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Blinatumomab prior to CD19 CAR T-cell therapy for the treatment of relapse/refractory ALL

Feb 17, 2021
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Regulatory agencies in Europe and the United States have approved two agents that target CD19 for the treatment of relapsed/refractory acute lymphoblastic leukemia in children and young adults: blinatumomab and anti-CD19 chimeric antigen receptor (CAR) T-cell tisagenlecleucel. It is known that both agents are associated with CD19 loss or downregulation. However, certain patients may receive both during the course of their treatments. Therefore, there is a high need to understand whether these treatments can be sequenced without inducing the development of resistance to CD19 targeting.

During 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Nirali Shah presented a talk on the impact on event-free survival (EFS) of using blinatumomab before CAR T-cell therapy.

Study design and patient baseline characteristics

  • This retrospective study included 420 patients, and the primary objectives were EFS and relapse-free survival (RFS) at 6 months following CD19 CAR infusion.
  • The secondary objectives were EFS and RFS at 12 months, as well as to evaluate any changes in CD19 expression.
  • Patients who were included were ≤ 25 years at time of diagnosis. The median age at infusion was 12.4 years (interquartile range [IQR], 7–17.1 years), with a median follow-up following infusion of 2.3 years (IQR, 1.6–3.3 years).
  • Out of the patients included in this study, 17.9% had previous exposure to blinatumomab and 57.3% achieved a complete response (CR). The median time to last blinatumomab infusion was 129 days (IQR, 79–304 days).
  • Of the three different CAR T-cell constructs used, ~20% of patients received commercial tisagenlecleucel.
  • Statistical assessment was carried out for all groups shown in Table 1, but a significant difference was only found between the group treated with blinatumomab and the blinatumomab-naïve patients for KMT2Ar prevalence (p = 0.03).

Table 1. Baseline patient characteristics1

Blina, blinatumomab; CAR, chimeric antigen receptor; CNS3, central nervous system status 3; EM, extramedullary; MRD, measurable residual disease.

Pre-CAR disease status

All (N = 420)

Prior blina (n = 75)

No blina (n = 345)

M1 or MRD-negative marrow, %

51.6

53.3

51.3

M2/M3 marrow, %

48.3

46.6

48.7

CNS3, %

1.1

0.0

1.2

Active EM disease, %

5.2

8.0

4.6

Circulating blasts, %

15.9

18.7

15.3

KMT2Ar, %

17.0

14.7

6.7

Key points

  • A total of 412 patients were available for evaluation of the response to CAR T-cells. Of these patients, 91% achieved CR (Table 2) and 88.1% were measurable residual disease-negative.
  • At the time of analysis, 234 patients remained alive and in CR, and the relapse rate was 39.8%.
  • Following CD19 CAR T-cell therapy, patients who had received blinatumomab previously were more likely to have residual disease.
  • Of the patients that had received blinatumomab previously, 18.3% were non-responders, compared with only 7% in the group that had not received blinatumomab previously.

Table 2. Response to anti-CD19 CAR T-cell therapy1

Blina, blinatumomab; CAR, chimeric antigen receptor; CR, complete response.

Previous therapy

CD19 CAR T-cell therapy response

CR

Non-CR

Total

Blina, %

14

3

17

No blina, %

77

6

83

Total (N = 412), %

91

9

100

  • Outcome was significantly worse in the blinatumomab group for both RFS (p = 0.027) and EFS (p = 0.0034) compared with patients without previous exposure.
  • The median RFS for the group exposed to blinatumomab was 20.3 months vs 44.9 months in the patients that had not received blinatumomab treatment previously, as shown in Table 3.

Table 3. RFS and EFS at 6 and 12 months1

Blina, blinatumomab; EFS, event-free survival; NE, not estimable; RFS, relapse-free survival.

Previous therapy

6-month RFS, %
(95% CI)

12-month RFS, %
(95% CI)

Median RFS, months
(95% CI)

6-month EFS, %
(95% CI)

12-month EFS, %
(95% CI)

Median EFS, months
(95% CI)

Blina

63.4
(49.6−74.4)

57.5
(43.4−69.2)

20.3
(5.85−34.4)

49.7
(37.8−60.5)

46.7
(34.9−57.6)

5.8
(3.9−20.3)

No blina

81.1
(76.3−85.0)

69.2
(63.7−74.1)

44.9
(28.4−NE)

72.1
(67.1−76.6)

59.6
(54.1−64.6)

22.6
(15.8−38.7)

  • Prior to CD19 CAR T-cell infusion in the blinatumomab group, 13% of patients had either negative, dim, or partial CD19 expression. In the group that had not received prior blinatumomab, the incidence was only 6.2%.
  • When CD19 expression was examined before and after blinatumomab treatment, 11.5% of patients were found to have switched to dim CD19 expression.

Conclusion

This study found that treatment with blinatumomab before CD19 CAR T-cell infusion was associated with significantly poorer outcomes in terms of RFS and EFS. Leukemic blast cells of patients who had been treated with blinatumomab showed more frequently a dim or no expression of CD19 antigens prior to CAR T-cell infusion and patients were at increased risk of not responding to CD19 CAR T-cell therapy.

The authors suggested that future studies should investigate whether there is an inherent risk for resistance to CD19 targeting in patients relapsing after blinatumomab and whether patients with prior blinatumomab might benefit from consolidation with hematopoietic stem cell transplantation.

  1. Taraseviciute A, Steinberg SM, Myers RM, et al. Pre-CAR blinatumomab is associated with increased post-CD19 CAR relapse and decreased event free survival. 2020;136(Supplement 1):13-14. DOI: 10.1182/blood-2020-139260

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