Exploring alternatives to CAR T-cell therapy
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In this installment of In Practice, Ryan D. Cassaday, MD, explains how to negotiate the delicate balancing act required when discussing alternatives to chimeric antigen receptor T-cell therapy with patients and referring colleagues.
Cassaday is associate professor in the department of medicine at University of Washington School of Medicine, associate professor in the clinical research division at Fred Hutchinson Cancer Research Center and attending physician in the hematologic malignancies program at Seattle Cancer Care Alliance.
As he points out, the promise and excitement around CAR T-cell therapy can result in patients and clinicians narrowly focusing on it as the next step in treating advanced hematologic malignancies, whether in a clinical trial or commercial setting. This can require diplomatic yet compassionate discussions about the pros and cons inherent among the entire range of choices available to a patient.
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Q: Have you experienced situations when an oncologist referred a patient for CAR-T, but an alternative clinical trial or standard-of-care treatment may have been more appropriate?
Yes. Lately, in my experience, this has occurred more commonly among patients with multiple myeloma. Despite the approvals of various agents — such as carfilzomib (Kyprolis, Amgen), pomalidomide (Pomalyst, Bristol-Myers Squibb), daratumumab (Darzalex, Janssen), isatuximab (Sarclisa, Sanofi), selinexor (Xpovio, Karyopharm Therapeutics) and others — some patients and providers are so intrigued or excited about the prospects of B-cell maturation antigen (BCMA)-targeted CAR T cells that these proven agents are seemingly overlooked. It also can occur in other diseases, including acute lymphoblastic leukemia. Ultimately, none of these approved agents — particularly for myeloma — is expected to provide durable disease control. Thus, the theoretical promise of CAR T cells seems to be enough to look past the lack of long-term data supporting their curative potential.
Q: How do you handle these cases when consulting with the referring physician?
I try to remind them diplomatically that our CAR T-cell studies are largely early-phase clinical trials that, despite the enthusiasm, do not have enough data so far to validate them as superior — much less comparable — to more established options. Although I’m always eager to offer patients the option to enroll in clinical trials, I must be mindful of the limitations.
Q: How do you handle these cases when communicating with patients and their families or caregivers?
I try to emphasize the investigational nature of CAR T cells and how we have relatively little long-term follow-up to ensure that early responses — which, admittedly, can happen at a very impressive rate — will hold up over time. This also comes at the cost of a significant risk for toxicity. For those who have not yet received some of the newly-approved agents, I remind them that we have proven drugs that we know can work for some patients, and that these can be very helpful in keeping their disease under control if they have a good response. During that time, we can gain more experience with CAR T cells, which may or may not validate this as a desirable approach.
Q: Could alternatives to CAR T cells include other cell-based therapies, such as tumor-infiltrating lymphocytes?
It certainly is possible. Other cellular therapies are largely lagging behind CAR T cells in terms of their development, so it may take years for them to become established options. That said, particularly for diseases where CAR T cells have yet to have a role, options such as T-cell receptor-modified T cells or tumor-infiltrating lymphocytes could prove to be highly effective in specific circumstances.
Q: Will the patient have choices in treatment options that include CAR-T?
This is true for specific cases. It is probably most applicable in relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, where outcomes of other standard options are relatively poor. For these patients, CAR T cells could be an option for which patients themselves could advocate. The same could be said for children and young adults with relapsed or refractory B-cell ALL.
Beyond these situations where we have FDA-approved products, it could be difficult for patients to actively choose CAR T cells over other available options, because CAR T cells would be investigational and thus less widely available and without convincing data supporting their use.
Q: What is your role in helping patients decide which treatment option is best for them?
My role is to provide them with the data for both cellular and more traditional therapies, when available. I also try to underscore the investigational nature of cellular therapies for most diagnoses and that, if we knew these treatments were better than the standard of care, we would offer them outside the context of prospective clinical trials. That said, if we already know that the prognosis following standard therapies is poor, any investigational approach (including CAR T-cells) could be very appropriate.
Q: Are there any decision-making algorithms or checklists that you or your institution follow when presenting a patient with treatment options?
This is probably most applicable for relapsed or refractory aggressive B-cell non-Hodgkin lymphomas. In general, for patients in first relapse with chemotherapy-sensitive disease, we still recommend consolidation with high-dose therapy and autologous stem cell transplantation. For adults with B-cell ALL — where this therapy remains investigational — I typically will not recommend CAR T cells unless the patient has received either inotuzumab ozogamicin (Besponsa, Pfizer) or blinatumomab (Blincyto, Pfizer). For other diagnoses where these cellular therapies remain exclusively investigational, I typically would try to ensure that the standard therapies have been considered and/or exhausted.
Q: Do you refer to professional guidelines on the topic during your consultation and decision-making process?
For the diseases for which CAR T cells are FDA-approved, National Comprehensive Cancer Network guidelines can be helpful. The American Society for Transplantation and Cellular Therapy has its own guidelines, which are a good resource.
Q: Are there certain alarm bells that clinicians should be aware of if CAR T-cell therapy is among the options they are considering for a patient?
Some alarm bells will be obvious, such as lack of expression of the target antigen of interest on the malignant cells. Patients who lack adequate social support to get them through these complicated therapies should be identified early to avoid inappropriate and awkward referrals. Referring physicians should avoid giving any systemic therapy in the days leading up to arrival at the cellular therapy center because this could impact the yield of T cells from apheresis, particularly for lymphoid malignancies. Sadly, this can be inadequate for patients with a relatively high burden of aggressive cancer at the time the referral was placed.
Q: Is there anything else you want other clinicians to know about alternatives to CAR T-cell therapy?
Clinicians should consult with a disease expert in that field before referring patients to a center offering CAR T-cell therapy. There may be standard-of-care options that are newly available and equally as promising as what has been observed with cellular therapies, or there may be alternative clinical trials for which a patient may be better suited. As impressive as some of the early data with CAR T cells have been, that does not mean this approach is best for everyone.
For more information:
Ryan D. Cassaday, MD, can be reached at cassaday@uw.edu.
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