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CAR T-Cell Gene Therapy in Non-Hodgkin Lymphomas: Present and Future


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To complement The ASCO Post’s continued comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel immunotherapies for patients with different types of non-Hodgkin lymphomas, such as large B-cell, diffuse large B-cell, secondary central nervous system (CNS), and mantle cell. For full details of these study abstracts, visit hematology.org/Annual-Meeting/.

Axicabtagene Ciloleucel in Large B-Cell Lymphomas

ABSTRACT 764: Postmarketing use and impact on outcomes of axicabtagene ciloleucel for the treatment of large B-cell lymphoma (LBCL) in the United States1

Methods: CIBMTR (the Center for International Blood & Marrow Transplant Research) data from 750 recipients of axicabtagene ciloleucel has been reported. Of them, 533 patients from 56 U.S. centers who had at least the first follow-up assessment submitted were included in the analysis. The median follow-up was 6.2 months (range, 1–16 months).

Results: Postapproval use of axicabtagene ciloleucel reported in this registry study in the United States, when compared with the registration ZUMA-1 trial,2 includes a larger proportion of patients 65 years of age and older (37%), patients with transformed (30%) or double/triple-hit (36%) lymphoma, and patients with a more compromised performance status. Grade ≥ 3 cytokine-release syndrome and neurologic toxicity were observed in 9% and 20% of the patients, respectively. The best overall response rate in patients with at least 6 months of follow-up (n = 326) was 84%, with most being complete responses. Outcomes were similar between younger and older patient populations.

Clinical Implications: Despite the differences in baseline characteristics that could have negatively impacted the outcomes, the best responses and toxicities with axicabtagene ciloleucel in the standard-of-care setting were comparable to those reported on the pivotal ZUMA-1 trial.2 However, longer follow-up is warranted to determine the durability of responses and progression-free and overall survival.

ABSTRACT 203: CD19 antigen loss with preservation of other B-cell lineage features in patients with LBCL who relapsed after axicabtagene ciloleucel3

Methods: Pretreatment tissue samples were available from 82 patients with LBCL, and 18 were available post-relapse from the pivotal ZUMA-1 study.2 Paired pretreatment and post-relapse samples were available for 16 patients. CD19, CD20, CD22, CD79a, and PAX5 H-scores were derived based on the proportion and intensity of antigen expression by immunohistochemistry. Scores of 0 to 5 were considered negative, and scores of 6 to 300 were considered positive. CD19 splice variants were assessed by RNA sequencing.

Results: In this cohort of patients treated with axicabtagene ciloleucel, a consistent treatment effect was observed regardless of the baseline CD19 H-score. Lack of CD19 expression was observed in 28% of relapse samples by immunohistochemistry. However, expression of other B-cell antigens including CD20, CD22, and CD79a was preserved in most relapse samples. RNA sequencing analysis revealed that antigen escape following axicabtagene ciloleucel may occur due to CD19 downregulation as well as alternative splicing due to loss of the chimeric antigen receptor (CAR)-binding epitope, similar to what has been described previously in B-cell acute lymphoblastic leukemia.4

Clinical Implications: These data indicate that loss of CD19 expression was common after axicabtagene ciloleucel therapy in LBCL and suggest that co-targeting or sequential targeting of alternate B-cell antigens is needed to improve the efficacy of anti-CD19 CAR T-cell products.

ABSTRACT 884: Detectable circulating tumor DNA (ctDNA) 28 days after axicabtagene ciloleucel is associated with poor outcomes in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)5

Methods: Tumor clonotype(s) was identified from tumor DNA extracted from archival paraffin-embedded tissue by polymerase chain reaction amplification of IgH-VDJ, IgH-DJ, and Ig kappa/lambda regions using universal consensus primers. ctDNA levels were measured in a multi-institution prospective study at baseline and serial time points for 1 year following axicabtagene ciloleucel infusion. Positron-emission tomography–computed tomography (PET-CT) scans were obtained at baseline; day 28; and during months 3, 6, and 12 after axicabtagene ciloleucel infusion. A Deauville score of 1 to 3 was considered PET-negative. Any detectable ctDNA was considered as minimal residual disease (MRD)-positive disease.

