Expert Pharmacists Answer Audience Questions on CAR T-Cell Therapy

In this commentary, Craig W. Freyer, PharmD, BCOP, and Andrew Lin, PharmD, BCOP, answer questions about the use of CAR T-cell therapy for various hematologic malignancies, current guidelines, and recent approvals. The questions were submitted by an audience of healthcare professionals during a recent live ProCE/Clinical Care Options satellite symposium held during the Hematology/Oncology Pharmacy Association annual conference.

How are you using CAR T-cell therapy as second-line treatment? What do you use as third-line therapy after CAR T-cell therapy?

Craig W. Freyer, PharmD, BCOP:
Several large phase III trials have recently evaluated CD19-targeted CAR T-cell therapy as second-line therapy for relapsed/refractory large B-cell lymphomas, with mixed results. In ZUMA-7, second-line axicabtagene ciloleucel provided a more than 4-fold improvement in event-free survival (EFS). In TRANSFORM, lisocabtagene maraleucel significantly prolonged EFS, progression-free survival, and complete response rate vs standard-of-care second-line therapy. By contrast, in the BELINDA study, tisagenlecleucel did not improve EFS compared with standard-of-care treatment.

Very recently, axicabtagene ciloleucel received FDA approval as second-line treatment for adults with large B-cell lymphoma who are refractory to first-line chemoimmunotherapy or experienced disease relapse within 12 months of initial treatment based on the favorable results from ZUMA-7. Lisocabtagene maraleucel is approved as third-line or later therapy, and I expect that results from TRANSFORM will also lead to expansion of this CAR T-cell therapy as second-line treatment. Regarding tisagenlecleucel in BELINDA, there are challenges in interpreting the data, and this study may need to be repeated with a different patient population.

There is no current consensus on what to use in patients who have failed CAR T-cell therapy in the second line. That said, numerous clinical trials are underway of targeted therapies that have suggested efficacy in patients who failed CAR T-cell therapy. One option may be to reinfuse CD19 CAR T-cells if they still express CD19 (either the same product as previously used or a different product). In our clinic, we have used pembrolizumab after CAR T-cell therapy. Those are some of the approaches we have taken, but again, there is currently no standard practice.

Andrew Lin, PharmD, BCOP:
I concur that expansion of the approvals for lisocabtagene maraleucel is likely, although I do not expect much change in clinical practice until the FDA labeling changes, because of insurance coverage. Whether to switch from CAR T-cell therapy to another class of drugs remains an open question. We have not done this much in our clinic but expect to increasingly consider it in the next few years with agents such as immune checkpoint inhibitors.

Does prior exposure to bendamustine preclude the use of CAR T-cell therapy?

Craig W. Freyer, PharmD, BCOP:
I don’t think so. We have treated a number of patients who had previously received bendamustine, with the caveat that more bendamustine equals more T-cell lymphopenia. In this situation, it might be preferable to use CAR-T cells earlier in the course of the disease, and to limit the number of bendamustine courses, to maintain adequate T-cell levels to be able to successfully manufacture a CAR T-cell product.

What prophylaxis should be used for immunosuppression related to COVID-19 treatment with monoclonal antibodies in patients receiving CAR T-cell therapy?

Andrew Lin, PharmD, BCOP:
This is an evolving question in our clinic. We have used prophylaxis for immunosuppression inconsistently, depending on where we are in the pandemic and the available supply of monoclonal antibodies used to treat COVID-19. We treat patients with a combination of 2 anti–SARS-CoV-2 antibodies, tixagevimab and cilgavimab, which has FDA Emergency Use Authorization for preventing COVID in patients who do not have a robust immune response to vaccination. In our clinic, we use tixagevimab/cilgavimab in patients about to start CAR T-cell treatment in the hope that we can bridge them to redo another primary vaccination series, but this is done on a case-by-case basis.

Craig W. Freyer, PharmD, BCOP:
In our clinic, we typically use tixagevimab/cilgavimab after CAR T-cell infusion once the hematologic toxicities have subsided and patients have become afebrile and are ready to return home. However, it is not always available.  

For patients receiving CAR T-cell therapy, when do you give granulocyte colony-stimulating factor (G-CSF)?

Andrew Lin, PharmD, BCOP:
At our institution, most physicians will not use it within the first 28 days. But there is a growing body of data that suggests that G-CSF can limit the duration of neutropenia. And, even if G-CSF is given within 28 days, there appears to be limited risk of increasing immune effector cell–associated neurotoxicity syndrome (ICANS) or cytokine-release syndrome (CRS). Yet, this remains an open question. I feel comfortable using G-CSF earlier, especially if there’s an infection.  

Craig W. Freyer, PharmD, BCOP:
In our clinic, we historically have not used G-CSF at all in patients receiving CAR T-cell therapy, as there are some mechanistic concerns regarding propagating CRS and neurotoxicity. However, the literature is increasingly showing that it does work and is safe. We have used G-CSF only in isolated cases without CRS. Of note, it is important to not use granulocyte-macrophage colony-stimulating factor in those patients.

For which patients receiving CAR T-cell therapy do you consider Pneumocystis jirovecii pneumonia (PJP) prophylaxis?

Craig W. Freyer, PharmD, BCOP:
We do use PJP prophylaxis in our clinic, especially for patients who are receiving lymphodepletion with fludarabine, as there is a risk of CD4+ lymphopenia. It can be started at any time, but definitely by Day 28. We tend to intermittently monitor CD4+ T-cell numbers following CAR T-cell therapy. Once patients reach a consistent level >200 cells/mm³ (somewhat borrowed from the AIDS/HIV literature), we consider de-escalating and stopping the PJP prophylaxis. We typically use antifungal prophylaxis only for patients who will be receiving fludarabine/cyclophosphamide, as these patients generally have deeper and more prolonged neutropenia than those receiving bendamustine, and continue it until the absolute neutrophil count is consistently above 500 cells/mm³. Patients receiving lymphodepletion with bendamustine tend to have less severe and later cytopenias, and they mostly do not need antifungal prophylaxis.

Andrew Lin, PharmD, BCOP:
In our practice, whether we use antifungal prophylaxis for patients receiving lymphodepletion can vary. It depends on the underlying disease and their prior treatments. We tend to use it more in the outpatient setting.  

Do you monitor for increases in inflammatory markers in patients receiving CAR T-cell therapy?

Craig W. Freyer, PharmD, BCOP:
We do in order to use it as a marker of CRS in patients receiving CAR T-cell therapy. For inpatients, we usually check these markers every day. Although there’s no threshold that can specifically guide treatment, repeated monitoring provides a sense of the rhythm of CRS, for example, whether things are getting better or getting worse. Of importance, we have seen very high ferritin levels, in excess of 300,000 ng/mL, in some patients with acute lymphocytic leukemia, but this may be lower in other cancers.

Have you had a chance to treat patients with the newer B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, ciltacabtagene autoleucel (cilta-cel)?

Craig W. Freyer, PharmD, BCOP:
Cilta-cel was just approved in February 2022 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. We do now have extensive experience with idecabtagene vicleucel, which also is directed toward BCMA. 

Andrew Lin, PharmD, BCOP:
We have treated several patients in the context of a clinical trial, but have yet to have our first commercial patient since the approval.

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