Best Practices for Early Referral and Bridging Therapy

Amit Patel, BSc, MBBS, PhD: Early referral to a CAR [chimeric antigen receptor] T center for autologous CAR T-cell therapy in the third-line space is critical. Unfortunately, patients who have relapsed/refractory disease in this setting are dying, and these patients need a rescue therapy given that they’ve already failed 2 lines of chemoimmunotherapy with or without radiotherapy in some cases. The time that the patient first becomes eligible based on their PET [positron emission tomography] scan after salvage therapy or on a biopsy after salvage therapy is when the clock starts, because that patient needs to have an apheresis procedure completed as soon as possible so that bridging therapy can start. When the patients have a manufactured product returned to site, that product needs to be infused into that patient after lymphodepletion at the earliest opportunity. Reducing the time between somebody being eligible for CAR T therapy and delivering it is a key metric in terms of efficacy and safety. We know that these patients are relapsed/refractory to chemoimmunotherapy, so more chemoimmunotherapy is not going to change the outcome of these patients who historically would have otherwise died.

In terms of bridging therapy approaches, it’s important to—at a very minimum—not allow the disease to progress any further. In other words, not to increase the tumor volume in that patient. The aim of bridging therapy is to achieve a response, and achieve the best response possible, to debulk the disease burden at the time of CAR T infusion. My advice would be as soon as the apheresis procedure has been completed, whether it’s on that day or the next day, those patients should commence bridging therapy immediately, and this should be meaningful bridging therapy.

For example, we tend to use a combination of rituximab, polatuzumab, and bendamustine, omitting bendamustine if they’ve had it previously. We combine this with radiotherapy if there is evidence of disease bulk, even if there are multiple sites involved. This combined approach, which is aggressive to try and debulk the total amount of tumor at the time of CAR T infusion, is what we would consider best practice globally. This does 2 things. It reduces the amount of tumor burden that’s there, and we know that the amount of tumor burden—whether it’s measured by total metabolic tumor volume, LDH [lactate dehydrogenase], or other markers of disease prior to CAR T infusion—is important from an efficacy and safety perspective. We know patients who have more disease on board might be expected to have a higher likelihood of developing cytokine release syndrome and neurotoxicity. So deliverability of CAR T-cell therapy after good bridging is what we now consider the standard of care.

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