Management of Pre-CAR-T Infusion Bridging Therapies
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In this installment of In Practice, Leo I. Gordon, MD, FACP, co-director of the hematologic malignancies program at Northwestern University Feinberg School of Medicine and medical director of the John and Lillian Matthews Center for Cellular Therapy at Robert H. Lurie Comprehensive Cancer Center, discusses the challenges and best practices from the time the decision is made to seek chimeric antigen receptor T-cell therapy until the genetically engineered T cells are infused back into the patient.
As Gordon pointed out, the decision to administer bridging therapy depends on whether the patient is participating in a clinical trial or receiving commercial CAR T-cell therapy, in addition to factors such as the speed of disease progression and disease location. Gordon explained that bridging therapy is aiming for a “window” where it can control the disease but not eliminate it, which would make the patient ineligible for CAR T-cell infusion.
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Q: What’s next after you and your patient have decided that CAR T-cell therapy is the treatment of choice?
It depends on whether we’re thinking about commercial CAR-T or a clinical trial. If we’re looking at a trial, and that’s my preference, we need to determine eligibility for a trial that’s open. We then need to investigate whether there are slots available because resources are often being shared with multiple institutions around the country, and only a limited number of patients can be treated at a given time. And sometimes, we must have current scans and recent biopsies available. If they were not performed recently, they may have to be repeated, depending on the trial.
If we are considering a commercial product — Yescarta (axicabtagene ciloleucel; Kite, Gilead) or Kymriah (tisagenlecleucel, Novartis) — we need to start the process of working with the insurance company to determine coverage for the treatment. You can’t do this unless there’s insurance coverage.
Next, for both clinical trial and commercial CAR T-cell therapy, we need to determine if there is a caregiver who will be available for the patients for at least a few months. Finally, we need to determine if the patient lives within 2 hours of the medical center, which is required for this type of treatment.
Q: What is the purpose of bridging therapy? Bridging therapy is not permitted for some trials nor for all CAR-T indications, correct?
Bridging therapy was not allowed in the initial ZUMA trial — the trial that led to the approval of Yescarta by the FDA. The purpose of bridging therapy is to control disease in patients who may have to wait up to 4 to 8 weeks to start CAR T-cell therapy. Those patients must be well enough and without symptoms to receive the therapy. There is a natural bias in selection of patients who are maybe more fit, less symptomatic, and have less disease and could wait longer to start treatment. Can the patient wait weeks? Is their disease is growing too quickly? Is it in the wrong location or it is pressing on certain organs? All of those factors are weighed into the decision to provide bridging therapy. We provide it to make sure the disease is still controllable after the eligibility determination and CAR T-cell manufacturing process.
The goal of bridging therapy is to control the disease, but we don’t want it to work too well. This is something we tell patients, and it seems somewhat counterintuitive. You don’t want to achieve complete remission for two reasons: one is we don’t know if the CAR T cells require an antigen to work. Otherwise, you won’t see cell expansion and you won’t get the full effect of the treatment. Theoretically, if the disease is gone, you may not see as good a response. Patients in a clinical trial must have measurable disease to qualify, so if you’ve gotten rid of the measurable disease with your bridging therapy, they no longer are candidates for the trial. With a commercial product, you don’t have that stipulation, but you do have the question of whether it will work as well without active disease present.
Q: Where would bridging therapy normally be administered?
In our experience, it’s usually done at the center that provides the CAR T-cell therapy. But I don’t see any reason why it couldn’t be done at the referring site, the initial site, and therefore in the community setting. It would be a lot easier for patients not to have to travel for bridging therapy, and nothing about the process requires that it be close to the center providing the CAR T-cell therapy. The patient could be in their own hospital, with their own oncologist, receiving bridging therapy.
Q: Which professional guidelines do you consult in your decision-making process?
There aren’t that many, really. National Comprehensive Cancer Network guidelines have incorporated information on which patients may be candidates for CAR T-cell therapy that, to some extent, mirrors the package insert for the commercial products. And although the NCCN guidelines are similar to the package insert, they are not identical.
Take, for example, large cell lymphoma: CAR T-cell therapy is FDA-approved for patients with diffuse large B-cell lymphoma who have progressed after two previous lines of therapy. For large cell lymphoma, a problem can occur if someone has received aggressive chemotherapy for follicular lymphoma. If the patient’s disease progressed to large cell lymphoma and the patient didn’t achieve complete response with their next treatment, then — according to NCCN guidelines — that patient could move on to CAR T-cell therapy. However, according to the package insert, this patient would be ineligible for CAR T-cell therapy because they haven’t had two previous lines of therapy specifically for their large cell lymphoma. The rationale for including those patients in the guidelines was that they’ve had two aggressive treatments for a lymphoma and they still have it.
Commercial insurers dictate that we follow either the NCCN guidelines or package insert and typically approve coverage for the uses they recommend.
Q: How do you decide what the appropriate bridging therapy might be?
It depends on the patient and the extent of disease. If you can get by with just a small amount of steroids, that would be sufficient; sometimes we use some mild chemotherapy, such as gemcitabine, with rituximab or rituximab alone. I also have used oral lenalidomide (Revlimid, Celgene). Lenalidomide is good because it has a very short half-life, measured in hours, and it’s preferred to not have the drug on board at the time of cell collection.
Lomustine and fludarabine often are used for lymphodepletion before CAR T-cell infusion. If you used those drugs as bridging therapy and started collecting T cells, you may lack enough lymphocytes or T cells and you won’t be able to do a quick collection. I try to stay away from drugs that have a purine ring analogue in their makeup — and lomustine and fludarabine both have that. However, they are good drugs to use for lymphodepletion.
Q: Will all patients and indications require preconditioning lymphodepletion for CAR T-cell therapy?
Yes. At least partial lymphodepletion will be required.
Q: What potential treatment-related adverse effects do you monitor for during either the bridging period or preconditioning therapy?
During bridging therapy, you want to do everything you can to not cause a toxicity that will stop you from proceeding with the treatment. For example, if somebody had aggressive chemotherapy as bridging that results in a low white blood cell count, they could get an infection, pneumonia or some other organ toxicity and would no longer be a good candidate for CAR T-cell therapy.
In terms of the preconditioning, we expect there will be toxicity. We are already into the process of CAR T-cell therapy once we do the lymphodepleting preconditioning therapy. The goal is to get rid of the patient’s own endogenous, nonmanipulated T cells and hopefully you can proceed and not see any infection before infusion of the CAR T cells.
Q: Are there any red flags that physicians should look for during the bridging or reconditioning phases?
I would look out for serious infection, pneumonia, sepsis or organ toxicity, especially of the lungs, liver or kidneys.
- For more information:
- Leo I. Gordon, MD, FACP, can be reached at l-gordon@northwestern.edu.
Disclosures: Gordon reports advisory board roles with Juno Therapeutics and Kite Pharma.
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