medwireNews: Patients with high-risk large B-cell lymphoma (LBCL) respond well to first-line treatment with the CD-19 targeting CAR-T therapy rapcabtagene autoleucel, suggests an interim analysis of an ongoing phase 2 study.
The high-risk characteristics of the patients in the study were an International Prognostic Index (IPI) score of 3–5 out of a possible 5 points, and/or double hit lymphoma, with genetic abnormalities in two associated genes.
There are “effective therapies” in frontline LBCL, and approximately 70% of patients do well,” said the study presenter at the 67th ASH Annual Meeting and Exposition in Orlando, Florida, USA.
“However, the patients with high clinical risk can have lower clinical response, with only approximately 50% of patients who do well.”
By comparison, Jason Westin (University of Texas MD Anderson Cancer Center, Houston, USA) reported that the complete response (CR) rate was “very high” with first-line rapcabtagene autoleucel in such patients, at 74% after a median follow-up of 8.5 months, and this was consistent across subgroups.
Patient characteristics and treatment protocol
The 53 patients with LBCL enrolled in the study had received two cycles of chemoimmunotherapy and were considered eligible for rapcabtagene autoleucel due to having a Deauville positron emission tomography (PET) score of 4–5 out of a possible 5 points, consistent with a partial response (91%) or stable disease.
Two patients then received optional bridging therapy of steroids or radiotherapy, while a subsequent 46 patients received a mandatory third cycle of chemoimmunotherapy as bridging therapy, after an amendment to the study protocol, “to keep their disease cadence for treatment,” the presenter commented.
Rapcabtagene autoleucel was manufactured within 2 days using the rapid T-Charge™ platform (Novartis, Basel, Switzerland), and after lymphodepletion, the patients received a single intravenous infusion, at a dose of 12.5 x106 cells/kg, with the first efficacy assessment 28 days later.
The patients (57% men) were aged a median of 59 years, ranging from 26–76 years, with 23% aged 65 years and older. Nearly all (98%) had stage III/IV disease and 87% had a lactate dehydrogenase (LDH) level above the upper limit of normal at diagnosis, and 21% prior to infusion.
Fifty-one percent of patients had an IPI score of 3 points but did not have double hit lymphoma, and 49% had an IPI score of 4–5 points or double hit lymphoma (32%).
Prior to treatment, 91% of patients had a partial response at screening, with Deauville PET scores of 4 points in 62% and 5 points in 36%.
Westin reported that the objective response rate was 89%, with the median duration of response not met in responders overall or those with a CR, and an estimated probability of an ongoing response at 6 months of 79% and 86%, respectively.
This level of response was consistent across subgroups based on cell of origin, LDH status, genetic abnormality, receipt of bridging therapy, and IPI and double hit risk factors.
Median progression-free survival (PFS) was also unreached in all patients and those with a CR at 3 months, with respective 6-month rates of 76% and 96%.
Low rates of CRS and ICANS
Westin said that “89% of patients had no clinically significant CRS [cytokine release syndrome],” which he defined as grade 2 or above, and there was no CRS of grade 3 or above.
Among the 49% of patients with low-grade CRS, the median time to onset was 11 days, and 26% were given tocilizumab.
The incidence of immune effector cell-associated neurotoxicity syndrome was also low, occurring in just 8% of patients, with only one grade 3 and no grade 4 events. The median time to onset was 15 days and all events resolved.
Hematologic disorders, including cytopenias, of grade 3 or above occurred in 96% of patients, but Westin noted that “most grade 3 or 4 cytopenias occurring within 1 month of infusion had resolved to grade 2 or lower by month 3.”
There were two deaths, both due to disease progression and not considered related to treatment.
The presenter pointed out that cellular expansion was high with rapcabtagene autoleucel, with the time to peak expansion a median of 13.8 days, and even at the low dose given the maximum CAR-T concentration was “comparable with that reported in the relapsed/refractory diffuse LBCL setting,” at 42,300 versus 41,800 copies/µg of DNA.
Westin concluded that “rapcabtagene autoleucel has promising safety and efficacy in patients with high-risk large B-cell lymphoma” and says that “further studies are warranted to confirm the comparable benefit of rapcabtagene autoleucel in frontline patients with high-risk large B-cell lymphoma.”
