Long-term outcomes following CAR T-cell therapy in B-cell malignancies

CD19-directed chimeric antigen receptor (CAR) T-cell therapies demonstrated potent activity in  early phase trials of patients with relapsed/refractory (R/R) B-cell malignancies and further achieved high complete remission (CR) rates in subsequent multicentre trials. More recently, B-cell maturation antigen (BCMA)-directed CAR T-cell therapies yielded high overall response rates (ORR) in patients with R/R multiple myeloma (RRMM).¹

These improved outcomes resulted in the U.S. Food and Drug Administration (FDA) approval of four CD19-targeted CAR T-cell therapies: axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and brexucabtagene autoleucel (brexu-cel) for R/R B-cell lymphomas; the latter two are indicated in B-cell acute lymphoblastic leukemia (ALL). Two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and cilta-cabtagene autoleucel (cilta-cel), have been FDA approved for RRMM. These CAR T-cell products share similar adverse effects with variable differences.¹

Although CAR T-cell therapy has significantly advanced the treatment landscape of B-cell malignancies, its labor-intensive process and cost warrants further understanding of its long-term outcomes.

Below, we summarize the review article published by Cappell et al.¹ in Nature Reviews Clinical Oncology on long-term outcomes following CAR T-cell therapy in B-cell malignancies, including data on efficacy and safety, factors associated with long-term remissions, and ongoing investigational strategies to improve durable remissions.

FDA-approved CAR T-cell products in B-cell malignancies

Below, we provide an overview of the treatment indications for all current FDA-approved CAR T-cell therapies in R/R B-cell lymphoma, B-ALL, and MM (Figure 1).

Figure 1. FDA-approved CAR T-cell therapies* 

B-ALL, B-cell acute lymphoblastic leukemia; CAR, chimeric antigen receptor; FDA, Food and Drug Administration; FL, follicular lymphoma; HSCT, hematopoietic stem cell transplantation; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; R/R, relapsed/refractory; RRMM, relapsed refractory multiple myeloma.
*Adapted from Cappell, et al.¹

Long-term efficacy outcomes¹

CD19 CAR T-cell therapy in B-cell lymphomas and CLL

Data from ten studies assessing CD19 CAR T cells in R/R B-cell lymphomas, chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia have provided ≥24 months follow-up data (Figure 2). At ≥2 years after CAR T-cell infusion, durable responses were observed in a subset of patients across all studies, CAR T-cell products, and malignancies. Overall, data suggest the curative potential of CAR T-cell therapy for some patients with R/R B-cell lymphomas.

Figure 2. Long-term efficacy in B-cell lymphomas and/or CLL/SLL* 

axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CRR, complete remission rate; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; EFS, event free survival; FL, follicular lymphoma; HGBCL, high-grade B-cell lymphoma; liso-cel, lisocabtagene maraleucel; MCL, mantle cell lymphoma; NR, not reported; PFS, progression-free survival; PMBCL, primary mediastinal large B-cell lymphoma; SLL, small lymphocytic leukemia; tFL, transformed follicular lymphoma; tisa-cel, tisagenlecleucel.
*Data from Cappell, et al.1
^†LCAR-B38M was later developed to cilta-cabtagene autoleucel and FMC63-28Z to axicabtagene ciloleucel.

CD19 CAR T-cell therapy in B-ALL

Data from 12 studies at a median follow-up of 1-year (range, 1–4.8 years) outline the long-term efficacy of CD19-targeted CAR T-cell therapies in B-ALL.

• High CR rates of 62–86% have been achieved, most of which are minimal residual disease (MRD)-negative remissions.

• Variable median event-free survival (EFS; median EFS, 3.1−24 months) rates reported with a substantial but variable number of patients proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT; 17−88%) in remission.
• Long-term studies (>24 months) on tisa-cel and brexu-cel in adult patients reported a CR of 69%, with a median EFS and relapse-free survival (RFS) of 5.6 and 7 months, respectively.
• Long-term data from the ELIANA trial (NCT02435849) of tisa-cel in younger patients (<25 years of age) yielded a CR rate of 82% and median EFS of 24 months; this indicates higher survival outcomes in pediatric vs adult populations.
  • The 3-year RFS for patients in ELIANA undergoing alloHSCT vs non allo-HSCT was 52% vs 48%, respectively; this highlights that a proportion of pediatric patients can achieve long-term remissions without allo-HSCT consolidation.
• Data on other CD19 CAR T-cell products in pediatric patients without allo-HSCT showed a relapse rate of 68–100%, demonstrating that long-term remissions can differ between CAR T-cell products in the pediatric population.
• Allo-HSCT is recommended in adults due to lower median EFS outcomes compared with pediatrics; data show an improved EFS for those receiving allo-HSCT after tisa-cel.
• Important factors to identify patients who could benefit from allo-HSCT include receipt of previous HSCT, loss of B-cell aplasia, previous treatments received, cytogenetics, MRD detection, and disease burden prior to CAR T-cell infusion.
• Overall, CD19-targeted CAR T-cell therapy can induce high CR rates in patients with B-ALL; however, its lower survival rates compared to B-cell lymphomas indicate a lack of curative potential without subsequent therapy in B-ALL.

