ABSTRACT
Axicabtagene ciloleucel (Axi‐cel) is a chimeric antigen receptor T‐cell (CAR‐T) therapy approved for the treatment of relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The registrational phase 1/2 ZUMA‐1 study cohorts 1 and 4 addressed toxicity management in terms of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) whereby tocilizumab and corticosteroids were deployed earlier in cohort 4. In this real‐world, single‐institution study of 119 patients receiving Axi‐cel CAR‐T therapy for R/R LBCL with 70 in cohort 1 and 49 in cohort 4, we demonstrate significantly less toxicity, intensive care unit (ICU) utilization, and cumulative steroid use with an early intervention strategy. Laboratory parameters and comorbidities did not significantly differ between groups except for a higher incidence of renal insufficiency in the cohort 4 group (28.6% vs. 4.3%, p < 0.01). The maximum grade CRS was significantly lower for cohort 4 versus 1 (1 vs. 2, p < 0.01). Furthermore, cumulative corticosteroid use was significantly less in the cohort 4 early intervention group (110 mg vs. 190 mg dexamethasone equivalents). These favorable findings did not have a deleterious impact on outcomes and efficacy with similar overall response rate, progression‐free survival, and overall survival with both toxicity management approaches.
1. Introduction
Diffuse large B‐cell lymphoma (DLBCL) is the most common type of non‐Hodgkin's lymphoma (NHL), accounting for at least 20%–50% of all NHLs [1]. Since the first approval of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL in 1997, there has been a significant increase in the remission rate, reaching up to 70%–80% [2]. Approximately 10%–15% of patients exhibit primary refractory disease, and 20%–25% of cases experience a relapse after the initial response, resulting in a poor two‐year overall survival (OS) of 20%–40% in these patients [3]. In such patients with relapsed or refractory disease (R/R), salvage chemotherapy followed by high‐dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (ASCT) was the standard second‐line treatment. In SCHOLAR‐1, patients with refractory DLBCL had poor outcomes (ORR 26%, CR 7%, median OS 6.3 months), driving the development of novel therapies such as CAR T‐cell therapy that transformed the treatment paradigm for aggressive lymphomas [4]. Multiple early single‐center CAR‐T therapy studies displayed initial promise with this modality, resulting in axicabtagene ciloleucel (axi‐cel), an autologous anti‐cluster of differentiation (CD)19 chimeric antigen receptor (CAR) T‐cell therapy approved for treatment of R/R DLBCL based on the results from cohorts 1 and 2 (N = 101) of the ZUMA‐1 trial (NCT02348216) [5, 6, 7]. The objective response rate was 82%, and the complete response (CR) rate was 54%. Axi‐cel continues to show excellent survival benefit at five‐year follow‐up with ORR at 83%, including a CR of 58% and continued response rate of 31%. The overall rate of survival was 52% at 18 months and 42.6% at 5 years [8, 9].
In the ZUMA‐1 trial, nearly all patients experienced adverse events, most commonly cytokine release syndrome (CRS; 93%, largely Grade 1–2) and ICANS (64%), with grade ≥ 3 events in 13% and 28%, respectively; importantly, most were manageable and reversible. CRS is driven by CAR T‐cell activation and pro‐inflammatory cytokine release, with interleukin‐6 (IL‐6) playing a central role; accordingly, the IL‐6 receptor antagonist tocilizumab is highly effective, remains the longest‐used treatment for CRS, and does not impair CAR T‐cell expansion [10, 11]. ICANS is less well understood but is thought to involve endothelial activation, blood–brain barrier disruption, and cytokine‐mediated neuroinflammation, with biomarkers such as IL‐6, IL‐10, GM‐CSF, and ferritin associated with severe events [8, 12, 13, 14].
