Strategic Management of CAR T-cell AEs in Hematologic Malignancies

Kimberly Noonan, DNP, ANP-BC, AOCN

Kimberly Noonan, DNP, ANP-BC, AOCN

For patients receiving chimeric antigen receptor (CAR) T-cell therapy, cytokine release syndrome (CRS) and neurotoxicity are the most common toxicities. A multidisciplinary approach to care is vital for these patients, explained Kimberly Noonan, DNP, ANP-BC, AOCN, in a presentation during the 24th Annual International Congress on Hematologic Malignancies.

"The main toxicities include [cytokine release syndrome and neurotoxicity] that are managed with supportive care and sometimes require monoclonal therapy and intensive care unit support," said Noonan, a nurse practitioner at Dana-Farber Cancer Institute. "[A] multidisciplinary approach is essential to provide comprehensive care to patients considering CAR T-cell therapy."

CAR T cells have shown the most promise targeting CD19 in B-cell malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), as well as BCMA in multiple myeloma. A successful target, she added, is one that is highly expressed on malignant cells and not on vital cells. For example, CD19 is present on all B cells while BCMA is expressed on plasma cells.

When determining the eligibility of patients to undergo treatment with one of the available or investigational CAR T-cell therapies, Noonan said that certain factors should be considered. Patients should have relapsed/refractory disease with limited therapeutic options, adequate organ status, good performance status, expression of target antigen, lymphopenia, can have adequate T cells collected or adequately engineered, no autoimmune disease, no active infections, relapsed but not aggressive disease, and insurance or financial support.

Specifically in B-cell lymphomas, 2 CAR T-cell products are currently approved for use. In October 2017, axicabtagene ciloleucel (axi-cel; Yescarta) was approved by the FDA for the treatment of adult patients with relapsed/refractory NHL, specifically for those with large B-cell lymphoma (LBCL) following 2 prior treatments, including patients with diffuse large B-cell lymphoma (DLBCL); it is also indicated for patients with primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.

The decision was based on findings from the single-arm ZUMA-1 study, results of which showed an objective response rate (ORR) of 82% and a complete response (CR) rate of 54%.¹With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a CR.

Results of a 3-year analysis of ZUMA-1 showed that axi-cel induced a median overall survival (OS) of 25.8 months for patients with refractory LBCL.²At a median follow-up of 39.1 months, the 3-year OS rate was 47% with axi-cel, with approximately 60% of patients having relapsed or progressed.

Tisagenlecleucel (Kymriah) was approved in May 2018 for use in adult patients with relapsed/refractory LBCL-including DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma-after 2 lines of systemic therapy.

The approval was based on efficacy demonstrated in the pivotal phase II JULIET trial. Updated findings published in the New England Journal of Medicine showcased a best ORR of 52% (95% CI, 41-62), which comprised a 40% CR rate and a 12% partial response rate in patients with relapsed/refractory DLBCL who were ineligible for or had disease progression after autologous hematopoietic stem cell transplantation.³

Tisagenlecleucel was initially granted FDA approval in August 2017 as a treatment for patients 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. The decision was based on results from the phase II ELIANA trial, in which the CAR T-cell therapy led to an ORR of 81%, and all patients who had a response were negative for minimal residual disease.⁴Moreover, the OS rates at 6 and 12 months were 90% and 76% respectively; the median duration of response (DOR) was 20 months.

BCMA-directed CAR T-cell therapy has also been explored in multiple myeloma. For example, idecabtagene vicleucel (bb2121) demonstrated an 85% ORR, including a 45% CR rate in patients with relapsed/refractory multiple myeloma, according to updated findings of the phase I CRB -401 trial.⁵Patients had previously received 3 lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were refractory to both agents. Additional data showed that the stringent CR rate was 36%, and the median DOR was 10.9 months.

Among BCMA, other targets of interest in myeloma include CD19, CD138, SLAMF7, light chains, and bispecific T-cell engager cells. The use of CAR T-cell therapy is also being explored in acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and solid tumors, Noonan said.

Safety Measures for CRS

What can pose as a challenge, Noonan explained, is the waiting period while CAR T cells are manufactured. If a patient's disease is not well controlled during this time, bridging therapy can be administered-and a washout period may be defined as well.