Results: This is the report on the preplanned analysis of the first 50 patients with at least a day 28 MRD assessment and 3 months of follow-up. An additional 4 patients with at least 3 months of follow-up but who did not have a day 28 MRD assessment were also included.

The study demonstrates similar rates of safety and efficacy with axicabtagene ciloleucel in patients with or without secondary CNS lymphoma.
— SYED ALI ABUTALIB, MD, AND SATTVA S. NEELAPU, MD

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Serologic MRD assessments at day 28: 56% (28 of 50) of patients were MRD-negative and 44% (22 of 50) were MRD-positive. Compared with patients who were MRD-positive, MRD-negativity correlated with improved median progression-free survival (not reached vs 2.96 months, P < .0001) and median overall survival (not reached vs 7.4 months, P = .0005).

PET scan assessments on day 28: A total of 46% (25 of 54) of patients were PET-negative and 54% (28 of 54) were PET-positive. Compared with PET-positive patients, PET-negative patients demonstrated an improved median progression-free survival (not reached vs 3.1 months, P = .0007) and overall survival (both not reached, P = .0096).

Comparison between serologic MRD and PET scan assessments on day 28: This analysis was able to identify patients who relapsed by 6 months with similar sensitivity, 71% (95% confidence interval [CI] = 48%–89%) and 77% (95% CI = 55%–92%), respectively. However, day 28 MRD status showed improved specificity as compared with day 28 PET-scan status: 94% (95% CI = 71%–99%) vs 63% (95% CI = 38%–83%).

Clinical Implications: Early identification of patients with increased relapse risk may allow for more timely intervention and consolidation strategies to improve outcomes after CAR T-cell therapy. These results provide a rationale for designing MRD-based risk-adaptive CAR T-cell clinical trials. If validated in larger studies, this sort of strategy has the potential to minimize the need for surveillance PET scans.

Tisagenlecleucel in DLBCL

ABSTRACT 766: Tisagenlecleucel for adults with relapsed or refractory DLBCL: Post-marketing analysis from CIBMTR Cellular Therapy registry6

Methods: CIBMTR data from patients with large B-cell lymphoma treated with tisagenlecleucel postapproval were reported. Efficacy and safety data were collected from patients with at least first follow-up assessment. Safety parameters assessed included cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome.7 Baseline information was available on 116 patients from 39 U.S. centers, and safety and efficacy outcomes were available on 83 and 80 patients, respectively.

Results: The median follow-up was 4.5 months (< 1–10.5 months). The overall response rate was 58%, including 40% achieving a complete response. The rates of grade ≥ 3 cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome were 3% and 6%, respectively. Of the products manufactured for these 116 patients, 31 were out-of-commercial specification, with low-cell viability (< 80%) being the most common reason. However, efficacy and safety outcomes were similar to those with batches meeting viability specifications.

Clinical Implications: Postmarketing efficacy of tisagenlecleucel for adults with DLBCL was comparable to that in the pivotal JULIET trial.8 The lower incidence of severe cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome is likely due to differences in grading systems and earlier use of tocilizumab and/or corticosteroids. Cell-product characteristics analyzed including percentage of viable cells did not appear to be associated with safety or efficacy, although larger sample size and longer follow-up are needed.

In the Future: Lisocabtagene Maraleucel in Relapsed or Refractory LBCL

ABSTRACT 241: Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase I study of lisocabtagene maraleucel in relapsed or refractory large LBCL9

Methods: Lisocabtagene maraleucel is an investigational anti-CD19 4-1BB CAR T-cell product with defined CD4-positive and CD8-positive composition (1:1 ratio) of CAR T cells. It was administered to patients with relapsed or refractory LBCL at one of three target dose levels (DLs) of 50 × 106 (DL1), 100 × 106 (DL2), or 150 × 106 (DL3) viable CAR-positive T cells in the dose-finding cohorts. All dose levels were expanded, and DL2 was chosen as the target dose level for dose confirmation. Primary endpoints were treatment-emergent adverse events and overall response rate.

