Long-Term Outcomes of Hyperbaric Oxygen Pretreatment in Autologous Hematopoietic Stem Cell Transplantation: A Pilot Clinical Trial

Introduction:

Autologous hematopoietic stem cell transplant (aHSCT) is an effective treatment for patients with multiple myeloma and lymphoma but carries a potential risk of morbidity and mortality. Improving hematopoietic stem cell homing and reducing engraftment time may improve outcomes and reduce complications in patients treated with aHSCT. Preclinical evidence has shown that when erythropoietin (EPO) binds to its EPO-receptor on infused umbilical cord blood (UCB) CD34+ stem cells, engraftment is impaired. Attenuation of this signaling with hyperbaric oxygen (HBO) is effective in improving engraftment in murine models infused with UCB CD34+ stem cells. The first clinical trial integrating HBO pretreatment in aHSCT was done at the University of Kansas Medical Center. HBO was given as 100% oxygen, 2.5 ATA for a total of 90 min, in a single treatment on Day 0, 6 hours before cell infusion. HBO therapy shortened engraftment time and decreased acute post-transplant events. The objective of this study is to evaluate overall survival (OS) and long-term outcomes for patients who received HBO prior to aHSCT.

Methods:

This was a retrospective chart review of patients at KUCC with multiple myeloma and lymphoma treated with HBO therapy prior to aHSCT through a Phase I clinical trial at KUCC from from March 2014 to December 2014. Patients were compared to a matched historical cohort treated with standard of care aHSCT at our institute. The primary outcome of our study was OS. Secondary outcomes were disease-free survival (DFS), time to neutrophil engraftment, post-transplant organ damage, development of autoimmune disease, and occurrence of secondary malignancies. Kaplan Meier curves were used to calculate OS and DFS. A t-test was used to compare the number of days of neutrophil engraftment. A chi-square test was used to evaluate and compare the incidence of organ dysfunction, secondary malignancies, and autoimmune disease between the HBO group and the historical cohort.

Results:

Of the 240 patients reviewed, 19 received HBO pretreatment and 221 did not. Median OS was not reached in the HBO pretreatment group and was 8.9 years for the historical control (p = 0.5749). Median DFS was 4.2 years in the HBO pretreatment group and 3.6 years in historical control (p = 0.34). Time to neutrophil engraftment was 6 days in HBO cohorts compared to 7 days in the historical controls (p < 0.0001). The incidence of secondary malignancies was significantly lower in the HBO pretreatment group (10.53% vs 28.05%, p = 0.0487). Rates of organ damage were reduced in the HBO cohort but did not reach statistical significance (47.37% vs 61.09%, p=0.12), as was autoimmune disease (0.0% to 7.69%, p = 0.10).

Discussion:

The administration of HBO prior to aHSCT demonstrated statistically significant decrease in engraftment time of neutrophils and in incidence of secondary malignancies compared to historical controls, both of which contribute to morbidity and mortality in patients treated with aHSCT. There was no statistical difference between OS and DFS. However, there were trends in reduction of developing long term organ damage and autoimmune diseases which may be related to decreased inflammation of HBO around time of transplant. The limitations of the study include small sample size and comparison of experimental arm to a historic cohort. These findings suggest that HBO is a well-tolerated and feasible procedure and may have a role in improving outcomes in patients receiving aHSCT. A phase 2 clinical trial utilizing HBO in aHSCT has been completed.

McGuirk:NEKTAR therapeutics: Consultancy; Novartis: Consultancy; Caribou bio: Consultancy; BMS: Consultancy; Kite: Consultancy; Allo Vir: Consultancy; Envision: Consultancy; Autolus: Consultancy; CRISPR therapeutics: Consultancy; Sana technologies: Consultancy; Legend biotech: Consultancy. Shune:BMS: Membership on an entity's Board of Directors or advisory committees; Norvatis: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Abhyankar:Incyte: Consultancy; CSL Behring, Miltenyi Biotec.: Research Funding. Abdelhakim:Iovance Biotherapeutics: Research Funding.