During the admission of CAR T-cell therapy, the risk of infusions reactions is possible, but small. Common adverse events (AEs) to dimethyl sulfoxide, which is included in the CAR T-cell products, include chest tightness, nausea, and sulfur-oxidizing bacteria.

However, it's the acute toxicity period, which is the first week following CAR T-cell infusion, in which patients are at highest risk for treatment-related AEs. These include neurotoxicity and CRS, the latter of which can occur in up to 90% of patients receiving this treatment and ranges from mild to severe cases.

To help manage these toxicities, grading tools are available to determine the level of both CRS and neurotoxicity via American Society for Transplantation and Cellular Therapy CRS Consensus Grading and the Encephalopathy Assessment Tools for Grading of ICANS, respectively.

CRS symptoms include high fever, myalgia, headache, nausea, anorexia, fatigue, hypotension, vascular leak, respiratory compromise, renal insufficiency, and coagulopathy.

While the risk of these AEs begin to decrease after 1 week, patients should still be closely monitored for the first 30 days after infusion. However, follow-up during clinical trials may require more frequent monitoring, especially for relapse, secondary relapse, and on-target/off-tumor toxicities.

Both FDA-approved CAR T-cell products have demonstrated high incidences of CRS. In an analysis of patients on studies who had been treated with tisagenlecleucel, the CRS rates were 77% and 57% in those with ALL and NHL, respectively.⁶In patients with NHL who received axi-cel, the rate of CRS was 93%.

Optimal management of CRS is key, Noonan said, explaining that thorough infectious work-up should be conducted with onset of fever. With grade 1 CRS, appropriate treatment involves supportive measures with antipyretics, fluids, and infection work-up. When CRS reaches grade ≥2, patients must be given tocilizumab (Actemra), given as a 1-hour infusion, which is approved by the FDA to treat patients with this condition. Should CRS not improve within 1 to 2 days, or if the patient becomes clinically unstable, additional tocilizumab with or without corticosteroids should be administered.

Beyond tocilizumab, other options being investigated for CRS include siltuximab, anakinra, and etanercept.

Neurotoxicity Management

While the etiology of neurotoxicity is less understood, Noonan said, its most likely cause is due to a dysfunction of the blood-brain barrier, and its occurrence varies between the available CAR T-cell therapies. It typically presents concurrently or following CRS, yet 10% of cases occur without the onset of CRS. Common symptoms, she added, include confusion, dysphasia, inability to complete daily activities, and encephalopathy. It can also progress to seizures, stupor, obtundation that requires airway protection, and, while rare, cerebral edema.

Neurotoxicity can come in forms of CAR-related encephalopathy syndrome, or immune-effector cell-associated neurotoxicities syndrome (ICANS). Following infusion of CAR T-cell therapy, the average onset is approximately 5 days and lasts for about 2 weeks and 1 week for patients with B-cell NHL and B-cell ALL, respectively.

For any ICANS-determined level of neurotoxicity, supportive care is considered optimal management, but at grade ≥2 the AE warrants steroid treatment. Unlike CRS, tocilizumab cannot be given alone to manage neurotoxicity; however, if it is concurrent with CRS, then tocilizumab can be administered in addition to steroids. Other causes of neurological changes should be thoroughly tested, Noonan explained.

For both grade ≥3 CRS and neurotoxicity, intensive care unit transfers should be considered, due to pressor requirements and obtundation.

Tumor lysis syndrome, cardiotoxicity, prolonged cytopenia, infection, hypogammaglobulinemia, and graft-versus-host disease are all potential toxicities related to CAR T-cell therapy, Noonan added.

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References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.N Eng J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
2. Neelapu SS, Rossi JM, Jacobson CA, et al. CD19-loss with preservation of other B cell lineage features in patients with large B cell lymphoma who relapsed post-axi-cel.Blood. 2019;134(suppl_1):203. doi: 10.1182/blood-2019-126218.
3. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.N Engl J Med. 2019;380(1):45-56. doi: 10.1056/NEJMoa1804980.
4. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Eng J Med. 2018;378:439-448. doi: 10.1056/NEJMoa1709866.
5. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma.N Eng J Med. 2019; 380:1726-1737 doi: 10.1056/NEJMoa1817226.
6. Yanez L, Sanchez-Escamilla M, Perales M-A, et al. CAR T cell toxicity: current management and future directions.HemaSphere. 2019;3(2):e186. doi: 10.1097/HS9.0000000000000186.