Toxicity management in CAR T‐cell therapy is an evolving field with ongoing efforts to improve the safety profile of this treatment without compromising the durable clinical benefit. Several cohorts have been added to the ZUMA‐1 trial for this reason. No specific hypothesis was tested in any of these studies. ZUMA‐1 Cohort 3 evaluated prophylactic tocilizumab on Day 2 and the anticonvulsant levetiracetam starting on Day 0, an intervention which had lower observed rates of grade ≥ 3 CRS (3% vs. 13%) but not grade ≥ 3 neurologic events (NEs) (41% vs. 28%) [8, 15]. Cohort 4 evaluated the rates and severity of CRS and NEs with earlier corticosteroid and tocilizumab use; levetiracetam prophylaxis and earlier corticosteroid and tocilizumab intervention was employed where corticosteroids were initiated starting at Grade 1 CRS (if no improvement after 3 days) and at Grade 1 NE, tocilizumab was initiated at Grade 1 CRS (if no improvement after 3 days), at Grade 2 or higher CRS and at Grade 2 or higher NE. This study showed an ORR ~73% and CR ~51% with no grade ≥ 3 and grade ≥ 3 ICANS ~13%–17% indicating improved safety without reduced efficacy [16]. ZUMA‐1 Cohort 6 investigated the effects of prophylactic corticosteroid use and early corticosteroid and/or tocilizumab intervention on the incidence of CRS and NEs in patients with R/R DLBCL. This study achieved ORR 95% and CR 80%, no grade ≥ 3 CRS, all‐grade CRS similar to earlier cohorts, all‐grade ICANS lower, and grade ≥ 3 ICANS ~18%, while maintaining high response durability (median DOR ~25.9 months, median PFS ~26.8 months, median OS not reached) [17, 18]. Butmab et al., showed use of prophylactic steroids in patients who received axi‐cel and brexu‐cel in relapsed/refractory Non‐Hodkin Lymphoma delayed onset of CRS without effecting OS, PFS, ORR, or CRR [19].
At our institution, as with many others during that period, the COVID‐19 pandemic, along with the pressing need to minimize intensive care unit (ICU) utilization, served as the primary rationale for transitioning from the standard approach to a cohort 4‐based management strategy. We hereby present, to our knowledge, the first study to report single‐institution, real‐world experience comparing cohort 4 to our previous cohort 1 axi‐cel recipients in terms of toxicity [CRS, ICANS, ICU utilization] and efficacy.
2. Methods
2.1. Study Design
This is a single institution retrospective study of histologically confirmed LBCL who underwent CAR‐T cell therapy with axi‐cel in the R/R setting at the University of Maryland Medical Center, either under the cohort 1 or cohort 4 based approach to toxicity management. All patients received standard fludarabine/cyclophosphamide lymphodepleting chemotherapy per FDA label. The transition from a cohort 1 to a cohort 4 approach occurred in March 2021 (see Table S1 for cohort 4 toxicity management). Thus, for cohort 1, we included patients up to February 2021, and for cohort 4, we included patients after April 2021. We did not include patients in the analysis from March 2021 given it was when the transition occurred. Through retrospective chart review, 119 patients who underwent CAR‐T cell therapy with axi‐cel under either cohort 1 or 4 approaches to toxicity management for R/R DLBCL were identified. The study was approved by the institutional review board at the University of Maryland Medical Center in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonisation. The primary end‐points studied were efficacy and toxicity between cohorts 1 and 4. OS and progression‐free survival (PFS) were estimated to assess the efficacy. Response assessments were done by Positron Emission Tomography/Computed Tomography (PET/CT) imaging. Incidence of CRS and ICANS was studied for toxicity; secondary outcomes included health care utilization of the cohort 1 versus cohort 4, which represents a change in toxicity management (earlier/higher doses of steroids). Adverse effects including CRS and ICANS were managed per Lee and ASTCT criteria [20].
