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Study Sheds Light on CAR T-Cell Therapy's Potential in Highly Aggressive Lymphoma Subgroup

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NEW YORK – Autologous CD19-directed CAR T-cell therapy could benefit patients with a rare and aggressive lymphoma subtype called Richter's transformation, according to a multicenter retrospective study presented during the annual meeting of the American Society of Hematology (ASH).

These patients — whose cancers begin as chronic lymphocytic leukemia but transform into more aggressive B-cell lymphomas in a process called Richter's transformation — have historically had poor outcomes and few, if any, treatment options, said Adam Kittai, a hematologist at Ohio State University, during a presentation of a multicenter retrospective study on Saturday.

"Survival is measured in months," Kittai said. "Even in the era of novel therapies … Richter's transformation represents an area of true unmet need in the realm of CLL and aggressive lymphomas."

Indeed, for patients who undergo Richter's transformation, which could include progression from CLL to large B-cell lymphoma or Hodgkin lymphoma, among other types of aggressive lymphomas, the median overall survival is just over eight months. The condition, which manifests suddenly, affects 2 percent to 10 percent of CLL patients. Because the condition is so rare, it has been difficult to study in clinical trials, and Kittai pointed out that Richter's transformation patients were excluded from the majority of trials that led to the approvals of CD19-directed CAR T-cell therapies for large B-cell lymphoma.

Previously, Kittai and his colleagues conducted a promising, albeit extremely small, trial in which Richter's transformation patients seemed to respond well to Gilead Sciences' CAR T-cell therapy Yescarta (axicabtagene ciloleucel). But researchers were limited in their ability to draw definitive conclusions from the just nine patients in that study.

In the study presented at this meeting, Kittai and colleagues decided to take a retrospective approach to assessing the activity of CAR T-cell therapy in a larger population of Richter's transformation patients, drawing on data collected at 12 academic centers in multiple countries.

They analyzed data from 69 Richter's transformation patients who received CD19-directed CAR T-cell treatment with Gilead's Yescarta or Tecartus (brexucabtagene autoleucel), Novartis' Kymriah (tisagenlecleucel), or Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel). According to Kittai, this is the largest study of Richter's transformation patients who have received CD19-directed CAR T-cell therapy.

The patients in the study had received a median of two prior treatments for their Richter's transformation, though they'd received a median of four prior therapies from the start of their CLL diagnoses. The median time from their CLL diagnoses to their Richter's transformation was six years.

"This represents a modern cohort of patients receiving our most modern therapies," Kittai said, noting that for their Richter's transformation study, 66 percent of patients had previously received BTK inhibitors and 50 percent had received Genentech and AbbVie's BCL-2 inhibitor Venclexta (venetoclax) alone or in combination with other therapies. Additionally, 84 percent had received one or both of these types of treatments at some point in their disease, be it for their initial CLL diagnoses or their subsequent Richter's transformation.

It took a median of 33 days for patients to receive their infusions after having their immune cells collected for the CAR T-cell therapy manufacturing.

After a median follow-up of over two years from the time these patients received their cell therapy infusions, the median progression-free survival was 4.7 months and the median overall survival was 8.5 months. Kittai acknowledged that these outcomes on CAR T-cell therapy are still dismal and that it reflects tremendous unmet medical need. But he highlighted the durable responses some of the patients had as an encouraging takeaway given their extremely aggressive disease.

"There is a tail end of this curve, giving hope that some patients are potentially cured of their disease in this patient population," he said. From the point of their Richter's transformation diagnosis, he noted, the median overall survival was 29.4 months, which suggests that there is a "selective group of patients who could receive two prior lines of therapy and CAR T-cell therapy and get up to this point."

Such a subset of patients who respond to therapy and remain progression-free was "borderline not heard of in patients with Richter's transformation," he added.

Of the patients analyzed in Kittai's multicenter retrospective study, the complete response and partial response rates on CAR T-cell therapy were 46 percent and 17 percent, respectively. For patients who experienced a complete response, the median duration of response was 27 months, and for those who had a partial response, the median duration of response was two months.

"There was a true delineation between those patients who had a complete response and those who had a partial response … really showing that if we get a partial response for patients with Richter's transformation, we should move them onto alternative therapy as soon as possible," he said.

As for toxicities, Kittai noted that the rates of serious side effects were a bit higher than what investigators would have expected for CAR T-cell therapy in standard large B-cell lymphoma. About 15 percent of patients had grade 3, 4, or higher cytokine release syndrome; about 36 percent of patients had grade 3 or 4 immune effector cell-associated neurotoxicity syndrome (ICANs), and about 20 percent of patients had grade 3 or 4 infections.

Prognostic factors, subset analyses

Since there was a subset of patients with improved outcomes in their analysis, Kittai and colleagues searched for characteristics that could help identify who might or might not benefit from these CD19-directed cell therapies. Ki-67 expression levels, for instance, seemed to be an independent prognostic factor for patients' death. A higher number of prior treatment lines was also associated with worse overall survival outcomes, which led Kittai to suggest that "earlier use of CD19 [CAR T-cell therapy] may be warranted."

Importantly, he noted that the specific product patients received didn't seem to be prognostic for overall survival.

Kittai and colleagues also performed a subgroup analysis on Richter's transformation patients with clonally related disease, who are known to be the highest-risk cohort. The outcomes in this group, however, were very similar to the overall cohort in the study.

Looking ahead, Kittai said that prospective trials are already under way that can validate and advance the findings from this retrospective study. Kittai's group, for example, is conducting a Phase II trial of Breyanzi plus BeiGene's BTK inhibitor Brukinsa (zanubrutinib) in Richter's transformation patients. There is also a City of Hope-sponsored Phase II Richter's transformation study of Breyanzi plus BMS's checkpoint inhibitor Opdivo (nivolumab) and Janssen and AbbVie's BTK inhibitor Imbruvica (ibrutinib). In a third Gilead-led Phase II basket trial, dubbed ZUMA-25, the firm is testing Tecartus in patients with rare B-cell malignancies including Richter's transformation.