Approved CAR-T therapies have reproducible efficacy and safety in clinical practice

ABSTRACT

CAR-T cell therapy has established itself as a highly effective treatment for hematological malignancies. There are currently six commercial CAR-T products that have been FDA approved for diseases such as B-ALL, LBCL, MCL, FL, MM, and CLL/SLL. “Real-world” studies allow us to evaluate outcomes from the general population to determine their efficacy and safety compared to those who were included in the original trials. Based on several well conducted “Real-world” studies that represent diverse populations, we report that outcomes from the original trials that led to the approval of these therapies are comparable to those in practice.

KEYWORDS:

• CAR-T
• CAR-T efficacy
• CAR-T safety
• CAR-T outcomes
• CAR-T real-world
• chimeric antigen receptor T-cell therapy outcomes

Introduction

The currently approved chimeric antigen receptor T (CAR-T) cell products are autologous T-cells that are genetically engineered to express a “CAR” that redirects T cells to kill tumor cells.¹ In pivotal clinical trials, CAR-T cells have demonstrated unprecedented anti-tumor efficacy leading to a shift in the treatment paradigm for plasma cell and lymphoid malignancies including B-cell acute leukemia (B-ALL), large B-cell lymphomas (LBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), multiple myeloma (MM), and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). To date, six commercial CAR-T cell products have been approved by the United States (US) Food and Drug Administration (FDA) for various types of relapsed or refractory (R/R) hematological malignancies, as listed in Table 1. Although many of these therapies were granted approval based on single-arm registration studies, it is important to note that the efficacy demonstrated was striking and sufficient for FDA-approval. However, the generalizability of results from these studies that had stringent eligibility criteria remained to be demonstrated. Aside from confirming efficacy, studies in routine clinical practice had to also demonstrate safety in patients not conforming to trial specified inclusion and exclusion criteria. Even in the pivotal clinical trials, CAR-T cells induced severe and life-threatening toxicities such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) requiring early and specialized management protocols at experienced centers. To this end, real-world outcome (RWO) studies conducted to date have met the important need to confirm efficacy but also establish the safety of infusing CAR-T cells outside of clinical trials.²

Table 1. List of commercially available CAR-T products (brand name, generic name, and abbreviated generic name), FDA approval date, target antigen, and current indications.

CAR-T Product	Initial FDA Approval	Targeted Antigen	Current Indications
Kymriah® Tisagenlecleucel (tisa-cel)	2017	CD19	Children and young adults ≤25 y with B-ALL that is refractory or in second or later relapse Adults with R/R LBCL, including diffuse DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from FL after 2 or more treatment lines Adults with R/R FL after 2 or more treatment lines
Yescarta® Axicabtagene ciloleucel (axi-cel)	2017	CD19	Adults with LBCL refractory to first line chemoimmunotherapy or relapse within 1 y Adults with R/R LBCL, including DLBCL not otherwise specified, primary high mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from FL after 2 or more treatment lines Adults with R/R FL after 2 or more treatment lines
Tecartus® Brexucabtagene autoleucel (brexu-cel)	2020	CD19	Adults with R/R MCL Adults ≥26 y with R/R B-ALL
Breyanzi® Lisocabtagene maraleucel (liso-cel)	2021	CD19	Adults with LBCL, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma refractory to first line chemoimmunotherapy or relapse within 12 months Adults with R/R LBCL after 1 treatment line in transplant-ineligible patients Adults with R/R LBCL after 2 or more treatment lines Adults with R/R CLL or SLL after 2 or more treatment lines which have included a BTK inhibitor and a BCL-2 inhibitor
Abecma® Idecabtagene vicleucel (ide-cel)	2021	BCMA	Adults with R/R MM after 2 (previously 4 as of March 2024) or more treatment lines which have included an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody
Carvykti® Ciltacabtagene autoleucel (cilta-cel)	2022	BCMA	Adults with R/R MM after 1 (previously 4 as of March 2024) or more treatment lines which have included an immunomodulatory agent, a proteasome inhibitor, and are refractory to lenalidomide.

Abbreviations: B-ALL, B-cell acute leukemia; R/R, relapsed or refractory; LBCL, large B-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; BTK, Bruton tyrosine kinase; BCL-2, B-cell lymphoma 2; BCMA: B-cell maturation antigen; MM, multiple myeloma.

The purpose of this review is to consolidate available RWO studies of patients treated with commercial CAR-T products and serve as a resource of “expected outcomes” or a “benchmark” for centers to compare their own CAR-T outcomes.

Materials and methods

A narrative review was conducted by searching the PubMed, American Society of Hematology (ASH), and American Society of Clinical Oncology (ASCO) databases for articles and abstracts published between January 2017 and February 2024, correlating with the FDA approval of the first commercial CAR-T in 2017.