Frequency distributions and descriptive statistics of on‐study demographic and clinical characteristics of the cancer patients were estimated. OS and PFS were defined from the date of CAR‐T to death or relapse; patients alive and without relapse were censored at the last follow‐up. Survival functions were estimated using the Kaplan–Meier method and compared using the log‐rank test. R Studio was used for all statistical modeling. All statistical tests were 2‐sided and conducted at the 0.05 level of significance. The median follow‐up time was estimated by the reverse Kaplan–Meier approach. Non‐relapse mortality (NRM) was defined as death without recurrent or progressive disease after CAR‐T therapy. Probabilities of NRM were estimated with the use of cumulative incidence curves, with relapse being a competing risk. We compared the cumulative incidences of NRM and relapse using the Grey test in the competing risk framework. Death without evidence of relapse was considered a competing event for the incidence of relapse. The occurrence of relapse was considered a competing event for the incidence of NRM.
3. Results
3.1. Baseline and Clinical Characteristics
One hundred and nineteen patients were included in the study analysis, 70 in Cohort 1 and 49 in Cohort 4. The median age was 62 (22–88) years‐old, 35% female gender, 76% advanced stage III‐IV disease, 22% with bulky ≥ 10 cm disease, 71% with diagnosis of Diffuse LBCL, and 26% with more than three lines of previous therapy (Table 1). The median follow‐up time at analysis was 1.5 years with the 95% CI of 1.2–1.6 years.
TABLE 1.
Selected clinical and demographic characteristics of all patients.
| All patients (N = 119) | |
|---|---|
| Age at CAR‐T infusion, median (range) in years | 62 (22–88) |
| Gender, number (%) | |
| Male | 77 (64.7) |
| Female | 42 (35.3) |
| Stage, number (%) | |
| I–II | 29 (24.4) |
| II–IV | 90 (75.6) |
| ECOG, number (%) | |
| 0 | 41 (34.5) |
| 1 | 71 (59.7) |
| 2 | 7 (5.8) |
| Disease Type, number (%) | |
| DLBCL | 84 (70.6) |
| PMBCL | 30 (25.2) |
| TFL | 5 (4.2) |
| Double expressor, number (%) | 25 (21) |
| Double or triple hit, number (%) | 29 (24.4) |
| Cell origin, number (%) | |
| GCB | 76 (63.9) |
| Non‐GCB | 43 (36.1) |
| IPI, number (%) | |
| 0 | 2 (1.7) |
| 1 | 24 (20.2) |
| 2 | 38 (31.9) |
| 3 | 53 (44.5) |
| 4 | 2 (1.7) |
| Number of prior lines of therapy, number (%) | |
| 0 | 2 (1.7) |
| 1 | 55 (46.2) |
| 2 | 38 (31.9) |
| 3 | 17 (14.3) |
| 4 | 6 (5) |
| 5 | 1 (0.9) |
| Bulky disease > 10 cm, number (%) | 26 (21.8) |
| Prior AutoSCT, number (%) | 18 (15.1) |
| CD19 positive by flow cyotmetry, number (%) | 47 (39.5) |
| CD19 positive by immunohistochemistry, number (%) | 17 (14.3) |
| Prior AlloSCT, number (%) | 5 (4.2) |
| Prior checkpoint inhibitor, number (%) | 8 (6.7) |
The pre‐infusion clinical characteristics did not significantly differ between groups except for a higher incidence of renal insufficiency in the cohort 4 group (28.6% vs. 4.3%, p < 0.01) (Table 2). ZUMA‐1 enrollment criteria were met in 63% versus 49% of patients in cohorts 1 versus 4 (p = 0.14).
TABLE 2.