Results: A total of 344 patients underwent leukapheresis; 269 patients received lisocabtagene maraleucel (DL1, n = 51; DL2, n = 177; DL3, n = 41). An additional 25 patients received a nonconforming product; the product could not be manufactured for 2 patients. Outcomes were similar between dose levels; therefore, data were pooled. Among patients evaluable for efficacy (n = 256), the overall response rate was 73% (95% CI = 67%–78%); the complete response rate was 53% (95% CI, = 47%-59%). The overall response and complete response rates were comparable across all patient subgroups. The duration of response at 12 months was 54.7% (95% CI = 46.7%-62.0%). The median progression-free survival was 6.8 months (95% CI = 3.3-14.1 months), with a 12-month progression-free survival rate of 44.1% (95% CI = 37.3%–50.7%). The median overall survival was 21.1 months (95% CI = 13.3 months to not reached). Any-grade cytokine-release syndrome occurred in 42% of patients, and 2% had grade ≥ 3 cytokine-release syndrome. Neurotoxicity occurred in 30% of patients (grade ≥ 3 in 10% of patients). Four patients had grade 5 adverse events related to lisocabtagene maraleucel (diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, and cardiomyopathy).

Clinical Implications: Transcend NHL 001 is the third pivotal trial of anti-CD19 CAR T-cell therapy in patients with relapsed or refractory LBCL. The study demonstrated durable clinical activity with a very favorable safety profile. A low incidence of severe cytokine-release syndrome and neurotoxicity allowed for outpatient administration at some centers. However, it is difficult to compare the results across the three pivotal trials (ZUMA-1,2 JULIET,8 and Transcend) because of differences in the trial designs and differences in baseline characteristics of patients.

Axicabtagene Ciloleucel in Secondary CNS Lymphoma

ABSTRACT 763: Experience with axicabtagene ciloleucel in patients with secondary CNS involvement (n = 17): Results from the U.S. Lymphoma CAR T Consortium10

Methods: In the ZUMA-12 trial leading to the U.S. Food and Drug Administration (FDA) approval of axicabtagene ciloleucel, patients with prior or active secondary CNS lymphoma involvement were excluded. In this study, clinical outcomes with axicabtagene ciloleucel in the standard-of-care setting in patients with secondary CNS lymphoma from the U.S. Lymphoma CAR T Consortium consisting of 17 U.S. academic centers were examined. All patients who underwent leukapheresis were included in the intention-to-treat analysis for response rate and event-free survival.

Results: At the time of leukapheresis, 21 patients had a history of (n = 11) or active (n = 10) secondary CNS involvement, and 277 patients had no CNS disease. Following axicabtagene ciloleucel infusion, the incidence of cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome, of any grade or grade ≥ 3, were comparable between the CNS and non-CNS cohorts. Use of tocilizumab and steroids was comparable between the two groups. No seizures or cerebral edema were noted in the CNS cohort. Of 18 patients with a history of or active secondary CNS lymphoma, the overall response rate was 61%, and ongoing response at 6 months was 44%. Among the eight patients with active CNS at the time of CAR T cell infusion, the overall response rate was 50%, with all ongoing at 6 months. The event-free survival was not significantly different between the CNS and non-CNS cohorts.

Clinical Implications: The study demonstrates similar rates of safety and efficacy with axicabtagene ciloleucel in patients with or without secondary CNS lymphoma. Although the sample size is small and follow-up is limited, these results support further investigation of axicabtagene ciloleucel in patients with secondary CNS lymphoma.

CAR T-Cell Therapy (KTE-X19) in Mantle Cell Lymphoma

ABSTRACT 754: KTE-X19, an anti-CD19 CAR T-cell therapy, in patients (n = 60) with relapsed or refractory mantle cell lymphoma (MCL): Phase II ZUMA-2 study11

Methods: Eligible patients were at least 18 years old, had an Eastern Cooperative Oncology Group performance score of 0 to 1, and must have received one to five prior therapies, including anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy, and a Bruton’s tyrosine kinase (BTK) inhibitor. The primary endpoint was overall response rate.

Results: As of July 24, 2019, 74 patients had undergone leukapheresis, and 68 (92%) received KTE-X19 with at least 1 year of follow-up (median, 13.2 months [range, 11.5–18.5 months]). Safety and efficacy analyses were performed in 68 and 60 patients, respectively. The median patient age was 65 years (range, 38–79 years), 25% of patients had a blastoid variant, and 17% had TP53 mutation.