The search strategy involved using various combinations, including ‘chimeric antigen receptor,’ ‘CAR-T,’ ‘outcomes,’ ‘real world,’ ‘B-ALL,’ ‘pre-B ALL,’ ‘acute lymphoblastic leukemia,’ ‘B-cell lymphoma,’ ‘follicular lymphoma,’ ‘mantle cell lymphoma,’ ‘multiple myeloma,’ ‘CLL,’ ‘chronic lymphocytic leukemia,’ ‘SLL,’ ‘small lymphocytic lymphoma,’ ‘tisagenlecleucel,’ ‘tisa-cel,’ ‘axicabtagene ciloleucel,’ ‘axi-cel,’ ‘brexucabtagene autoleucel,’ ‘brexu-cel,’ ‘lisocabtagene maraleucel,’ ‘liso-cel,’ ‘idecabtagene vicleucel,’ ‘ide-cel,’ ‘ciltacabtagene autoleucel,’ and ‘cilta-cel.’ These keywords were used to identify relevant articles.

Articles were then selected based on relevance to CAR-T outcomes, CAR-T real-world data, commercial CAR-T products, and specific disease outcomes. Studies were excluded if they did not report three or more of the major outcomes (complete response rate, objective response rate, progression or event-free survival, overall survival, and CRS or ICANS ≥ grade 3) we analyzed in this review. Studies were also excluded if the patient cohort was presumed to be included in larger registries and provided no additional outcomes regarding specific sub-groups. The selection process was conducted independently by two different reviewers. Disagreements were thoroughly discussed with a third reviewer to promote inter-rater reliability. Limitations include possible duplication of patients, and oversight of potentially relevant studies due to our search methodology. Statistical analyses were conducted using Fisher’s exact test.

RWO studies by indications of CAR-T cells

B-ALL

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and while the 5-y survival has improved to up to 90%, prognosis remains poor in patients with recurrence.³ B-cell acute lymphoblastic leukemia (B-ALL) accounts for approximately 85% of cases of ALL and has been the focus of many novel therapies.⁴ In recent years, CAR-T has emerged as a promising treatment modality for R/R B-ALL. There are currently two commercial CAR-T products approved by the FDA for use in B-ALL: tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel). National Comprehensive Cancer Network (NCCN) guidelines currently recommend tisa-cel in patients <26 y old and with refractory disease or ≥2 relapses and brexu-cel for adolescents and adults with refractory disease or ≥2 relapses.⁵ For Philadelphia-positive R/R B-ALL, it is also recommended that tyrosine kinase inhibitors be utilized prior to any CAR-T product.⁵ Tisa-cel was first approved for R/R B-ALL in children and young adults up to 25 y of age in 2017. The ELIANA trial enrolled 75 children and young adults aged less than 21 y at the time of diagnosis with a median age of 11 y.⁶ An updated analysis of 75 patients that had at least 3-months of follow-up reported an overall remission rate, defined as the complete remission rate (CRR) with or without hematologic recovery of 81%.⁶ Event-free survival (EFS), defined as the time from infusion to the earliest of the following: no response, relapse before a response was maintained for 28 d, or relapse after having complete remission with or without hematologic recovery, was estimated to be 50% at 12-months, while overall survival (OS) was 76% at the same time point.⁶ Furthermore, 6% of patients had grade ≥3 CRS and 13% of patients had a grade 3 neurological event with no neurological adverse effects reported above this grade.⁶

There have been at least five real-world studies for tisa-cel in R/R B-ALL with three studies having a patient age population similar to ELIANA, ranging from 11.8 to 13.2 y old (Table 2).^7–11 By contrast, Brissot et al. featured a cohort of young adults, with a median age of 24, and Ghorashian et al. studied the effects of tisa-cel in children under 3 y old (median age of 0.4 y old), a population that was not originally included in the landmark trial.^9,11 The average complete remission rate in the RWO cohort was 87% (584/672) comparable to 81% in ELIANA (p = .184).^6–11

Table 2. Comparison of real-world studies of tisa-cel in B-ALL to the ELIANA trial.

Tisa-cel in B-ALL
	Clinical Trial	Real-World Outcomes
Cohort	ELIANA^Citation6	CIBMTR^Citation7	PRWCC^Citation8	Europe (EBMT)^Citation9	Germany^Citation10	Europe (Ghorashian)^Citation11
Patients infused and included in analysis (n)	75	255	183	118	81	35
Age (years, median)	11	13	12	24	12	0.4
CRR (%)	81%	86%	85%	91%	88%	86%
EFS 12 months (%)	50%	52%	Not reported	Not reported	Not reported	69%
OS 12 months (%)	76%	77%	Not reported	Not reported	Not reported	84%
CRS ≥3 grade (%)	6%	16%	21%*	Not reported	9%	14%
ICANS ≥3 grade (%)	13%	9%	7%*	Not reported	5%	0%

Abbreviations: tisa-cel, tisagenlecleucel; B-ALL, B-cell acute lymphoblastic leukemia; CRR, complete response rate; EFS, event-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Analysis included 184 patients.