Baseline clinical characteristics by cohort.
| All patients (N = 119) | Cohort 1 (N = 70) | Cohort 4 (N = 49) | p | |
|---|---|---|---|---|
| Low LVEF (< 50%), number (%) | 9 (7.6) | 7 (10) | 2 (4.1) | 0.30 |
| Elevated total bilirubin, number (%) | 4 (3.4) | 4 (5.7) | 0 (0) | 0.14 |
| Prior CD 19 target therapy, number (%) | 1(0.8) | 0 (0) | 1 (2) | 0.41 |
| History of CNS involvement, number (%) | 10 (8.4) | 5 (7.1) | 5 (10.2) | 0.74 |
| Renal insufficiency, number (%) | 17 (14.3) | 3 (4.3) | 14 (28.6) | < 0.01 |
| ZUMA 1 criteria met, number (%) | 68 (57.1) | 44 (62.9) | 24 (49) | 0.14 |
3.2. Biomarker Analysis
There was no difference between cohorts 1 and 4 with respect to the median absolute lymphocyte counts on leukapheresis or serum biomarkers of lactate dehydrogenase (LDH), fibrinogen, c‐reactive protein (CRP), or ferritin at either date of CAR‐T infusion or the maximum value up to Day 14 (Figure 1 and Table 2 in Supporting Information for biomarker analysis by cohort).
FIGURE 1.
Overall survival by cohort. Overall survival of cohorts 1 versus 4 up to 24 months from infusion.
3.3. Safety
Compared with cohort 1, cohort 4 had an overall lower incidence of high‐grade (≥ 3) CRS and ICANS. The median maximum grade CRS was significantly lower for cohort 4 versus 1 (1 vs. 2, p < 0.01). Nearly all 119 patients (92.4%) had all grade CRS (Figure 2). There was no statistically significant difference between all grade CRS between cohort 4 and 1 (91.8% vs. 92.9%). There were no cases of high‐grade CRS reported in cohort 4, and it was 7.1% in cohort 1, p‐value of 0.08. There was no statistically significant difference between the distribution of grade of ICANS (p = 0.14) and in all grade ICANS (60% vs. 53%), although the high grade ICANS distribution may be different (34.3% vs. 18.4%, p = 0.06) (Table 3 Supporting Information for incidence of CRS and ICANS by cohort) (Figure 3).
FIGURE 2.
CRS toxicity grades by group.
TABLE 3.
Management of toxicities and resource utilization by cohort.
| Characteristic | All patients (N = 119) | Cohort 1 (N = 70) | Cohort 4 (N = 49) | p |
|---|---|---|---|---|
| Total corticosteroid dose, median (range) in dexamethasone equivalent mg | 164 (10–1920) | 190 (52–1630) | 110 (10–1920) | 0.03 |
| Days of corticosteroids, median (range) | 2 (0–86) | 7 (0–72) | 2 (0–86) | 0.54 |
| Tocilizumab given | 85 (71.4%) | 53 (75.7%) | 32 (65.3%) | 0.23 |
| Siltuximab given | 9 (7.6%) | 5 (7.1%) | 4 (8.2%) | > 0.99 |
| ICU admission | 50 (42%) | 42 (60%) | 8 (16.3%) | < 0.01 |
| Hospital admission duration | 14 (8–80) | 14 (8–60) | 14 (8–80) | 0.64 |
| Discharge disposition | 0.56 | |||
| Home | 99 (83.2%) | 56 (80%) | 43 (87.7%) | |
| Long‐term care | 10 (8.4%) | 8 (11.4%) | 2 (4.1%) | |
| Hospice | 5 (4.2%) | 3 (4.3%) | 2 (4.1%) | |
| Other | 5 (4.2%) | 3 (4.3%) | 2 (4.1%) |
FIGURE 3.
ICANS toxicity grades by group.
3.4. Treatment and Resource Utilization
The duration of steroid use was comparable in both; however, the total steroid use (dexamethasone equivalent in mg) was notably lower in cohort 4 (110 mg vs. 190 mg, p = 0.03). The utilization of tocilizumab and siltuximab was similar in both groups. Anakinra was not a widely used regimen and not readily available for us at the time of study, which limited its use in our patient population. The rates of admission to the ICU were significantly higher for cohort 1 ~ 190 mg (52–1630) compared with cohort 4 ~ 110 mg (10–1920) (60% vs. 16.3%, p < 0.01, OR = 7.5, 95% CI: 6.0–18.2). The median duration of hospital admission was 14 days in both cohorts. In both cohorts, over 80% of patients were discharged home after CAR‐T therapy and did not need placement in a rehabilitation center or long‐term facility (Table 3).