The overall response rate by independent radiology review was 93% (95% CI = 84%–98%), with a complete response rate of 67% (95% CI = 53%–78%). After a median follow-up of 12.3 months (range, 7.0–32.3 months), median progression-free survival and overall survival were not reached, and 57% of all patients and 78% of patients with a complete response remained in remission. Cytokine-release syndrome (Lee criteria12) of any grade and grade ≥ 3 was observed in 91% and 15% of patients, respectively. Neurologic events occurred in 63% of patients (31% grade ≥ 3). There were no grade 5 cytokine-release syndrome or neurologic adverse events. Expansion of CAR T cells in blood was associated with an objective response and MRD negativity at week 4. However, expansion was also associated with grade ≥ 3 cytokine-release syndrome and neurologic events. In addition, peak levels of multiple inflammatory cytokines in serum were associated with severe cytokine-release syndrome and neurologic events.

Clinical Implications: The ZUMA-2 study11 is the first multicenter pivotal phase II study of anti-CD19 CAR T-cell therapy in patients with relapsed or refractory MCL. With at least 1 year of median follow-up, KTE-X19 demonstrated a manageable safety profile and significant and durable clinical benefit, with the majority of patients achieving complete response. If approved by the U.S. FDA, this therapy could provide a therapeutic option for patients with relapsed or refractory MCL who have a major unmet need when they relapse after therapy with a BTK inhibitor. ν

DISCLOSURE: Dr. Abutalib has served on advisory boards for AstraZeneca and Partner Therapeutics. Dr. Neelapu has received research support from Kite/Gilead, Cellectis, Poseida, Merck, Acerta, Karus, BMS, Unum Therapeutics, Allogene, and Precision Biosciences; served as a consultant/advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, Merck, Precision Biosciences, Cell Medica, Incyte, Allogene, Calibr, and Legend Biotech; and holds patents related to cell therapy.

REFERENCES

1. Pasquini MC, Locke FL, Herrera AF, et al: Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor T cell therapy, axicabtagene ciloleucel, for the treatment of large B cell lymphoma in the United States. 2019 ASH Annual Meeting & Exposition. Abstract 764. Presented December 9, 2019.

2. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.

3. 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. 2019 ASH Annual Meeting & Exposition. Abstract 203. Presented December 7, 2019.

4. Sotillo E, Barrett DM, Black KL, et al: Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 5:1282-1295, 2015.

5. Frank MJ, Hossain N, Bukhari A, et al: Detectable circulating tumor DNA 28 days after the CD19 CAR T-cell therapy, axicabtagene ciloleucel, is associated with poor outcomes in patients with diffuse large B-cell lymphoma. 2019 ASH Annual Meeting & Exposition. Abstract 884. Presented December 9, 2019.

6. Jaglowski S, Hu ZH, Zhang Y, et al: Tisagenlecleucel chimeric antigen receptor T-cell therapy for adults with diffuse large B-cell lymphoma: Real world experience from the Center for International Blood & Marrow Transplant Research Cellular Therapy Registry. 2019 ASH Annual Meeting & Exposition. Abstract 766. Presented December 7, 2019.

7. Lee DW, Santomasso BD, Locke FL, et al: ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 25:625-638, 2019.

8. Schuster SJ, Bishop MR, Tam CS, et al: Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 380:45-56, 2019.

9. Abramson JS, Palomba ML, Gordon LI, et al: Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel in relapsed/refractory large B cell lymphomas. 2019 ASH Annual Meeting & Exposition. Abstract 241. Presented December 7, 2019.

10. Bennani NN, Maurer MJ, Nastoupil LJ, et al: Experience with axicabtagene ciloleucel in patients with secondary CNS involvement: Results from the US Lymphoma CAR T Consortium. 2019 ASH Annual Meeting & Exposition. Abstract 763. Presented December 9, 2019.

11. Wang ML, Munoz J, Goy A, et al: KTE-X19, an anti-CD19 chimeric antigen receptor T cell therapy, in patients with relapsed/refractory mantle cell lymphoma: Results of the phase 2 ZUMA-2 study. 2019 ASH Annual Meeting & Exposition. Abstract 754. Presented December 9, 2019.

12. Lee DW, Gardner R, Porter DL, et al: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-195, 2014.


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