An analysis of the cilta-cel safety profile yielded promising results, according to nurse investigators.
Ciltacabtagene autoleucel (cilta-cel; Carvykti) demonstrated a generally manageable safety profile consistent with previous studies in patients with multiple myeloma, according to results from the phase 2 CARTITUDE-2 study (NCT04133636).1
Data presented by Mary Steinbach, DNP, FNP-C, APRN, during the 48th Annual Oncology Nursing Society Congress demonstrated that the most common adverse events (AEs) to emerge with this treatment include cytokine release syndrome (CRS), cytopenias, infections, and neurotoxicities—such as immune effector cell-associated neurotoxicity syndrome (ICANS).
“Nursing professionals play a crucial role in identifying and managing AEs and educating patients about the safety risks associated with cilta-cel,” said Steinbach, a nurse practitioner at the University of Utah Huntsman Cancer Institute.
Cilta-cel, which targets BCMA, was previously approved by the FDA for adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody, based on results from the CARTITUDE-1 study (NCT03548207). Although this trial showcased deep and durable response rates in heavily pretreated patients, it also demonstrated potential safety risks with the agent that nurses must be prepared to manage. Nurse investigators therefore sought to characterize the agent’s safety profile, based on findings from the CARTITUDE-2 trial.
CARTITUDE-2 had a 3-cohort design;
The overall response rates (ORR) with cilta-cel in cohorts A, B, and C were 95%, 100%, and 60%, respectively.
Patients in cohort A (n = 20) experienced any-grade and grade 3/4 AEs of neutropenia at a rate of 95% vs 95%, respectively. Any-grade or grade 3/4 AEs included thrombocytopenia (80% vs 35%), anemia (75% vs 45%), lymphopenia (70% vs 70%), and leukopenia (55% vs 55%).
CAR T–related AEs of special interest of any-grade and grade 3/4, respectively, included CRS (95% vs 10%), neurotoxicity (30% and 5%) including ICANS (15% vs 0%), and infections (45% and 5%).
In cohort B, there were no treatment-related deaths. Patients (n = 19) experienced any-grade and grade 3/4 neutropenia at a rate of 95% vs 90%, respectively. Thrombocytopenia (58% vs 26%), anemia (58% vs 47%), lymphopenia (47% vs 47%), and leukopenia (32% vs 32%) also occurred in this cohort. The CAR T–related AEs of special interest included CRS (84% vs 5%), neurotoxicity (26% vs 5%) including ICANS (5% vs 0%) as well as movement and neurocognitive toxicities (MNTs; 5% vs 5%) among others (21% vs 5%), and infections (53% vs 21%).
Finally, in cohort C patients (n = 20), the rate of any grade and grade 3/4 neutropenia was 90% and 90%, respectively. The rates of thrombocytopenia were 80% and 70%, anemia 70% and 55%, lymphopenia 35% and 35%, and leukopenia 55% and 55% at any grade and grade 3/4, respectively. CAR T–related AEs of special interest included CRS (60% and 0%), neurotoxicity (20% and 10%) including ICANS (20% and 10%), and infections (30% and 15%).
“There was 1 case of MNTs, which occurred in a patient enrolled in cohort B who had at least grade 3 CRS and achieved complete response. Follow-up is currently ongoing for this patient,” Steinbach said.
By day 60, most cases of grade 3 or higher cytopenias decreased in severity to grade 2 or lower. The incidence of prolonged grade 3/4 neutropenia at day 60 was 20%, 10%, and 10%, across cohorts A, B, and C, respectively. With severe lymphopenia, the rate of prolonged toxicity was 5%, 10%, and 15%; and the rates of grade 3/4 thrombocytopenia at day 60 were 15%, 16%, and 25%, respectively.
Time to toxicity onset, as well as the duration of CRS and ICANS, were similar among the 3 cohorts. In cohort A, the median time to onset for CRS was 7 days (range, 5-9) with a duration of 3 days (range, 2-12). In cohort B, the median onset time was 8 days (range, 5-11) with a duration of 3.5 days (range, 1-7), and in cohort C, the median onset time was 7.5 days (range, 2-10) with a duration of 5.5 days (range, 3-10).
For patients who developed ICANS in cohort A, the median time to onset was 8 days (range, 7-10) with a duration of 3 days (range, 1-3). In cohort B, the median time to onset was 11 days in cohort B with a duration of 4 days. In cohort C, the median onset time was 9 days (range, 4-13) with a duration of 7 days (range, 4-20).
