CAR-T delays necessitate ongoing coordination of bridging therapy for multiple myeloma
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Chimeric antigen receptor T cells are one of the newest immunotherapy options for multiple myeloma treatment.
Their novelty and effectiveness led to a surge in demand among a patient subgroup in dire need of new therapies for relapsed or refractory disease, leading to widespread manufacturing and administration delays that slowed access to CAR-T.
This resulted in greater need for bridging therapy to prevent patients from developing uncontrollable disease or tumor-related organ dysfunction prior to CAR-T administration, according to Madhav V. Dhodapkar, MBBS, professor in the department of hematology and medical oncology at Emory University School of Medicine and director of Winship Center for Cancer Immunology.
Community-based physicians who refer patients for CAR-T should develop relationships with colleagues at providing centers to assist in the bridging therapy process, he added.
“The important message is to ... maintain open lines of communication with CAR-T centers,” Dhodapkar told Healio. “We are certainly looking for that from our community colleagues so we can optimize [patient] outcomes.”
In this installment of In Practice, Dhodapkar — chair of Society for Immunotherapy of Cancer’s (SITC) Multiple Myeloma Immunotherapy Guideline Expert Panel — explains why bridging therapy is necessary in many cases and how clinicians should approach the decision-making process.
Healio: What is the goal of bridging therapy for patients with relapsed or refractory multiple myeloma who are eligible for CAR-T?
Dhodapkar: The key thing for community physicians to be aware of is that the primary goal for bridging therapy is to achieve control of and reduce tumor mass prior to CAR-T administration. CAR-T given in the context of uncontrolled disease or high tumor burden is associated with higher risk for complications, such as cytokine release syndrome. In some cases — including those with organ dysfunction that occurs with higher tumor mass — patients can be prevented from receiving CAR-T despite having gone through the manufacturing process. For these reasons, it is important to consider whether to provide bridging therapy prior to CAR-T.
Healio: What level of coordination is required to provide bridging therapy, and will outside referrals to a CAR-T center receive bridging therapy in the community setting?
Dhodapkar: In principle, it is feasible both ways, either by providing bridging therapy at the CAR-T center or arranging for it at the referring physician's office. Both methods require significant coordination because — most of the time — the fixed date for leukapheresis has been set and the approximate dates for CAR-T administration become available. It is important to have this process coordinated so the patient is fully recovered from bridging therapy before CAR T cells are administered.
Healio: For whom is bridging therapy recommended prior to CAR-T?
Dhodapkar: There is no one-size-fits-all approach for bridging therapy. Initial clinical trials required that bridging therapy no involve any new drugs, but that often is not practical because one of the goals of bridging therapy is to make sure there is some reduction of tumor mass. If there already is evidence that a tumor is refractory to initial therapies, giving the same agents again may not be effective enough to control the disease until CAR-T administration. Our center’s approach to bridging therapy requires an assessment of the patient’s tolerance of and response to prior therapies to choose who is appropriate for bridging therapy and, in those cases, what the best option is.
Healio: Has your center experienced manufacturing delays for commercially available CAR-T to treat multiple myeloma?
Dhodapkar: Manufacturing delays have occurred, but a bigger challenge has been having availability of slots to administer CAR T cells to patients. This includes availability and coordination of infusion clinic slots for both the apheresis portion prior to manufacturing and final administration of the genetically modified therapy. We hope to have this issue resolved at our center soon. Bridging therapy becomes relevant in both cases, particularly if you are treating a patient with rapidly progressive disease. In this setting, the optimal approach would be to provide some form of bridging therapy, if possible, to achieve adequate tumor control prior to CAR-T.
Healio: Have these delays led to increased use of bridging therapy in the real-world setting?
Dhodapkar: Yes, and for multifactorial reasons it has become quite important to maintain adequate disease control implementations while patients are waiting for CAR T-cell therapy.
Healio: Are multiple bridging regimens available, and what is the optimal selection process?
Dhodapkar: Multiple therapies are being tried or have been tested. Agent selection typically depends on the specific patient's history, in terms of the drugs to which they responded best and the drugs that may have the least likelihood of causing adverse effects. Bridging therapy should avoid causing severe cytopenias that can lead to subsequent issues in providing CAR-T. Bridging therapy selection also should minimize risk for developing new organ toxicities — such as kidney failure — or lead to an active infection.
Finally, clinicians should avoid using bridging therapies that target the same molecule as CAR-T. For example, B-cell maturation antigen for patients with multiple myeloma, because this is the target used by both commercially available CAR-T and many others in development.
Healio: Are there guidelines regarding the use of bridging therapy?
Dhodapkar: SITC has published guidelines for immunotherapy that provide clinicians with some advice on bridging therapy. SITC anticipates a follow-up to the initial 2020 guidelines for immunotherapy of multiple myeloma in the coming months to incorporate more information about these kinds of issues now that that the FDA has approved both CAR-T and bispecific antibodies for multiple myeloma.
Healio: Are there patients for whom bridging therapy is not advised?
Dhodapkar: Yes. Patients in this category include those who have a relatively low tumor burden and those with slow-growth disease that is anticipated to remain largely unchanged by the time they come back for CAR-T infusion. In both cases, there is absolutely no reason to incur the risk for toxicities from bridging therapy. Determining what is best for the patient will require ongoing coordination between the referring community physician and the CAR-T center.
Healio: Does bridging therapy affect CAR-T outcomes or safety?
Dhodapkar: Published literature suggests bridging therapy does not impact outcomes, but it likely has allowed many patients with multiple myeloma to receive CAR T-cell therapy. Without bridging therapy, one could speculate that many CAR-T recipients likely would have developed significant organ dysfunction from the underlying malignancy being uncontrolled and, therefore, become unable to receive CAR-T.
Healio: Is there anything else that you would like to mention?
Dhodapkar: Bridging therapy has become a very important and rapidly moving topic of interest to referring physicians as they begin to appreciate the importance of CAR T cells as treatment modality for hematologic malignancies. Ongoing communication between referring physicians and CAR-T centers is needed to help prioritize and rationalize the choice of giving a bridging therapy and decide what treatment is best to give at a particular time. This coordination between community-based clinicians and cell therapy centers will become even more important as treatments like CAR-T and bispecific antibodies move into earlier lines of therapy.
The challenge with CAR-T ... is that access is suboptimal right now. Hopefully that will change. There is a possibility that the CAR-T manufacturing and infusion process will shorten to a matter of days. If such faster or off-the-shelf therapies are approved, it would reduce the need for and risk involved with bridging therapy. There are many ongoing efforts to address the timing issues from multiple directions, and I think we will see the results of those studies in the next couple years.
For more information:
Madhav V. Dhodapkar, MBBS, can be reached at Emory University, Health Science Research Building., 1760 Haygood Drive NE, Room E330, Atlanta, GA 30322; email: madhav.v.dhodapkar@emory.edu.
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