Two cohorts reported their EFS and OS significantly different from other studies. The Pediatric Real-World CAR Consortium (PRWCC) study did not report an overall EFS or OS for their 183 patients.⁸ Instead, the main purpose of their paper was to review outcomes separately between primary refractory, first relapse, and second relapse cohorts. The EFS for the primary refractory, first relapse, and second relapse groups was 59%, 49%, and 47%, respectively, and the OS for the primary refractory, first relapse, and second relapse groups was 85%, 69%, and 70%, respectively.⁸ The European Society for Blood and Marrow Transplantation (EBMT) study also similarly divided their cohort into patients who were in complete remission (CR) and those not in CR (non-CR) prior to initiating tisagenlecleucel therapy. The OS and EFS of the CR group was 66% and 89%, respectively, and the OS and EFS of the non-CR group was 39% and 62%, respectively.⁹ For the two studies (CIBMTR and Ghorashian et al.) that compared EFS and OS at 12 months as in the ELIANA trials, the EFS (52% and 69%) and OS (77% and 84%) were similar to ELIANA’s EFS and OS (50% and 76% respectively).^7,11 The rate of CRS ≥ 3 grade in real-world studies was slightly higher at 16% (91/554) compared to 6% in ELIANA (p = .026), and the rate of ICANS ≥ 3 grade was 7% (40/554), which was not statistically significant compared to 13% in ELIANA (p = .072), with the caveat that there may have been differences in grading toxicities across the studies.^6–11

Brexu-cel was approved in 2021 for adults with R/R B-ALL based on the ZUMA-3 trial which included 55 participants.¹² This trial achieved a CRR of 71%, EFS of 58% at 6 months, and OS of 71% at 12 months.¹² CRS ≥ grade 3 occurred in 24% of patients and ICANS ≥ grade 3 occurred in 25%.¹²

There have been two real-world studies from the US assessing the outcomes of brexu-cel. The largest study comes from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the other one is from the real-world outcomes collaborative of CAR-T in ALL (ROCCA).^13,14 Results of ZUMA-3 were comparable among most major outcomes other than the incidence of CRS (Table 3).^12–14 The CRR of 81% (164/203) from RWO studies was not statistically different from the 71% seen in ZUMA-3 (p = .137).^12–14 However, the incidence of CRS ≥ 3 grade in real-world studies was found to be lower at 8% (17/203) compared to 24% in ZUMA-3 (p = .004).^12–14 Lastly, there was no significant difference in cases of ICANS ≥ 3 grade with an incidence of 29% (58/203) in real-world studies compared to 25% in ZUMA-3 (p = .736).^12–14 It is important to note that there were differences in the way toxicities were graded across studies, and thus no definitive conclusions are possible from cross-study comparisons.

Table 3. Comparison of real-world studies of brexu-cel in B-ALL to the ZUMA-3 trial.

Brexu-cel in B-ALL
	Clinical Trial	Real-World Outcomes
Cohort	ZUMA-3^Citation12	US CIBMTR^Citation13	ROCCA^Citation14
Patients infused and included in analysis (n)	55	138	65
CRR (%)	71%	76%	91%
EFS 6 months (%)	58%	53%	59%
OS 6 months (%)	Not reported (71% at 12 months)	78%	87%
CRS ≥3 grade (%)	24%	9%	7%
ICANS ≥3 grade (%)	25%	24%	39%

Abbreviations: brexu-cel, brexucabtagene autoleucel; B-ALL, B-cell acute lymphoblastic leukemia; CRR, complete response rate; EFS, event-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

Large B-cell lymphomas

Large B-cell lymphomas (LBCL) include a wide variety of tumors characterized by large lymphoid cells of B-cell lineage, usually defined by having a nucleus larger than a macrophage or twice the size of a normal lymphocyte, that form sheets or clusters.¹⁵ Diffuse large B-cell lymphoma (DLBCL), a subtype of LBCL, is the most common Non-Hodgkin lymphoma (NHL) in the Western World and accounts for 30 to 40% of cases.^15,16 Anti-CD19 CAR-T cell therapy has proven to be a valuable asset in the treatment of R/R LBCL and there are currently three commercial products that have been FDA approved. NCCN guidelines have been updated to recommend CAR-T as early as second-line treatment for R/R LBCL.¹⁷ Axicabtagene ciloleucel (axi-cel) became the first product to receive approval for R/R LBCL after two or more lines of treatment, based on the 2017 ZUMA-1 trial. For its phase-II study, ZUMA-1 enrolled 111 patients with R/R LBCL, of which 101 patients with a median age of 58 received the infusion.¹⁸ Initial objective response rate (ORR) was 82%, including a 54% CRR.¹⁸ CRS ≥ 3 grade occurred in 13% of patients and ICANS ≥ 3 grade in 28%.¹⁸ An updated analysis of 108 patients from the ZUMA-1 phase-I and II trial participants showed a 12-month PFS of 44% and a 12-month OS of 59%.¹⁸

