Hyperbaric Oxygen Decreases Clinical Features Associated with Engraftment Syndrome in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Engraftment syndrome (ES) is a complication of hematopoietic stem cell transplantation (HSCT) commonly presenting as fever, skin rash, and diarrhea mediated by the elevation of pro-inflammatory cytokines, including interleukin-6 (IL-6) (Spitzer 2001; Maiolino et al. 2003; Khandelwal et al. 2016).At our institution, we are conducting phase I-II clinical trials investigating the effect of hyperbaric oxygen (HBO) in patients undergoing autologous HSCT for multiple myeloma. HBO can decrease the production of pro-inflammatory cytokines (Benson et al. 2003; Kudchodkar et al. 2008) and could therefore theoretically reduce the incidence and severity of ES.In this retrospective analysis, we investigate the impact of HBO on the frequency and severity of ES and serum levels of IL-6. Since ES manifestations include diarrhea, which overlaps with gastrointestinal (GI) mucositis, we evaluated oral and GI mucositis.Methods: Patient data was collected from day +5 to +15 of HSCT. Patients were placed in three cohorts, those who did not undergo HBO (n-HBO), received a single treatment of HBO (s-HBO) and received multiple treatments of HBO (m-HBO). Patients in the n-HBO and s-HBO cohorts were enrolled in the completed phase II clinical trial (NCT03398200). Patients in the m-HBO cohort were enrolled in the ongoing phase I study (NCT04862676) (Figure 1). Grading of oral and GI mucositis was based on the common terminology criteria for adverse events. Enzyme-linked immunosorbent assay for IL-6 was performed from patient plasma samples collected on day +1, +3, +7, and +15 of transplant.Results: A total of 86 patients were included in the study. Any grade oral mucositis incidence was 42.4%, 28.6%, and 0% for n-HBO, s-HBO, and m-HBO, respectively (p=0.03) (Figure 2). There was insufficient evidence of a difference in the incidence of GI mucositis between cohorts. The incidence of ES, meeting either the Spitzer or Maiolino Criteria, for the n-HBO, s-HBO, and m-HBO cohorts was 27% (95% confidence interval (CI) 13.8%-44.1%), 21.1% (95% CI 9.6%-37.3%), and 20.0% (95% CI 2.5%-55.6%), respectively (p=0.88). The median number of days with fever for n-HBO, s-HBO, and m-HBO was 1 day (Interquartile range (IQR) 0-2), 1 day (IQR 0-2) and 0 days (IQR 0-1), respectively (p=0.06). Pairwise comparisons using mixed models of IL-6 concentration on day +7 of transplant for m-HBO vs. s-HBO, m-HBO vs. n-HBO, and s-HBO vs. n-HBO resulted in p-values 0.13, 0.11, and 0.85, respectively (Figure 3).Conclusion: In this retrospective study of clinical trial patients, we have shown a statistically significant decrease in the incidence of oral mucositis in patients receiving m-HBO therapy. Additionally, there was a trend towards less ES, less fever and lower concentrations IL-6 with increasing HBO treatments, a trend which may become significant with a larger sample size.