3.5. Efficacy
There was no statistically significant difference in response at Day 30 (88.2% vs. 93.8% ORR), 6‐month response rate (87.9% vs. 92.3%), and 12‐month response rate (87.9% vs. 92.3%). The PFS and OS were not different between the groups (Figure 1). There was no difference in the cumulative incidence of relapse (HR = 0.83, the 95% CI: 0.47, 1.48). The NRM may have been higher in cohort 4 (HR = 2.21, the 95% CI: 0.76, 6.40), but this was not significant (p‐value = 0.14) (Figure S2 for NRM).
4. Discussion
Optimal management of CAR‐T therapy's most common adverse effects, CRS and ICANS, remains an evolving topic with concern for compromising clinical safety and efficacy with intervening too early or too late [15, 16, 17, 21, 22]. Compared to the initial cohorts 1 and 2 of ZUMA‐1, patients in cohort 4 received corticosteroid and/or tocilizumab earlier, as described in Table 1.
In our real‐world experience with a cohort 1 versus 4 approach, we found an overall decrease in the incidence of high‐grade CRS and ICANS in the cohort 4 group. We found that the median maximum grade of CRS was significantly lower for cohort 4 (1 vs. 2, p < 0.001). Furthermore, there was no incidence of high‐grade CRS reported in cohort 4 as compared to cohort 1 (0% vs. 7%). To our knowledge, this is the first study to compare the median maximum grade of CRS among the real‐world R/R B‐cell lymphoma patients receiving axi‐cel of these cohorts. The significantly lower median grade of CRS supports prior recommendations that tocilizumab/corticosteroids should be administered at the early onset of CRS to reduce high‐grade toxicity [16]. This is similar to prior outcomes reported in the cohort 1 study by Neelapu et al., where cohort 1 and 2 had higher rates of high‐grade CRS incidence (13%), and another study done by Topp et al., where 2% of the cohort 4 cases had high‐grade CRS [16].
We did not find any significant difference in the median maximum grade of ICANS in cohort 4 as compared to cohort 1. However, there was a numerically lower number of cases of high‐grade ICANS reported in cohort 4 as compared to cohort 1, although it did not reach significance (18.4% vs. 34.3%, p = 0.06). This finding is similar to that reported in the ZUMA‐1 cohort 4 study, where the incidence of high‐grade ICANS was 17% compared with 28% in cohort 1. These findings are promising and pave the way to better optimize and manage CRS and ICANS.
Importantly, we found that in addition to improving safety, early corticosteroid and/or tocilizumab intervention did not compromise axi‐cel efficacy. There was no statistically significant difference in response rate at Day 30 (93.8 vs. 88.2%), 6 months (92.3% vs. 87.9%), and 12 months overall response rate (100% vs. 96.4%) between cohort 4 and cohort 1 in our study. Given prior concerns that corticosteroid therapy may have a deleterious impact on CAR‐T cell efficacy, these results are reassuring and in line with prior studies [23, 24, 25]. With longer follow‐up for ZUMA‐1 cohorts 1 and 4 (median 27.1 months), the ongoing response rate was 58%, suggesting durability of response was not impacted. In our study, PFS and OS were not significantly different between the groups. There were no differences in the cumulative incidence of relapse (HR = 0.83, 95% CI: 0.47, 1.48) and in NRM between cohorts 1 and 4 (HR = 2.21, 95% CI: 0.76, 6.40, p = 0.14). These are results from univariable tests and due to the rather small sample size and number of events, we could not utilize multivariable statistical models.
