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2023-03-10T10:01:25.000Z

DESCAR-T analysis: outcomes following anti-CD19 CAR T-cell failure

Mar 10, 2023
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Learning objective: After reading this article, learners will be able to cite a new clinical development in aggressive B cell lymphoma.

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Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has significantly improved therapeutic management in patients with relapsed/refractory (R/R) aggressive B-cell lymphomas, demonstrated by its efficacious responses in the JULIET, ZUMA-1, TRANSFORM trials, and real-world studies such as CIMBTR, CART consortium registry, and French, Spanish and German multi-centric studies. Despite these promising results, data from both clinical trials and real-world settings have shown that patients still experience relapsed disease/disease progression following CAR T-cell infusion; therefore, CAR T-cell failure remains a major issue that needs to be addressed.1

The Lymphoma Hub has previously reported real-world results from the DESCAR-T registry in patients with diffuse large B-cell lymphoma treated with CAR T-cell therapy. Here, we summarize an article by Di Blasi et al. on outcomes in patients with aggressive B-cell lymphomas registered in DESCAR-T who experienced disease progression/relapse disease following CAR T-cell infusion1; we also describe outcomes for the late CAR T-cell failure cohort in a similar patient subset presented by Erbella at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition.2

DESCAR-T analysis: Outcomes after CAR T-cell therapy failure1

Study design

The DESCAR-T registry (NCT04328298) includes patients who were eligible for CAR T-cell therapy for a hematologic malignancy. This multicentric analysis focused on patients with R/R aggressive B-cell lymphomas who were registered in DESCAR-T from August 2018 until the time of analysis, which was April 2021.

The primary endpoint studied was overall survival (OS)-2, defined as the period from CAR T-cell infusion failure until death or last follow-up.

Secondary endpoints included:

  • progression-free survival (PFS)-2, defined as the period of time from first progression/relapse after CAR T-cell infusion according to the Cheson 2014 response assessment criteria until next progression/relapse after further treatment;
  • baseline characteristics of patients;
  • proposed salvage treatment at failure and treatment responses; and
  • prognostic factors associated with PFS-2 and OS-2.

The day of CAR T-cell infusion was identified as Day 0 (D0). Following this, outcomes were reported according to the timing of relapse; D0–D30 (very early), D31–90 (early), and >D90 (late).

Results1

Baseline characteristics

At the time of analysis, 680 patients in total were registered with R/R aggressive BCL, 550 of whom were infused with either tisagenlecleucel (n = 350) or axicabtagene ciloleucel (n = 200). After a median follow-up of 7.9 months, 238 patients were in the CAR T- cell failure cohort, 22.7% with very early failure; 42.9% with early failure; and 34.5% with late failure. For these cohorts, the median time of failure after CAR T-cell infusion was 2.7 months. Baseline characteristics for the CAR T-cell failure cohort according to the timing of relapse are summarized in table 1.

Table 1. Selected baseline characteristics for very early, early and late CAR T-cell failure cohorts*

Characteristic, % (unless
otherwise stated)

Total
(n = 238)

Very early
(n = 54)

Early
(n = 102)

Late
(n = 82)

Age 65 years

38.2

53.7

73.5

58.5

Histology

 

 

 

 

               DLBCL NOS

74.8

66.7

80.4

73.3

               PMBL

4.6

5.6

2.0

7.3

               HGBCL

1.3

3.7

1.0

0

               Transformed FL

13

13.0

12.7

13.4

               Other

6.3

11.1

3.9

6.1

>3 lines of prior therapy

57.1

74.1

48

57.3

Prior autologous transplant

19.3

16.7

20.6

19.5

ECOG PS at registration ≥2

12.2

23.1

13.5

3.7

LDH prior to infusion > UNL

38.9

67.4

35.1

22.6

Bulky disease (>5cm)

38.7

51.6

43.6

25.5

aaIPI 2-3

57.0

15.7

7.6

1.3

Bridging therapy

87.8

90.7

87.2

86.5

Neutropenia prior to infusion
(<1 G/L)

13.5

18.8

13.0

11.1

Lymphopenia prior to infusion

99.4

100

98.6

100

Ferritin prior to infusion >UNL

84.7

88.1

85.1

81.3

Median CRP prior to infusion (range), mg/L

20(6-50)

39(0-349)

18(1-376)

12.5(0-204)

aaIPI, age-adjusted International Prognostic Index; CRP, c-reactive protein; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FL, follicular lymphoma; HGBCL, high grade B-cell; LDH, lactate dehydrogenase; NOS, not otherwise specified; PMBL, primary mediastina B-cell lymphoma; lymphoma; UNL: upper normal limit.
*Adapted from Di Blasi, et al.1
Others histologies include, 3B-FL n=2, Primary central nervous system lymphoma n=1, transformed marginal zone lymphoma n=3, unclassifiable Hodgkin/DLBCL n=l

Progression-free survival-2 and overall survival-2 outcomes

Overall, PFS-2 outcomes were poor in the CAR-T failure cohort, with 71.6% and 81.8% of patients experiencing either relapsed/progressive disease at 6 and 12 months, respectively. Similarly, OS outcomes were consistently poor over time, with an OS-2 of 47.9% and 26.9% at 6 and 12 months, respectively. By timing of failure, patients in the very early failure cohort had the worse OS-2 and PFS-2 outcomes. The median PFS-2 and OS-2 outcomes overall, and by the timing of relapse, are reported in Table 2.

