ASH 2025 | Double-dose axi-cel as second-line therapy for high-risk R/R LBCL: interim Phase Ib results

In second-line large B-cell lymphoma, there still remains a big unmet need in patients who have elevated LDH. Several real-world studies have shown that elevated LDH at the time of apheresis is associated with poor outcomes. In this clinical trial, in this Phase 1b, investigator-initiated clinical trial, we aim to dose the axi-cel at two pre-specified time points in patients who are high-risk as defined by high LDH at the time of apheresis. So in this patient population, it was a second-line elevated LDH patient population, they got the first infusion of axicabtagene ciloleucel or Yescarta at the standard time at day zero and the second infusion occurred between day seven and day ten. 

The rationale for double dosing of axicabtagene ciloleucel was the following. Number one, we wanted to use a single lymphodepletion regimen so that only one lymphodepletion regimen is utilized for both the infusions. The effect of lymphodepletion wears off, and immune reconstitution generally occurs at day 14, day 21. So under the umbrella of the first lymphodepletion, we wanted to have the first infusion done, as well as the second infusion between day 7 and 14. The main idea was to improve the target-to-effector ratio by increasing the dose, but in a time-separated fashion. The idea was also to infuse the second product when most of the early inflammation has settled down, when most of the early tumor killing has already been done by the standard of care, and the second set of cells that comes in, they provide better immunosurveillance for patients. 

The trial was designed in a very patient safety-oriented manner. First, we did a safety run-in with a quarter of the dose of the standard of care infusion between day 7 and day 14. The intent was to make sure the second infusion doesn’t result in similar toxicity that is seen with the first infusion. Once we established that the safety run-in phase, that the safety of the second infusion was quite good and we did not experience any dose-limiting toxicity, we dose-escalated to full dose of second infusion between day 7 and 14. To our surprise, a pleasant surprise, we did not see any toxicity at the time of second infusion. We saw a fraction of the patients experiencing very low-grade fever-like episodes. We call that cytokine release syndrome, where it was a fever of 100.4, 100.6, very low-grade inflammatory syndromes that we saw in these patients with the second infusion. We did not experience or see, we did not see any high-grade events whatsoever in this patient population with the second infusion. Also, there were no dose-limiting toxicities that were seen throughout the clinical trial. So the second infusion was incredibly safe. 

More impressively, we saw very good expansion of the second product that was infused between day 7 and day 14, and yet no toxicity. Historically, we would expect the patient outcomes to be quite poor in these elevated LDH patient populations. Generally speaking, based on real-world data as well as the registrational data, it appears that the outcomes at, for example, progression-free survival at one year for these patients would be below 50%. So PFS at one year of below 50%. What we saw in our patient population, which was mostly primary refractory, nearly 70% primary refractory patients, and elevated LDH, both known poor prognostic factors, we saw a CR rate of 79% with an objective overall response rate of 81%. That is a very high response rate which was largely durable in this very high-risk population.

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