CAR T-Cell Therapy for Richter’s Transformation

Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Anti-CD19 Chimeric Antigen Receptor T-cell therapy for Richter’s Transformation: An International, Multicenter, Retrospective Study by Kittai, et al published in the Journal of Clinical Oncology March 29th, 2024.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the June 10th issue of JCO titled, “Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study,” by Kittai et al. This report addresses the real world efficacy of CAR T-cell therapy for patients with Richter transformation of CLL to large B cell lymphoma, which represents a high risk group of patients with an unmet need for novel and more effective therapeutic agents than are currently available. Richter's represents the transformation of chronic lymphocytic leukemia, or CLL, to an aggressive lymphoma, most often a large B cell lymphoma, most similar to diffuse large B cell lymphoma or DLBCL. Treatment for Richters is often modeled after treatment practices for DLBCL. However, there's no clear standard of care and outcomes for these patients lag behind those of large B cell lymphoma patients otherwise.

An important advance in recent years in the DLBCL field is the approval of anti CD19 CAR T-cell therapy in the second and third line settings. However, patients with Richter transformation were largely excluded from these pivotal trials. This study in JCO thus set out to address what the real world outcomes were for patients with Richters who were treated with CAR T-cell therapy across 12 centers internationally. The study included 69 patients across these twelve sites, with a median age of 63 years at diagnosis of Richters and a median of six years after initial CLL diagnosis. Included patients received a median of four prior lines of therapy for either CLL or Richters, with a median of two prior lines of therapy for Richters, although two patients had not received any prior therapy for their Richter transformation.

The most recent prior treatments included chemoimmunotherapy in 29% of patients, followed by BTK inhibitors in 19%, as well as combinations of BTK inhibitors and BCL2 inhibitors in 12%. 17% of patients had not received prior therapy for their CLL before their diagnosis with Richters, 58% of cases had known TP53 mutations at time of transformation, and 41% exhibited deletion 17p by FISH. Prior to receiving CAR T-cell therapy, 86% of patients required additional bridging therapy, most commonly with a BTK inhibitor or chemoimmunotherapy. A diverse set of commercial CAR T-cell products were represented in this study, with the majority of patients at 64% receiving axi-cel, 25% receiving tisa-cel, 10% receiving liso-cel, and one patient received brexu-cel in an investigational setting. Median time from apheresis to CAR T infusion was 34 days, and 59% of patients continued on a BTK inhibitor throughout CAR T-cell therapy.

When we move on to look at responses, 66 out of 69 patients were available for response. Three patients died related to adverse events after infusion and before response assessment, with the best overall response of complete response or CR in 46% of patients and partial response or PR in 17% for an overall response rate of 63%. With a median follow up time of 24 months, the median PFS in the study was 4.7 months and the median OS was 8.5 months. For those who achieved a CR, the median duration of response was an impressive 27 months, and for those achieving PR, the median duration of response was only two months. The two year PFS rate was thus 28%, and the two year OS rate was 38%. Four patients who achieved a CR went on to receive an allogeneic stem cell transplant. Among those whose disease progressed, 8% had relapse involving the CNS, compared to 10% of patients having CNS involvement prior to CAR T in this study population. The authors were also able to look at minimal residual disease, or MRD testing for CLL in a subset of 27 patients in this study. MRD was undetectable by PCR or flow in either blood or bone marrow in 81% of these 27 patients. However, not all of these patients had paired pre and post CAR T samples available for comparison, thus limiting more detailed interpretation.

In an analysis of risk factors linked to adverse outcomes, the study authors found in a multivariable analysis for overall survival that a greater number of prior lines of therapy for Richters, a higher Ki-67 proliferation index, and a higher baseline LDH and CRP were all associated with shorter OS. They did not find an association between patterns of BTK inhibitor use, whether prior to apheresis, as a part of bridging, or concurrent with CAR T-cell therapy, to be associated with either PFS or OS. In evaluating rates of toxicities for patients with Richters treated with CAR T, the authors find that grade 3 or higher cytokine release syndrome or CRS occurred in 16% of patients and grade 3 or higher neurotoxicity or ICANS occurred in 37%. They did not find any baseline features associated with higher risk of severe CRS, however, did find that prior venetoclax exposure was associated with severe ICANS.

Overall, the authors find that CAR T-cell therapy is a feasible and effective therapy for Richter transformation of CLL to large B cell lymphoma, thus contributing data to support this additional therapeutic option in a high risk patient population with unmet therapeutic needs. While the PFS and OS rates are lower than those of their large B cell lymphoma counterparts, overall response rate of 63% and particularly the CR rate of 46% with a duration of response of 27 months for this group is quite promising. Those who achieved less than a CR had a much shorter duration of response and progressed quickly, and overall, the median overall survival of the whole study population is only over eight months, which reflects the high risk and poor outcome nature of treatment for Richters with currently available therapies. As the authors discuss, it is likely that the efficacy of CAR T-cell therapy is somewhat overstated in their results by virtue of not being able to include patients who were intended for CAR T-cell therapy but could not receive it in this retrospective study. This represents one of the many real world challenges patients and clinicians treating Richters face. However, the promising results for those who were able to receive CAR T-cell therapy represent a path forward for future investigations for Richters patients.

One of the avenues of future pursuit is the addition of BTK inhibitors to CAR T-cell therapy. A subset of patients included in this study received BTK inhibitors for CLL before, during, and after CAR T-cell therapy, and although limited by subgroup analysis and statistical power constraints, this study's authors did not find a difference in outcomes for those who received BTK inhibitors in these settings. Toxicities with severe CRS and ICANS were higher than rates reported in large B cell lymphoma CAR T trials. However, as the authors note, these were comparable to the study of liso-cel toxicity in CLL patients. Higher rates of infection related deaths were also noted compared to large B cell lymphoma patient counterparts, however, in line with comparable CLL patient studies and thus likely related to the unique biology of Richters arising from CLL rather than de novo large B cell lymphoma.

In summary, this important work evaluating the outcomes of patients with Richter's transformation treated with anti CD19 CAR T-cell therapy in the commercial setting provides important evidence as to the efficacy of this therapy among patients with an unmet need for efficacious and novel therapies to improve outcomes. As this group of patients is often excluded from clinical trials, this data is particularly important and should drive forward future studies focusing on and or including patients with Richters, given the benefits seen for a subset of patients who achieve a response in the study. While the antecedent CLL distinguishes Richters from de novo large B cell lymphoma biologically along with differences in prior treatment regimens, this study in JCO suggests that future strategies targeting improving baseline disease factors prior to CAR T-cell therapy, including successfully bridging patients to CAR T, reducing risk of CRS and ICANS with treatment, and improving long term efficacy after CAR T with novel constructs, and CAR design, may all be promising next steps in the advancement of CAR T-cell therapy for patients with Richter transformation.

This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.