Despite utilizing corticosteroids earlier in CRS and ICANS management, the total corticosteroid use was significantly lower in cohort 4 ~110 mg (10–1920) versus cohort 1 ~190 mg (52–1630) (p = 0.026), which was similar to prior studies where cohort 4 had significantly lower corticosteroid use than cohorts 1 and 2. We hypothesize that the decreased cumulative corticosteroid use is perhaps more important than the time of intervention (early versus delayed) in the impact on CAR‐T cell kinetics, function, and ultimately response.
To our knowledge, this is the first real‐world study to compare resource utilization in terms of ICU admission by cohort toxicity management [26]. The odds of being admitted to the ICU were notably higher for cohort 1 than for patients with a cohort 4 strategy (OR = 7.5, the 95% CI: 6.0–18.2). ICU admission following CAR‐T infusion was much lower in cohort 4 (16.3% vs. 60%, p < 0.001). This suggests that earlier use of corticosteroids decreases the overall need for corticosteroids and decreases the severity of CRS, and hence the lower odds of ICU admission. Most patients (> 80%) were discharged home after CAR‐T therapy and did not need placement in a rehabilitation center or long‐term facility, explaining further that early intervention prevents the patients from having severe morbidity. There was no significant difference found in the maximum levels of biomarkers like CRP, LDH, and ferritin between the two cohorts, which are known predictors of toxicity occurrence.
The early use of corticosteroid and/or tocilizumab intervention resulted in lower incidence of high‐grade adverse events, lower overall corticosteroid use without compromising CAR‐T therapy efficacy in axi‐cel recipients with R/R B‐cell lymphomas.
5. Conclusion
The use of an early toxicity intervention strategy based upon ZUMA‐1 cohort 4 in the real‐world results in significantly lower high‐grade CRS, decreased cumulative steroid dose, and a 73% reduction in ICU utilization without significantly impacting efficacy in terms of incidence of relapse, PFS, or OS. Our real‐world experience with the adoption of a cohort 4 strategy suggests that patient morbidity may be greatly attenuated without compromising CAR‐T therapy response. This is of particular importance as CAR‐T therapy moves into the outpatient setting and various prophylactic and early toxicity intervention strategies are being studied. The need for longer follow‐up to evaluate the impact early use of corticosteroids has on CAR‐T persistence and PFS, and OS at greater than 5 years remains to study long‐term outcomes.
Discussion of supplemental material: The supplemental material in this publication includes a reference of the cohort 4 CRS and ICANS toxicity management (Table S1), routine laboratory biomarker analysis between cohorts 1 and 4 (Figure S1 and Table 2), and a comparison of CRS and ICANS between cohorts 1 and 4 (Table S3).
Author Contributions
C.S. contributed to writing the original draft, review and editing; O.G. contributed to methodology, formal analysis, and software. P.M., H.A., I.P. contributed to data curation. G.G. contributed to writing the original draft. A.B., J.L., S.T.L., M.K., J.Y., N.H., M.N., N.A., M.U.M., J.M., A.P.R., and S.D. contributed to review and editing. F.L. contributed to conceptualization, data curation, project administration, visualization, supervision, writing, and review and editing.
Funding
The authors have nothing to report.
Ethics Statement
This study was approved by the institutional review board of the University of Maryland.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Cohort 4 adverse event management, per Lee and ASTCT criteria
Table S2: Biomarkers analysis by cohort
Table S3: Toxicity in terms of CRS and ICANS by cohort
Figure S1: Biomarker analysis and corticosteroid dosing by cohort
Figure S2: Cumulative incidence of relapse by cohort
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article and its Supporting Information.