In addition to its role in B-ALL, tisa-cel also found success as a third line therapy for R/R LBCL and was approved in 2017 after promising results from the JULIET trial. This cohort of 115 patients with a median age of 56 had an ORR of 53% and CRR of 39% after tisa-cel infusion.¹⁹ Follow-up at 12 months showed an estimated OS of 48% and median PFS was 2.9 months for all infused patients.¹⁹ CRS ≥ 3 grade occurred in 23% of patients and ICANS ≥ 3 grade in 11%.¹⁹

Lisocabtagene maraleucel (liso-cel) became the third commercially available CAR-T product for R/R LBCL and was approved as a second-line treatment option in 2022 after the TRANSCEND NHL 001 trial. The efficacy analysis included 256 patients who had one or more lines of treatment and PET-positive disease.²⁰ Results demonstrated an ORR of 73% with 53% of patients achieving a CRR. PFS at 1-y was 44% with an estimated 1-y OS of 58%.²⁰ To evaluate the safety profile of liso-cel, 269 patients who had received at least one dose of liso-cel were monitored.²⁰ Only 2% of patients had a reported CRS ≥ 3 grade, while 10% of the cohort had ICANS ≥ 3 grade.²⁰

Following their initial success, subsequent trials led to the approval of axi-cel and liso-cel as second-line therapy options for LBCL. The ZUMA-7 trial compared axi-cel to standard of care (SoC) in 359 patients with R/R LBCL after first-line therapy, of which 180 were assigned to the axi-cel group.²¹ Axi-cel proved to be superior to SoC in median EFS (8.3 months vs. 2 months), 24-month EFS (41% vs. 16%), 24-month OS (61% vs. 32%), ORR (83% vs. 50%), and CRR (65% vs. 32%).²¹ Similarly, tisa-cel was tested as second line and compared to SoC in the TRANSFORM trial that featured 184 patients of which half were randomized into the tisa-cel group.²² Tisa-cel also showed to have improved outcomes compared to SoC in significant endpoints including median EFS (10.1 months vs. 2.3 months), 12-month EFS (45% vs. 24%), 12-month OS (79% vs. 64%), ORR (86% vs. 48%), and CRR (66% vs. 39%).²² Due to their recent approval, there is limited real-world evidence available for axi-cel as second-line therapy and liso-cel in general. However, large studies across the US and various European Countries have provided insight into the outcomes of axi-cel and tisa-cel for R/R LBCL after two or more treatment lines. Although a systematic review and meta-analysis of CAR-T LBCL outcomes was recently published by Jacobson et al., including studies up to June 2022, our goal in this section is to provide updated information and to highlight important outcomes from the largest available cohorts.²³ It is, however, important to note that this study found that axi-cel was associated with better response rates when compared to tisa-cel but that axi-cel proved to be more toxic which was corroborated in our analysis and could be hypothetically due to specifics in the design of the CAR-T products.²³ The largest axi-cel group included in our analysis comes from the CIBMTR in the US, which includes 1,297 patients, of which at least 57% would have been ineligible for ZUMA-1.²⁴ The US tisa-cel cohort is small in comparison but provides information on 84 patients who received tisa-cel across 8 US academic institutions with 44% of patients being ineligible for the landmark JULIET trial.²⁵ Other registries included in this section of our review include the DESCAR-T in France, the German Lymphoma Alliance (GLA) and the German Registry for Stem Cell Transplantation (DRST), the Spanish GETH-TC and GELTALMO groups, and the United Kingdom (UK) CAR-T registry.^26–29 These RWO cohorts allow us to analyze LBCL outcomes of anti-CD 19 CAR-T therapy and compare them to the original trials to validate their efficacy and safety profile.

In axi-cel RWO cohorts (Table 4), ORR was 73% (1494/2037) which is slightly lower than 82% in ZUMA-1 (p = .049).^{18,24,26–29} CRR of 54% (1096/2037) in real-world studies was not statistically different than the 54% reported in the landmark trial (p = .090).^{18,24,26–29} The incidence of CRS ≥ 3 grade of 8% (161/2037) and ICANS ≥ 3 grade of 21% (434/2037) were also not statistically significant in comparison to 13% and 28% from ZUMA-1, respectively (p = .089 and p = .137).^{18,24,26–29}

Table 4. Comparison of real-world studies of axi-cel in LBCL to the ZUMA-1 trial.

Axi-cel in LBCL
	Clinical Trial	Real-World Outcomes
Cohort	ZUMA-1^Citation18	US^Citation24	France^Citation26	Germany^Citation27	Spain^Citation28	UK^Citation29
Patients infused and included in analysis (n)	101	1,297	209	173	134	224
ORR (%)	82%	73%	80%	74%	60%	77%
CRR (%)	54%	56%	60%	42%	42%	52%
PFS 12 months (%)	44%*	47%	47%	35%	41%	42%
OS 12 months (%)	59%*	62%	64%	55%	51%	57%
CRS ≥3 grade (%)	13%	8%	5%	10%	8%	8%
ICANS ≥3 grade (%)	28%	24%	14%	16%	16%	20%

Abbreviations: axi-cel, axicabtagene ciloleucel; LBCL, large B-cell lymphoma; ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Analysis included 108 patients from both phase-I and II trials.