Overall, there were 19 deaths across cohorts following the cilta-cel infusion with 13 due to disease progression and 6 due to AEs including COVID-19 infection (n =1) and sepsis (n = 1) in cohort A as well as COVID-19 pneumonia (n = 2), C. difficile colitis (n = 1), and subarachnoid hemorrhage (n = 1) in cohort C. The study authors noted that more infection-related deaths in cohort C likely occurred because patients had experienced greater immune suppression and more extensive previous treatments.
Approaches for the Management of AEs
Nurses should monitor blood counts for detections of prolonged or recurrent cytopenias and provide supportive care in addition to monitoring for signs of infection. Granulocyte-colony stimulating factor may also be given to patients with cytopenia who are not experiencing CRS.
Treatment of CRS should encompass close monitoring of laboratory testing with an emphasis on pulmonary, renal, and hepatic function. Supportive measures such as tocilizumab, corticosteroids, and anakinra may be given as treatments and nurses should evaluate patients for infection. Those with severe CRS who have not responded to supportive measures should be evaluated for hemophagocytic lymphohistiocytosis as well.
After the first signs of neurotoxicity, monitoring for ICANS—with daily ICE assessments—should be initiated. Neuroimaging for patients at increased risk may be appropriate. Patients may also need to be evaluated by a neurologist. Nurses may administer nonsedating antiseizure medication and can consider corticosteroids for patients who are not experiencing concurrent CRS or for patients with more severe ICANS.
Of note, patients who develop MNTs may require effective bridging therapy to reduce tumor burden. These patients will require early and aggressive treatment of CRS and ICANs, and will need to undergo handwriting assessments and extended monitoring. According to thestudy authors, in CARTITUDE, these management strategies explained that among approximately 250 patients in the CARTITUDE program, implementation of management strategies decreased the incidence of MNTs from 6% to less than 0.5%.
Authors noted that the guidelines for specific grading and CRS/ICANS management can also be found both in the American Society for Transplantation and Cellular Therapy guidelines and in the cilta-cel package insert.
As part of the CARTITUDE-2, patients underwent screening from 1 to 28 days, apheresis, bridging therapy, as needed. They went on to receive cyclophosphamide at 300 mg/m2 plus fludarabine at 30 mg/m2 5 and 3 days prior to infusion; they underwent the cilta-cel infusion, and preceded to postinfusion assessments. The target dosing for cilta-cel was 0.75 x 106 (0.5-1.0 x 106) CAR T viable T cells /kg (day 1).
Demographics were determined to be similar across cohorts.
The median number of prior lines of therapy were 2 (range, 1-3), 1, (range, 1-1), and 8 (range, 4-13) in cohorts A, B, and C, and the median number of years since diagnosis were 3.5 (range, 0.7-8.0), 1.15 (range, 0.5-1.9), and 6.3 (2.5-16.3) years since diagnosis, respectively. The median patient age was 60 years (range, 38-75), 58 years (range, 44-67), and 62.5 years (range, 44-81) in cohorts A, B, and C. The majority of patients were males (65.0% vs 73.7% vs 60.0%) and patients were White (90.0% vs 73.7% vs 60.0%), Black (10.0% vs 10.5% vs 5.0%), Asian (0% vs 5.3% vs 0%), or not reported (0% vs 10.5% vs 0%), respectively.
The percentage of patients with bone marrow plasma cells of 60% or greater was 15.0% vs 21.1% vs 32.0%. The rate of patients with extramedullary plasmacytomas of 1 or greater was 15.0% vs 15.8% vs 25.0% and the percentage of patients with high-risk cytogenetic profile wer 35% vs 20% vs 15%.
The percentage of patients with triple-class refractory disease was 40.0% vs 15.8% vs 90.0%, the rate of penta-drug refractory disease was 5% vs 0% vs 55%, and the percentage of patients who were refractory to their last line of therapy was 95.0% vs 78.9% vs 95.0%, respectively. The rate of previous exposure to triple-class agents was 65.0% vs 21.1% vs 100.0% and the rate of previous exposure to penta-drugs was 20% vs 0% vs 90%, in cohorts A, B, and C, respectively.
For patients who were evaluable for minimal residual disease (MRD) with a sample at the 10-5 threshold, MRD negativity occurred at rates of 100.0% in cohort A (n = 16), 93.3% in cohort B (n = 15), and 70% in cohort C (n = 10).
Steinbach M, Jackson CC, Suarez J, Pacaud L, Riccobono C, and Aronson E. Identification and management of adverse events associated with ciltacabtagene autoleucel for treatment of multiple myeloma in CARTITUDE-2. Poster Presented at: 48th Annual Oncology Nursing Society Congress; April 26-30, 2023; San Antonio, Texas. Accessed April 20, 2023. https://ons.confex.com/ons/2023/meetingapp.cgi/Paper/13551