References
- 1. Wang S. S., “Epidemiology and Etiology of Diffuse Large B‐Cell Lymphoma,” Seminars in Hematology 60, no. 5 (2023): 255–266, 10.1053/j.seminhematol.2023.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Klener P. and Klanova M., “Drug Resistance in Non‐Hodgkin Lymphomas,” International Journal of Molecular Sciences 21, no. 6 (2020): 2081–2081, 10.3390/ijms21062081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Bachanova V., Perales M. A., and Abramson J. S., “Modern Management of Relapsed and Refractory Aggressive B‐Cell Lymphoma: A Perspective on the Current Treatment Landscape and Patient Selection for CAR T‐Cell Therapy,” Blood Reviews 40 (2020): 100640, 10.1016/j.blre.2019.100640. [DOI] [PubMed] [Google Scholar]
- 4. Crump M., Neelapu S. S., Farooq U., et al., “Outcomes in Refractory Diffuse Large B‐Cell Lymphoma: Results From the International SCHOLAR‐1 Study,” Blood 130, no. 16 (2017): 1800–1808, 10.1182/blood-2017-03-769620. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Kochenderfer J. N., Dudley M. E., Feldman S. A., et al., “B‐Cell Depletion and Remissions of Malignancy Along With Cytokine‐Associated Toxicity in a Clinical Trial of Anti‐CD19 Chimeric‐Antigen‐Receptor–Transduced T Cells,” Blood 119, no. 12 (2012): 2709–2720, 10.1182/blood-2011-10-384388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Kochenderfer J. N., Dudley M. E., Kassim S. H., et al., “Chemotherapy‐Refractory Diffuse Large B‐Cell Lymphoma and Indolent B‐Cell Malignancies Can be Effectively Treated With Autologous T Cells Expressing an Anti‐CD19 Chimeric Antigen Receptor,” Journal of Clinical Oncology 33, no. 6 (2015): 540–549, 10.1200/jco.2014.56.2025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Kochenderfer J. N., Somerville R. P. T., Lu T., et al., “Long‐Duration Complete Remissions of Diffuse Large B Cell Lymphoma After Anti‐CD19 Chimeric Antigen Receptor T Cell Therapy,” Molecular Therapy 25, no. 10 (2017): 2245–2253, 10.1016/j.ymthe.2017.07.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Neelapu S. S., Locke F. L., Bartlett N. L., et al., “Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma,” New England Journal of Medicine 377, no. 26 (2017): 2531–2544, 10.1056/nejmoa1707447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Neelapu S. S., Jacobson C. A., Ghobadi A., et al., “5‐Year Follow‐Up Supports Curative Potential of Axicabtagene Ciloleucel in Refractory Large B‐Cell Lymphoma (ZUMA‐1),” Blood 23 (2023): 2307–2315, 10.1182/blood.2022018893. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hughes A. D., Teachey D. T., and Diorio C., “Riding the Storm: Managing Cytokine‐Related Toxicities in CAR‐T Cell Therapy,” Seminars in Immunopathology 46, no. 3–4 (2024), 10.1007/s00281-024-01013-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Santomasso B., Bachier C., Westin J., Rezvani K., and Shpall E. J., “The Other Side of CAR T‐Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden,” in American Society of Clinical Oncology Educational Book, vol. 39 (2019), 433–444, 10.1200/edbk_238691. [DOI] [PubMed] [Google Scholar]
- 12. Landry K. and Thomas A. A., “Neurological Complications of CAR T Cell Therapy,” Current Oncology Reports 22, no. 8 (2020): 83, 10.1007/s11912-020-00935-6. [DOI] [PubMed] [Google Scholar]
- 13. Brudno J. N., Lam N., Vanasse D., et al., “Safety and Feasibility of Anti‐CD19 CAR T Cells With Fully Human Binding Domains in Patients With B‐Cell Lymphoma,” Nature Medicine 26, no. 2 (2020): 270–280, 10.1038/s41591-019-0737-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Parker K. R., Migliorini D., Perkey E., et al., “Single‐Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off‐Tumor Targets for CAR‐T Immunotherapies,” Cell 183, no. 1 (2020): 126–142.e17, 10.1016/j.cell.2020.08.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Locke F. L., Neelapu S. S., Bartlett N. L., et al., “Preliminary Results of Prophylactic Tocilizumab After Axicabtageneciloleucel (Axi‐Cel; KTE‐C19) Treatment for Patients With Refractory,Aggressive Non‐Hodgkin Lymphoma (NHL),” Blood 130 (2017): 1547, 10.1182/blood.V130.Suppl_1.1547.1547. [DOI] [Google Scholar]