For tisa-cel RWO studies, the reported ORR was 56% (381/677) and CRR 37% (252/677) which accounts for no statistical difference compared to an ORR of 53% and CRR of 39% from the JULIET trial (p = .543 and p = .755)^19,25–29 PFS at 12 months, which was not reported in the landmark trial, was lowest in the UK registry at 27%, while highest in the French and Spanish registries at 33%.^26–29 OS at 12 months ranged from 44% to 59% compared to 48% reported in JULIET.^19,25–29 The incidence of CRS ≥ grade 3 at 9% (58/679) and ICANS ≥ grade 3 at 4% (29/679) were lower than the observed rates of 23% and 11% in the original trial, respectively (p < .001 for both).^19,25–29 These results are summarized in Table 5.

Table 5. Comparison of real-world studies of tisa-cel in LBCL to the JULIET trial.

Tisa-cel in LBCL
	Clinical Trial	Real-World Outcomes
Cohort	JULIET^Citation19	US^Citation25	France^Citation26	Germany^Citation27	Spain^Citation28	UK^Citation29
Patients infused and included in analysis (n)	115	84	209	183	127	76
ORR (%)	53%	41%*	66%	53%	54%	57%
CRR (%)	39%	35%*	42%	32%	34%	44%
PFS 12 months (%)	Not reported	32%	33%	24%	33%	27%
OS 12 months (%)	48%	59%	49%	53%	47%	44%
CRS ≥3 grade (%)	23%	1%	9%	13%	6%	8%
ICANS ≥3 grade (%)	11%	1%	3%	7%	5%	4%

Abbreviations: tisa-cel, tisagenlecleucel; LBCL, large B-cell lymphoma; ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Analysis included 82 patients.

Mantle cell lymphoma

Mantle Cell Lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin’s lymphoma that is challenging to treat. CAR-T therapy is currently a second line as per NCCN guidelines, however typically a third-line or subsequent, option for the treatment of MCL for progressive disease after treatment with prior covalent Bruton Tyrosine Kinase (BTK) inhibitors.¹⁷ Current therapeutic options for MCL are not considered curative, leading to several successive lines of therapy and the inevitability of developing resistant disease.³⁰ At present, brexu-cel is the sole CAR-T product approved for the treatment of R/R MCL.

In the pivotal ZUMA-2 multicenter phase-II trial, brexu-cel was administered to 68 of 74 enrolled patients with R/R MCL who had been treated with chemoimmunotherapy and BTK inhibitor therapy.³¹ Based on an updated analysis, the ORR was 93% and CRR was 67%.³² At 12 months, the estimated PFS and OS were 61% and 83%, respectively.³¹ CRS grade ≥3 occurred in 15% of patients and ICANS grade ≥3 in 31%.³¹ This study established brexu-cel as an effective option for patients with R/R MCL and was granted accelerated approval for the treatment of such.

Real-world data for brexu-cel have demonstrated similar efficacy and safety compared to the results of ZUMA-2. In the US Lymphoma CAR-T Consortium, 189 patients from 16 US institutions underwent leukapheresis, 168 (89%) of which received brexu-cel.³³ The majority (79%) of these patients did not meet the ZUMA-2 eligibility criteria.³⁴ The most common reasons for not meeting the criteria were prior therapy, cytopenias and renal dysfunction.³³ ORR was 90% with a CRR of 82%, 12-month estimated PFS was 59% and OS was 75%.³³ CRS and ICANS grade ≥3 occurred in 8% and 32% of patients, respectively.³³ Interestingly, patients with recent bendamustine treatment, defined as within 24 months before leukapheresis, were found to have shorter PFS and OS.³³ Other studies included in this review come from the European Early Access Program, France’s DESCAR-T cohort, and the National CAR-T Clinical Panel in the UK with comparable reports to ZUMA-2, as outlined in Table 6.^31–37

Table 6. Comparison of real-world studies of brexu-cel in MCL to the ZUMA-2 trial.

Brexu-cel in MCL
	Clinical Trial	Real-World Outcomes
	ZUMA-2^Citation31,Citation32	US^Citation33	Europe^Citation34	France^Citation35	UK^Citation36
Patients infused and included in analysis (n)	68	168	33	47	49
ORR (%)	91%*	90%	91%	88%**	90%
CRR (%)	68%*	82%	79%	62%**	83%
PFS 12 months (%)	61%	59%	51%	Not reported (58% at 6 months)	56%
OS 12 months (%)	83%	75%	61%	Not reported	72%
CRS ≥3 grade (%)	15%	8%	3%	9%	12%
ICANS ≥3 grade (%)	31%	32%	36%	9%	24%

Abbreviations: brexu-cel, brexucabtagene autoleucel; ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Analysis included 60 patients. **Analysis included 42 patients.