BCMA-directed CAR T-cell therapy in RRMM

Compared with other B-cell malignancies, there is less data on the long-term outcomes following BCMA-directed therapies in RRMM. Here, we report data from six studies at a median follow-up of ≥1 year (range, 13–48 months).

• ORR of 73–100% and CRs of 33−83% with frequent MRD-negative remissions reported
• Long-term remissions observed in a subset of patients across all studies without the use of consolidative or maintenance therapy
• Median PFS varied significantly across studies, ranging from 5.2 to 27 months
• Longest follow-up data on idecabtagene vicleucel at a median of 13 months reported median PFS of 8.8 months; 33% patients achieving CR had a median DOR of 19 months
• Long-term follow-up data at a median of 28 months on cilta-cel in the US and Japan reported a PFS of 55% at 27 months, although median DOR was not estimable and median PFS not reached
• Another long-term study on cilta-cel at median follow-up of 48 months in patients based in China showed a median PFS of 18 months
• Data show that BCMA-targeted therapies can achieve durable remissions in patients with RRMM, though there is a risk of progression over time

Factors associated with long-term remissions¹

Several factors have been linked with durable remissions following CAR T-cell therapy, including depth of response, type and characteristics of malignancy, tumor burden and location, lymphodepletion chemotherapy, and CAR T-cell levels. Figure 3 summarizes the clinical data for each factor.

Figure 3. Factors associated with long-term remissions* 

B-ALL, B-cell acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CR, complete response; EMD, extramedullary disease; MM, multiple myeloma; MRD, minimal residual disease
*Adapted from Cappell, et al.¹

Long-term adverse effects¹

Although there is limited data regarding long-term adverse effects following CAR T-cell therapy, the most commonly observed toxicities thus far include B-cell depletion, hypogammaglobulinemia, cytopenias, and infections. Risk factors associated with cytopenias include higher-grade cytokine release syndrome, multiple prior lines of therapy, allo-HSCT ≤1 year prior to CAR T-cell infusion, baseline cytopenia, and the presence of bone marrow malignancy. Available data indicate an increased risk of infections; however, there is no evidence so far on the long-term risk of secondary malignancies post CAR T-cell infusion. Table 1 reports long-term safety data occurring ≥90 days post CAR T-cell infusion across MM, B-ALL, and B-cell lymphomas.

Table 1. Long-term toxicities in CAR T-cell therapies*

Ongoing investigational strategies in CAR T-cell therapy

There are ongoing investigational strategies to improve outcomes following CAR T-cell therapy by optimizing all areas of the process, including patient selection, pre- and post-CAR T-cell infusion treatment, and cell manufacturing (Figure 4).

Figure 4. Investigational strategies to improve CAR T-cell therapy* 

CAR, chimeric antigen receptor; EMD, extramedullary disease; RRMM, relapsed refractory multiple myeloma.
*Adapted from Cappell, et al.¹

Given that antigen escape is an established relapse mechanism in CAR T-cell therapy, strategies such as dual antigen targeted CAR T-cells are being actively studied. We have previously reported key data from three investigational studies assessing dual-targeted CAR T-cell therapies in DLBCL, MCL, and Richter’s transformation, which demonstrated promising activity. Long-term analyses in B-cell lymphomas and B-ALL have also reported disease relapse due to antigen loss, suggesting that a combination strategy could prove beneficial in overcoming resistance.

Fully human CAR T-cell products have demonstrated CAR T-cell persistence but have not yet demonstrated improved efficacy. Development of substituted single-chain with heavy-chain variable domains such as cilta-cel have demonstrated high efficacy; however, prospective analyses are needed.

Axi-cel as a first-line therapy in high-risk B-cell lymphomas has been investigated in the ZUMA-12 trial (NCT03761056), demonstrating CR rates of 78%, 86% of which were durable. Other ongoing trials assessing CAR T-cells in earlier lines include axi-cel versus standard of care in first-line high-risk B-cell lymphoma (ZUMA-23; NCT05605899); and cilta-cel in newly diagnosed MM (CARTITUDE-5; NCT04923893). Emerging data have indicated that γ-secretase inhibitors before BCMA-targeted CAR T-cell therapy, ibrutinib prior to CD19-targeted CAR T-cells, and immune-checkpoint inhibitors after CAR T cells could be viable options to alter antigen expression and/or CAR T-cell function. 

Conclusion

Overall, long-term data demonstrate the high efficacy and minimal levels of toxicity associated with BCMA/CD19-targeted CAR T-cell therapy in hematological malignancies. While CAR T-cells induce durable remissions and have curative potential in B-cell lymphomas, it remains an important bridging therapy to allo-HSCT for durable efficacy in B-ALL. CAR T-cells can attain prolonged remission in MM, though its curative potential is not yet established. The ongoing research efforts in CAR T-cell development are likely to further improve durable remissions and expand its treatment indications.