Table 2. Median PFS-2 and OS-2 outcomes*

Outcomes, %

Median PFS-2

Median 0S-2

Overall

2.8

5.2

Timing of relapse

 

 

               Very early

1.7

1.9

               Early

2.6

6.1

               Late

4.2

9.6

OS, overall survival, PFS, progression-free survival.
*Data from Di Blasi, et al.1

Efficacy outcomes to salvage therapy following CART-cell failure

In total, 154 patients in the CAR T-cell failure cohort received salvage treatment. Lenalidomide, either alone or in combination, was administered to 38.3%; bispecific antibodies to 7.1%; targeted treatment to 21.4%; radiotherapy to 11%; and immuno-chemotherapy regimens to 20% of patients. In all evaluable patients (n = 120), 14.1% achieved an overall response. The median PFS-2 after bispecific antibodies, lenalidomide, targeted therapy, and immuno-chemotherapy was 3.7, 3.8, 2.1, and 2.4 months, respectively; however, a statistically significant benefit was not found between treatment types.

Prognostic factors for PFS-2 and OS-2

In multivariate analyses, there was no association found between treatment type (bispecific antibodies, lenalidomide, or targeted therapy) after CART-cell failure and PFS-2. Analysis of OS-2 showed a similar trend for bispecific antibodies or target therapy; however, a significantly better OS-2 outcome for patients receiving lenalidomide was reported. Factors significantly associated with a worse PFS-2 outcome were identified as high LDH at time of infusion (p < 0.0001) and abnormal levels of ferritin at time of infusion (p = 0.01). Additionally, prognostic factors revealed for worse OS-2 were high LDH (p = 0.01), elevated CRP levels (p = 0.003); and very early relapse (p = 0.0009).

LYSA study from DESCAR-T registry: late failure cohort2

A later DESCAR-T analysis was conducted for patients in the late CAR-T failure cohort, which was defined as relapse/progression at Month 3 or longer after CAR T-cell infusion. The study design, primary, and secondary endpoints were similar to the study above.1

Outcomes2

With a median follow-up of 12.4 months, the April 2022 analysis reported that 977 patients were treated with either tisagenlecleucel or axicabtagene ciloleucel, 145 of which corresponded to the late failure cohort; the median time to failure for this patient subset was 4.11 months. At baseline, most of these patients had DLBCL (75%) and most presented with high-risk disease at registration; this included 60% with ≥2 age-adjusted International Prognostic Index, 85% with advanced stage disease, and 51% receiving three or more prior lines of treatment.

In this late cohort, the PFS-2 outcomes were poor, with a PFS of 41.3% at 6 months and a median PFS-2 of 4.2 months. Similarly, outcomes were also poor for OS-2, with 63.2% of patients alive at 6 months and a median OS-2 of 12.1 months. Of the 124 patients who received treatment at CAR-T failure, 74 were evaluable for response and 16.1% achieved an overall response.

By treatment group, a higher overall response rate was seen for the bispecific antibody and targeted therapy groups (37.5% and 30%) compared with other systemic treatments (anti-PD1, 0%; chemotherapy, 20%; lenalidomide, 18.2%). A significantly better PFS-2 (p = 0.001) was observed in the bispecific versus chemotherapy group, with a 6-month PFS-2 of 77.5%. For 6-month OS-2, a significant benefit was observed for both the bispecific antibody and targeted therapy group at 92.9% and 76.6%, respectively.

Conclusion and future directions

Overall, the DESCAR-T registry study by Di blasi et al. revealed dismal outcomes for patients with R/R aggressive BCL who experience relapse/progression after CAR T-cell therapy; this was markedly evident in patients with very early progression. The data by treatment group showed that salvage immunotherapy with bispecific antibodies and lenalidomide at CAR T-cell failure could improve PFS outcomes in this patient subset. Longer follow up analyses are needed to evaluate the longer-term responses.

Poor prognostic outcomes were also observed in patients with late CAR T-cell failure (>3 months after CAR-T infusion) in the extended follow-up LYSA study. Analysis showed that bispecific antibodies could be an effective salvage therapy and further investigations, into the mechanisms of CAR-T-cell failure and new treatment strategies, are likely to improve outcomes for patients with late relapse/progression.

In a recent journal club webinar by the International Academy for Clinical Hematology,3 which included panelists Ali Bazarbachi, Roberta Di Blasi, and Mohamed Mohty, the article by Di Blasi et al. was discussed as well as future directions. Key topics of discussion included the identification of  predictive factors for the risk of CAR T-cell relapse according to the timing of failure (early versus late) and the use of bispecific antibodies as salvage therapy in this patient population.

  1. Di Blasi R, Gouill S L, Bachy E, et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022; 140(24):2584-2593. DOI: 1182/blood.2022016945
  2. Erbella F. Late failure of aggressive B-cell lymphoma following CAR T-cell therapy: a Lysa study from the Descar-T registry. Oral abstract #553. 64th American Society of Hematology Annual Meeting and Exposition; Dec 11, 2022; New Orleans, US.
  3. Bazarbachi A, Di Blasi R, Mohty M. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy. IACH Journal Club. https://www.youtube.com/watch?v=eZvCNCvBSUE. Jan 26, 2023.

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