Abstract
Autologous stem cell transplantation (ASCT) in hematological malignancies remains an important therapy for eligible patients with multiple myeloma (MM) and non-Hodgkin and Hodgkin lymphomas (NHL and HD). Favorable clinical outcomes of ASCT correlate with robust immune reconstitution, including recovery of the absolute lymphocyte count on days 15 (D15) and 30 (D30) post-ASCT, as well as lymphocyte subsets like CD8 effector T cells and NK cells (1). The graft content of lymphocytes and lymphocyte subsets has also been found to be a predictor of immune recovery and clinical outcomes after ASCT (2).
Previous studies have shown that anti-CD38 monoclonal antibodies lead to: a) T cell expansion, b) expansion and activation of effector T cells, c) reduction in the number and activity of immunosuppressive cells such as T and B regulatory cells, and myeloid-derived suppressor cells (MDSCs) (3). Based on these observations, we hypothesized that administration of an anti-CD38 antibody (Isatuximab) during both the pre-stem cell collection period and post-ASCT period would lead to improved immune recovery after ASCT. To test this hypothesis, we conducted a prospective randomized phase 2 clinical trial.
Patients planned to undergo ASCT for MM, NHL, HD were enrolled in the clinical trial (NCT05346809). Patients undergoing their first ASCT were eligible, and those with prior exposure to CD38 antibody were excluded. After enrollment, patients were randomized to the Isatuximab (Isa) or control arm in a 2:1 ratio. Patients in the control arm underwent standard stem cell collection and transplant procedures. Patients in the Isa arm received two weekly doses of IV Isatuximab (10 mg/kg) prior to initiating G-CSF for stem cell collection, followed by 3 additional doses on D15, D22, and D30 post-ASCT.
Our primary endpoint was the D30 absolute lymphocyte count, with the hypothesis that patients in the Isa arm would experience a 20% increase (with a pooled standard deviation of 20%) in the mean total lymphocyte count on D30 compared to the control group. A total of 39 patients were planned for enrollment. Detailed immunophenotyping of the apheresis product and peripheral blood at D30, D60, D90, D180, and 1 year post-ASCT in both arms was performed using full-spectral flow cytometry.
To date, a total of 8 patients (5 males) been enrolled and treated and their data are presented here. The median age of patients is 68 years (range: 31–74). Five patients had MM, and three patients had NHL. Four patients have been enrolled in each arm, received all doses of Isa, and have finished one year of follow-up. Patients tolerated the therapy well, and no adverse effects were attributed to Isatuximab. All enrolled patients underwent successful stem cell collection and ASCT.
Preliminary results comparing the two arms show a trend towards improved D30 absolute lymphocyte count in the Isa arm compared to the control arm (median ALC 2.6 vs. 1.1 x 10³/µL, P=0.1).
Multi-color flow cytometry analysis of the apheresis products revealed significant differences between Isa-treated patients and controls. Isa treatment reduced NK cell frequency, consistent with CD38-directed depletion. Concurrently, Isa shifted the phenotype of both classical and non-classical monocytes toward MHC-II-high and CD38-neg cells, consistent with fit but quiescent cells. Isa also promoted a more naïve (CD45RA+) and CD38-neg CD8+ T cells in the product.
Favorable immunomodulatory effects were also demonstrated at D90 in peripheral blood in the Isa arm, which showed a shift toward a more differentiated monocyte phenotype (CD49f+). Increased expansion of both CD4⁺ and CD8⁺ lymphocytes in the Isa arm. Isa treatment promoted activation and effector differentiation of CD8⁺ T cells, with reduced exhaustion markers and stem-like traits
Use of Isatuximab in the pre-stem cell collection and immediate post ASCT period leads to favorable changes in the immune repertoire of both the stem cell product and peripheral blood at short-term recovery from ASCT. Further study of this approach is warranted in patients undergoing ASCT.
