NextGen 2024: Bone Marrow Transplantation (BMT) Session Part 3

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Key Insights

Multiple approaches exist to assess immune recovery and reconstitution, and combining them can optimize outcomes.
For rare diseases, standardizing immune reconstitution evaluation after BMT is crucial for therapeutic efficacy.
Poor outcomes post-BMT in JIA patients are associated with infections, macrophage activation syndrome, and disease relapse, all linked to poor immune reconstitution.
Novel methods are needed to evaluate immune reconstitution in JIA BMT, as current methods like chimerism and flow cytometry are inadequate.
Evaluation should prioritize innate immune activity, regulatory and effector T cells, thymic function, B cells, plasma cells, and the influence of donor HLA-haplotype and phenotype.

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1. Immune Reconstitution after Bone Marrow Transplant NextGen Therapies in SJIA, Still’s & MAS Conference November 14, 2024 Jim Connelly, MD Vanderbilt University Medical Center

3. Measures of Immune Reconstitution (IR) • Immune cell phenotyping o Focus in BMT has been on T (transplanter) cells and mostly on CD4+ recovery o Advantages: Basic flow cytometry available at most centers; sorted cells can be used to evaluate split chimerism o Disadvantages: Limited ability to look at early (<D+30) IR; Advanced phenotyping (high dimensional flow cytometry, mass cytometry) expensive and less available; Quantitative recovery does not always equal functional reconstitution • Immune cell function o Advantages: Can evaluate memory response to specific antigens for decisions on viral monitoring/prophylaxis o Disadvantages: Less available at many centers; Response depends on exposure to antigen of interest

4. Measures of Immune Reconstitution (IR) •Transcriptome (gene expression through RNA analysis) o Advantages: Provides large amount of gene expression data at the single cell level; identify donor versus recipient at the single cell level o Disadvantages: Expensive (difficult to do across multiple time points); Not all inflammation is bad •Secretome (cytokines, chemokines) o Advantages: Inexpensive; Can be conducted before cellular recovery (<D+30); Certain cytokines/chemokines may be valuable for identifying primary disease activity o Disadvantages: Not all cytokines/chemokine measurements are sensitive (IL1); Certain cytokines/chemokines may be applicable to only particular diseases (IL18, CXCL9)

5. Measures of Immune Reconstitution (IR) • Chimerism (donor versus recipient) o Advantages: Predictive of relapse in malignancy and disease remission in some non-malignant disorders o Disadvantages: May not be as predictive of disease remission in immune dysregulatory disorders; Usually limited to myeloid (CD33) and T (CD3) cells • Limitations on studies to date: o Almost all analyses have been done on recipient peripheral blood with focus on T-(transplanter)-cell o Static analyses for dynamic recovery o Inability to measure donor versus recipient IR via non-genetic means o Studies conducted on large cohorts with variable disease and transplant approaches o Large IR variability complicates analysis in rare diseases with small patient numbers

6. Importance of T-cell (CD4+), B-cell Recovery Non-Relapse Mortality (NRM) and chronic (c)GVHD based on CD4+ T-cell (>57 cells/µL), B-cell (>35 cells/µL) Recovery at D+100 Troullioud Lucas et al. Cytotherapy 2023;

7. Immune Recovery in JIA Early IR (D+0-D+100): Antigen driven and homeostatic proliferation Late IR (D+100-D+365): Homeostatic proliferation (off IST) and thymic production T-cell Recovery after Pediatric BMT Segregated by Conditioning Serotherapy Lymphocyte Recovery after BMT for JIA Willemsen et al. BBMT 2015; 21:473-482 Silva et al. Blood Advances 2018; 2:7

8. Impact of Chimerism on BMT Outcomes in JIA Silva et al. Blood Advances 2018; 2:7

9. Macrophage (rheuMatologist) Cell Murine Alveolar Macrophage (AM) Recovery after Congenic BMT with Different Conditioning Regimens Hubbard et al. ExpLungRes 2008; 34(5):263-275

10. Summary of BMT and JIA BMT IR • Multiple ways to evaluate immune recovery and reconstitution and combining modalities can maximize success and minimize deficiencies of each strategy • For rare diseases, it is imperative to harmonize IR evaluation post-BMT amongst a variable patient population to assess therapeutic efficacy • Poor outcomes in patients with JIA post-BMT are highlighted by significant infectious disease, macrophage activation syndrome, and relapsed disease, all potential consequences of poor IR • For JIA BMT we need to develop novel ways to look at IR given that current methods (peripheral blood, chimerism, flow cytometry) are inadequate o Evaluation should focus on innate activity (secretome, monocyte/macrophage*), regulatory and effector T cells, thymic function, B cells and plasma cells*, and impact of donor HLA-haplotype and phenotype on outcomes *Higher resistance to conditioning therapy