Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma.

in HemaSphere by Sophia Stock, Veit L Bücklein, Viktoria Blumenberg, Giulia Magno, Alica-Joana Emhardt, Alessandra M E Holzem, David M Cordas Dos Santos, Christian Schmidt, Stefanie Grießhammer, Lisa Frölich, Sebastian Kobold, Michael von Bergwelt-Baildon, Kai Rejeski, Marion Subklewe

TLDR

  • The study found that immune recovery after CD19 CAR-T therapy is associated with improved progression-free survival and overall survival in B-NHL patients, but IR impairment is common, especially postprogression.
  • Product-specific differences in IR patterns emerged, and patients with refractory disease had limited IR recovery.

Abstract

Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4T helper (T) cells > 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels >4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed Tcells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper Tcell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months,< 0.0001) and overall survival (OS) (34.9 vs. 4.0 months,< 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months,= 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.

Overview

  • The study aimed to assess patterns of immune recovery (IR) in 105 B-cell non-Hodgkin lymphoma (B-NHL) patients after CD19 chimeric antigen receptor (CAR-T) therapy.
  • The study used a retrospective observational design, characterized by longitudinal assessment of lymphocyte subsets and immunoglobulin levels.
  • The primary objective was to examine the prognostic impact of immune reconstitution on patient outcomes, including progression-free survival (PFS) and overall survival (OS).

Comparative Analysis & Findings

  • Patients with any IR recovery experienced extended PFS (median 20.8 vs. 1.7 months) and OS (34.9 vs. 4.0 months) compared to those without recovery.
  • Notable product-specific differences emerged, including deeper T-cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products.
  • Patients with refractory disease were less likely to display any IR recovery (72%), and those who progressed or relapsed early showed diminished IR at the time of progression/relapse compared to late progression/recurrence.

Implications and Future Directions

  • The study highlights the profound immune deficits observed after CD19 CAR-T and sheds light on the intersection of IR and efficacy in B-NHL.
  • IR impairment postprogression carries significant implications for subsequent T-cell-engaging therapies and treatment sequencing.
  • Future studies should investigate novel strategies to enhance IR and improve patient outcomes, particularly for patients with refractory disease.
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