Brexu-cel pooled RWO cohorts had an ORR 90% (262/292) and CRR of 79% (231/292), neither of which was significantly different from the ORR of 91% (55/60) and CRR of 68% (41/60) reported in ZUMA-2 (p = .814 and p = .090, respectively).^32–37 The incidence of CRS grade ≥3 in RWO pooled cohorts was 8% (24/297) and ICANS grade ≥3 was 28% (82/297) which were also not significantly different from rates of CRS grade ≥3 of 15% (10/68) and ICANS grade ≥3 of 31% (21/68) in the pivotal trial (p = .105 and p = .654, respectively).^31–37

Follicular lymphoma

Follicular Lymphoma (FL) represents the second most common lymphoma diagnosed in the Western Hemisphere.³⁸ As per NCCN guidelines, CAR-T therapy is recommended as a third-line treatment option for patients with FL.¹⁷ There are currently two CAR T-cell therapies approved for all types of R/R FL: tisa-cel and axi-cel.

The ELARA phase-II trial tested tisa-cel in adults with R/R FL after 2 or more treatment lines, or who relapsed after autologous stem cell transplantation. Ninety-seven patients received tisa-cel, of whom 94 were evaluated for efficacy endpoints.³⁹ This cohort achieved an ORR of 86% with a CRR of 69%, while the rate of grade ≥3 CRS was 0% and grade ≥3 ICANS was 3%.³⁹ Updated results with a median follow-up of 29 months, estimated 24-month PFS, and OS rates at 57%, and 88%, respectively, which favors a durable efficacy and a favorable safety profile.³⁴ Salles et al. performed a retrospective comparative analysis comparing the use of tisa-cel in ELARA to standard therapy from a matched real-world cohort from ReCORD-FL, a global retrospective study of patients with R/R FL.⁴⁰ They found a 1.9-fold higher CRR (69% vs. 37%), a 1.4-fold higher PFS at 12 months (71% vs. 52%) and a death risk reduction of 80%.⁴⁰ These results were corroborated by another study comparing ELARA outcomes to matched real-world data from the US Flatiron Health Research Database, which also favored tisa-cel with a CRR of 69% vs. 18% and an ORR of 86% vs. 58%.⁴¹

Axi-cel was studied in 124 enrolled patients with R/R FL, in the global, multi-center, phase-II trial ZUMA-5.⁴² Updated analysis from ZUMA-5 showed patients with R/R FL had an ORR of 94% and a CRR of 79%.⁴³ Estimated 18-month PFS and OS were 69% and 88%, respectively.⁴³ The rate of CRS grade ≥3 was 6% and ICANS grade ≥3 15%.⁴² A study comparing the ZUMA-5 R/R FL cohort to matched data from the international SCHOLAR-5 study for R/R FL patients who initiated a third or higher line of therapy found that ORR (94% vs. 50%) and CRR (79% vs 30%) were higher in the ZUMA-5 group.⁴⁴

A US CIBMTR cohort of 151 infused patients, of whom 40% would not have met the eligibility criteria for ZUMA-5, was analyzed to provide insight into the RWO of axi-cel in R/R FL.⁴⁵ Real-world analysis from the French DESCAR-T registry included 70 patients who had at least 1-month follow-up with PET-CT evaluation (62 tisa-cel and 8 axi-cel).⁴⁶ A summary of the results from the clinical trials and the real-world studies can be found in Table 7.

Table 7. Comparison of real-world studies of tisa-cel and axi-cel in FL to their landmark trials.

Tisa-cel and Axi-cel in FL
	Clinical Trial		Real-World Outcomes
	ELARA^Citation38,Citation39	ZUMA-5^Citation42,Citation43	US^Citation45	France^Citation46
Product(s)	Tisa-cel	Axi-cel	Axi-cel	Tisa-cel and Axi-cel
Patients infused and included in analysis (n)	97	127	151	70 (62 Tisa-cel and 8 Axi-cel)
ORR (%)	86%*	94%	93%	98%
CRR (%)	69%*	79%	84%	88%
PFS 12 months (%)	67%	78%	88% (6 months)	72% (6 months)
OS 12 months (%)	88% (at 24 months)	93%	96% (at 6 months)	97% (at 6 months)
CRS ≥3 grade (%)	0%	6%	2%	1%
ICANS ≥3 grade (%)	3%	15%	13%	4%

Abbreviations: tisa-cel, tisagenlecleucel; axi-cel, axicabtagene ciloleucel; FL, follicular lymphoma; ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Analysis included 94 patients.

Axi-cel in the US CIBMTR cohort had an ORR of 93% (140/151) and CRR of 84% (127/151) which were not significantly different from those seen in the ZUMA-5 trial which had an ORR of 94% (79/84) and CRR of 79% (66/84) (p = .792 and p = .293, respectively).^43,45 The incidence of CRS grade ≥3 of 2% (3/151) and ICANS grade >3 13% (20/151) in the US CIBMTR cohort were also not significantly different from rates of CRS grade ≥3 of 6% (8/124) and ICANS grade ≥3 of 15% (19/124) seen in ZUMA-5 (p = .070 and 0.729, respectively).^42,45 Disease response and adverse events rates were not compared for tisa-cel as the French DESCAR-T registry did not provide a breakdown of outcomes and toxicities by product.