- 16. Topp M. S., Meerten T., Houot R., et al., “Earlier Corticosteroid Use for Adverse Event Management in Patients Receiving Axicabtagene Ciloleucel for Large B‐Cell Lymphoma,” British Journal of Haematology 195, no. 3 (2021): 388–398, 10.1111/bjh.17673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Oluwole O. O., Bouabdallah K., Muñoz J., et al., “Prophylactic Corticosteroid Use in Patients Receiving Axicabtagene Ciloleucel for Large B‐Cell Lymphoma,” British Journal of Haematology 194, no. 4 (2021): 690–700, 10.1111/bjh.17527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Oluwole O. O., Forcade E., Muñoz J., et al., “Long‐Term Outcomes of Patients With Large B‐Cell Lymphoma Treated With Axicabtagene Ciloleucel and Prophylactic Corticosteroids,” Bone Marrow Transplantation 59, no. 3 (2024): 366–372, 10.1038/s41409-023-02169-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Butman J., Habib A., Welkie R. L., et al., “Steroid Prophylaxis in Patients Receiving CAR T‐Cell Therapy for Relapsed and Refractory Non‐Hodgkin Lymphoma,” Transplantation and Cellular Therapy 31, no. 2 (2025): S229–S229, 10.1016/j.jtct.2025.01.350. [DOI] [Google Scholar]
- 20. Lee D. W., Santomasso B. D., Locke F. L., et al., “ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells,” Biology of Blood and Marrow Transplantation 25, no. 4 (2019): 625–638, 10.1016/j.bbmt.2018.12.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Brudno J. N. and Kochenderfer J. N., “Recent Advances in CAR T‐Cell Toxicity: Mechanisms, Manifestations and Management,” Blood Reviews 34 (2019): 45–55, 10.1016/j.blre.2018.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Chohan K. L., Siegler E. L., and Kenderian S. S., “CAR‐T Cell Therapy: The Efficacy and Toxicity Balance,” Current Hematologic Malignancy Reports 18, no. 2 (2023): 9–18, 10.1007/s11899-023-00687-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Davila M. L., Riviere I., Wang X., et al., “Efficacy and Toxicity Management of 19‐28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia,” Science Translational Medicine 6, no. 224 (2014): 224ra25–224ra25, 10.1126/scitranslmed.3008226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Strati P., Nastoupil L. J., Westin J. R., et al., “Clinical and Radiologic Correlates of Neurotoxicity After Axicabtagene Ciloleucel in Large B‐Cell Lymphoma,” Blood Advances 4, no. 16 (2020): 3943–3951, 10.1182/bloodadvances.2020002228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Gardner R. A., Finney O., Annesley C., et al., “Intent‐To‐Treat Leukemia Remission by CD19 CAR T Cells of Defined Formulation and Dose in Children and Young Adults,” Blood 129, no. 25 (2017): 3322–3331, 10.1182/blood-2017-02-769208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Sainatham C., Goloubeva O., Margiotta P., et al., “Real World Experience With a Zuma −1 Cohort 4 Adopted Approach to CRS and Icans in CAR‐T Recipients,” Blood 142, no. Supplement 1 (2023): 2122–2122, 10.1182/blood-2023-183002. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Cohort 4 adverse event management, per Lee and ASTCT criteria
Table S2: Biomarkers analysis by cohort
Table S3: Toxicity in terms of CRS and ICANS by cohort
Figure S1: Biomarker analysis and corticosteroid dosing by cohort
Figure S2: Cumulative incidence of relapse by cohort
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article and its Supporting Information.