previous lines of therapy including 84% with previous exposure to a BTKi, BCL2i or both.

CAR-T products were axi-cel (64%), tisa-cel (25%), liso-cel (10%) and brexucabtagene autoleucel (1%).

The study, published in the Journal of Clinical Oncology [link here], found complete response (CR) in 46% patients, partial response (PR) in 17%, stable disease in one patient (1%), and progression of disease in 21 patients (30%).

“After a median follow-up of 24 months after CAR-T infusion, the median PFS was 4.7 months (95% CI, 2.0 to 6.9) and the median OS was 8.5 months.”

1-year and 2-year OS rates were 42.9% and 38.3%. The median duration of response was 27.6 months for patients achieving CR compared with 2.1 months for patients achieving PR.

“Among patients with confirmed clonally related RT, response rates and survival were numerically similar to those of the overall study population,” the study said.

The investigators said their cohort represented “…a typical, modern cohort of patients with RT, who represent a high unmet medical need”.

They added that CAR-T cells had revolutionised treatment of LBCL and that their findings suggested that similar remission rates can also be achieved in heavily pretreated patients with RT.

The study identified higher baseline LDH and CRP associated with shorter PFS and OS while additionally, a greater number of previous lines of therapy for RT and higher baseline tumour Ki67 proliferation index were also associated with shorter OS.

This suggested that CAR-T may be more effective for RT if used as an earlier line of therapy or with low tumour burden.

“As in LBCL, we believe that future efforts to enhance disease control pre-CAR-T in RT will be important.”

They also recommended short interval follow-up scans in patients with PR to detect either response evolution to CR or early progression.

Safety

The study said the CAR-T was delivered with manageable toxicity in a very heavily pretreated patient population of mostly older patients.

However grade ≥3 CRS occurred in 16% patients and grade ≥3 ICANS in 37% patients which was “…somewhat higher than those seen in the pivotal trials of de novo LBCL.”

As well, grade ≥3 infections occurred in 14 patients (20%) with nine deaths including from COVID-19.

“As with CAR-T-cell therapies in LBCL, infection remains the major cause of nonrlapse mortality and rigorous attention to anti-infective prophylaxis and measures to mitigate risks related to COVID-19 disease should be implemented,” they said.

“Our data support the continuous exploration of CAR-T-cell therapy for RT through prospective clinical trials.”

Co-investigators included Dr Mark Dowling and Philip Thompson from the Peter MacCallum Cancer Centre, Associate Professor Emily Blyth from Westmead Hospital and Dr Vinay Vangru from the Royal Prince Alfred Hospital.