Multiple myeloma

Multiple Myeloma (MM) is the second most common hematologic malignancy, contributing to approximately 2% of cancer-related deaths in the US.⁴⁷ CAR T-cell therapy has emerged as a promising therapeutic modality for the effective treatment of multiple myeloma. Current FDA-approved CAR T-cell therapies for R/R MM include idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) which differ from other commercial products by targeting the B-cell maturation antigen (BCMA) instead of CD19.

Ide-cel was first approved in 2021 for adult patients with R/R MM based on the results KarMMa trial. In this trial, 128 patients were treated with ide-cel after ≥4 lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.⁴⁸ Results were notable for an ORR of 73% and a CRR of 33%.⁴⁸ Grade 3 or higher CRS occurred in 5% and grade 3 or higher ICANS in 3% of the infused population.⁴⁸ An updated phase-II trial was notable for median PFS of 8.8 months and median OS of 18.4 months.⁴⁹

Cilta-cel was initially approved in 2022 for the same indication as ide-cel in R/R MM. Approval was based on results of the CARTITUDE trial, which consisted of 97 patients who received a cilta-cel infusion.⁵⁰ Results showed an ORR of 97% with a CRR of 67%, while estimated 12-month PFS and OS were 77% and 89%, respectively.⁵⁰ CRS grade 3 or higher occurred in 4% patients and ICANS grade 3 in 9%.⁵⁰

In regards to the comparative efficacy between cilta-cel and ide-cel, there remains a need for further studies that perform a head-to-head comparison of these two therapies. A recent study used an unanchored matching-adjusted indirect comparison (MAIC) approach to estimate their relative efficacy using data from the CARTITIDE-4, CARTITUDE-1 and KarMMa-3 trials. Patients in the cilta-cel group demonstrated a statistically significant reduction of 49% in the risk of disease progression or death compared to the ide-cel group and were significantly more likely to achieve an overall response.⁵¹

Given the highly stringent eligibility criteria of clinical trials, recent studies have investigated real-world outcomes to evaluate the safety and efficacy of ide-cel after four or more lines of treatment (Table 8). Data regarding real-world patients treated with cilta-cel is limited given that it has been approved for about 2 y. The CIBMTR registry study, which included 603 patients, is the largest available study and reported comparable results to KarMMa.⁵² The other two studies summarized in this section highlight outcomes for patients that would have been excluded from the KarMMA trial. The Myeloma CAR-T Consortium analyzed 159 patients, of which 119 would have been ineligible for KarMMa, while the US Myeloma Innovations Research Collaborative (USMIRC) featured 69 patients that would have not met the inclusion criteria.^53,54 Interestingly, the cohorts with excluded patients had a better ORR with 87% (190/228) of patients achieving this result compared to 73% in KarMMa (p = .020).^48,53,54 CRR also fared slightly better in these cohorts, with 44% (100/228) achieving this result vs. only 33% in the landmark trial (p = .043).^48,53,54 Further analysis involving all RWO studies showed no statistical differences in CRS ≥ 3 when comparing 3% (26/831) to 4% in the trial (p = .646).^8,49,52–54 However, RWO cohorts appear to have a slightly lower incidence of ICANS ≥ 3 with 4% (36/831) reporting this outcome compared to 9% in KarMMa (p = .035).^8,49,52–54

Table 8. Comparison of real-world studies of ide-cel in MM to KarMMA trial.

Ide-cel in MM
	Clinical Trial	Real-World Outcomes
	KarMMa^Citation48,Citation49	CIBMRT^Citation52	Myeloma CAR-T Consortium^Citation53	USMIRC^Citation54
Patients infused and included in analysis (n)	128	603	159	69
ORR (%)	73%	71%	84%	93%
CRR (%)	33%	27%	42%	48%
PFS	8.8 months (median)	62% (6 months)	8.5 months (median)	8.5 months (median)
OS	19.4 months (median)	82% (6 months)	12.5 months (median)	19.4 months (median)
CRS ≥3 grade (%)	4%	3%	3%	4%
ICANS ≥3 grade (%)	9%	4%	6%	3%

Abbreviations: ide-cel, idecabtagene vicleucel; MM, multiple myeloma; ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

Building on their initial success, both ide-cel and cilta-cel have been granted FDA approval to treat R/R MM in earlier lines of treatment as of April 2024. Ide-cel was approved as third-line treatment for triple-class-exposed R/R after the successful KaRRMMa-3 trial, which compared this product to SoC in patients that had received two to four previous lines of therapy. In this trial, 254 patients were randomized to the ide-cel arm and 132 to SoC.⁵⁵ In the intention-to-treat analysis, ide-cel was superior to SoC in median PFS (13.3 months vs. 4.4 months),12-month PFS (55% vs. 30%), ORR (71% vs. 42%), and CRR (39% vs. 5%).⁵⁵ Similarly, cilta-cel was also granted extended approved in April 2024 but as a second-line treatment option for R/R MM. This approval was based on the CARTITUDE-4 trial which featured 419 patients who had received one to three previous lines of treatment and were randomized into the cilta-cel group or SoC.⁵⁶ In the intention-to-treat analysis, cilta-cel outperformed SoC in ORR (85% vs. 67%), CRR (73% vs. 22%), and PFS (76% vs. 49%).⁵⁶ The current NCCN guidelines have also been updated to recommend the use of CAR T-cell therapy for R/R MM after at least 1–2 prior therapies.⁵⁷ Cilta-cel is recommended after one prior therapy (that includes an immunomodulatory drug and a proteasome inhibitor) and if refractory to lenalidomide.⁵⁷ Ide-cel is recommended after two prior therapies (including an immunomodulatory drug, an anti-CD38 monoclonal antibody and a proteasome inhibitor).⁵⁷ While anti-BCMA CAR-T cell therapy has achieved impressive outcomes in R/R MM, relapse continues to occur despite these treatments and further improvement is required. Potential mechanisms being explored include identifying novel targets, optimizing CAR structure and exploring dual-targeted CAR-T cell therapy.⁵⁸

Chronic lymphocytic leukemia and small lymphocytic lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) represent the same entity of indolent NHL with different nomenclature based on the location of the immature lymphocytes. CLL is most commonly diagnosed in older adults and accounts for 25–30% of total leukemias in the US.⁵⁹ Most recently, liso-cel was approved for R/R CLL/SLL after two lines of therapy in March 2024. The TRANSCEND CLL 004 trial enrolled 137 patients with CLL/SLL, of whom only 117 received an infusion of liso-cel.⁶⁰ Efficacy analysis showed an ORR of 43% with a CRR of 18%.⁶⁰ Grade 3 or higher CRS and ICANS were reported in 9% and 18% of patients, respectively.⁶⁰ Due to its recent approval, there are no RWO studies of liso-cel and it is not yet listed as a treatment option for CLL/SLL in the NCCN guidelines.

Conclusion

Despite the impressive potential of commercial CAR-T, specific therapy-related issues such as adverse effects, optimal harvesting and infusion strategies, resistance, and recurrence after CAR-T have emerged as potential challenges to its growth. In addition, rare but concerning cases of secondary hematological malignancies developing after CAR-T therapy have led to black box warnings on these products.⁶¹ Although there are at least 22 reported cases of T-cell malignancies after CAR-T, not much is known related to the mechanism and direct impact of the CAR’s in the pathogenesis of these malignancies.⁶² This potential association warrants close and long-term monitoring of patients infused with CAR-T but should not deter us from considering CAR-T as a potential treatment option due to its widespread benefits.

In this review, we report that available RWO studies have shown comparable results to landmark trials, validating the efficacy of commercially available products across different hematological diseases. As a consistent theme, in all indications where the eligibility criteria have been extended beyond those on the pivotal trials (e.g.: age, organ function status, etc.), outcomes have yielded similar efficacy as reported from landmark trials. In regards to toxicity, the results suggest that there are similarities in the safety profiles of CAR-T products as reported in landmark trials when compared to RWO cohorts. However, important differences can be noted, such as the higher incidence of CRS grade 3≥ in patients with B-ALL who received tisa-cel. The lack of robust data collection, as seen in phase I and II trials, alongside with changes in the grading of CRS and ICANS over the years, makes it challenging to confidently validate the safety profile of CAR-T in clinical practice.

In addition, the medical complexity of cancer patients, equity in healthcare, and lack of enrollment of underrepresented minorities across pivotal trials (i.e, only 11% of ZUMA-1 participants were nonwhite) present an ongoing challenge in the general practice.¹⁸ As we continue to strive for equity and adequate representation in clinical trials, our review provides clinicians with contemporary benchmarks in practice of response and toxicity rates in their patients, including those who may not meet the original trial eligibility criteria. Future studies should continue to evaluate long-term outcomes of CAR-T cell therapy across diverse patient populations to expand our knowledge of CAR-T and understand its optimal role in treating hematological malignancies.

Author contribution statement

The contributing authors agree to be responsible for all aspects of this work and have reviewed the manuscript prior to submission. DG, HW, MN, and JP were involved in literature review, data analysis, and writing of the manuscript. DG and PL led the development and editing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.

Notes on contributors

Daniel Goyco Vera

Dr. Daniel Goyco Vera is a graduate of the Internal Medicine Residency Program at Baylor College of Medicine. During residency, he was selected for the American Society of Hematology Minority Resident Hematology Award Program for his research proposal in evaluating CAR-T outcomes in underrepresented groups. His interests include hematological malignancies, immunotherapy, and outcomes research. Dr. Goyco Vera will be completing his Hematology-Oncology fellowship at UT Southwestern.