Long-term outcomes of hyperbaric oxygen pretreatment in autologous hematopoietic stem cell transplantation

Autologous hematopoietic stem cell transplantation (aHSCT) is an effective treatment for hematologic malignancies. Hyperbaric oxygen (HBO) pretreatment has demonstrated safety and feasibility, improved neutrophil engraftment, and reduced mucositis in patients undergoing aHSCT. This was a retrospective review comparing 19 patients who completed HBO therapy prior to aHSCT with a 225-patient historical control cohort. Median overall survival was not reached in the HBO cohort and was 9 years in the historical control cohort (p = 0.59). Median relapse-free survival was 4.2 years in the HBO cohort and 3.7 years in the historical cohort (p = 0.34). The HBO cohort had a lower cumulative incidence of non-relapse mortality, although the difference was not statistically significant (p = 0.057). Excluding non-melanoma skin cancers, the incidence of secondary malignancy was reduced in the HBO cohort (5.26% vs. 22.07%, p = 0.074). Rates of organ damage were reduced in the HBO cohort but did not reach statistical significance (47.4% vs. 61.3%, p = 0.12). Rates of cardiac (5.3% vs. 23.9%; p = 0.046) and renal (15.8% vs. 42.8%; p = 0.016) organ damage were significantly reduced in the HBO cohort. There was less autoimmune disease observed in the HBO cohort compared with the historical control cohort (0.0% vs. 7.69%; p = 0.14). Overall, HBO therapy before aHSCT showed trends toward lower non-relapse mortality and a lower incidence of secondary malignancy. The incidence of cardiac and renal damage was significantly reduced. These findings indicate that HBO is well tolerated and may improve outcomes in patients undergoing aHSCT.

Introduction

Autologous hematopoietic stem cell transplantation (aHSCT) has proven to be an effective therapeutic option for patients with lymphoma and multiple myeloma. In the setting of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL), aHSCT improves overall survival (OS) and progression-free survival (PFS) and is a curative therapy for a substantial group of patients with relapsed or refractory disease (1–5). Although not curative in patients diagnosed with multiple myeloma (MM), aHSCT has been demonstrated to have a significant impact on event-free survival and serves as a consolidative therapy that achieves durable remissions for most patients, even in the era of chimeric antigen receptor T cells (CAR-T) (6–9). In the United States, approximately 12,000 patients receive aHSCT each year for hematological malignancies (10, 11).

While aHSCT has proven to be effective, it is associated with a significant side effect profile due to the intense high-dose chemotherapy conditioning administered before stem cell infusion. Patients often experience pancytopenia lasting days to weeks, leading to infectious and non-infectious complications (12, 13). The most common complication in patients undergoing aHSCT is infection, usually bacterial, and is related to neutropenia and mucosal damage (12–14). Antibiotics are typically used to prevent and treat infections in aHSCT patients; however, despite this treatment, infections related to neutropenia remain a common cause of early mortality in patients undergoing aHSCT (12, 13, 15). The use of granulocyte colony-stimulating factors (G-CSF) can improve neutrophil counts and reduce the risk of infection, but its use has not been shown to improve mortality rates (12). Among non-infectious complications, cytopenias, including thrombocytopenia and anemia, are frequently observed in patients (14, 16). With severe anemia and thrombocytopenia, patients are at risk for hemorrhagic complications, and most patients require transfusion support after aHSCT (17, 18). Transfusion support remains the standard treatment for these conditions; however, transfusion support is associated with adverse health effects, high cost, and a significant logistical burden (16, 17). In addition, organ damage, including heart failure, acute kidney injury (AKI), chronic kidney disease (CKD), and autoimmune disease, are all possible complications that contribute to the morbidity and mortality associated with aHSCT (19–21). Collectively, these complications contribute to the high cost of aHSCT, estimated at US$200,000, which places a substantial financial burden on patients and the healthcare system (22). Because of these side effects, transplant patients often require close monitoring, frequent and prolonged hospitalizations, and concurrent supportive therapies. Improved pretreatment strategies are needed to reduce the burden of complications for patients undergoing aHSCT.

Previously, our group demonstrated that erythropoietin (EPO) plays a role in the homing and engraftment of infused hematopoietic stem cells by binding to its EPO receptor (EPO-R) on cluster of differentiation (CD)34+ cells (23, 24). Inhibiting EPO-R expression or reducing EPO levels via hyperbaric oxygen (HBO) pretreatment can lead to improved stem cell engraftment (24). A pilot clinical trial of HBO therapy at our center for patients undergoing aHSCT demonstrated that HBO was well tolerated, and patients treated with HBO had a lower incidence of mucositis and required fewer growth factor injections (25). Herein, we present the long-term outcomes of patients who underwent aHSCT after HBO therapy in this pilot clinical trial, including overall survival, relapse-free survival, non-relapse mortality, and long-term aHSCT-associated toxicities, as well as the incidence of secondary malignancies, autoimmune disease, and organ damage.

Methods

Patients

This was a retrospective chart review of patients with multiple myeloma and lymphoma treated with hyperbaric oxygen (HBO) therapy before autologous hematopoietic stem cell transplantation (aHSCT) through a Phase I clinical trial at the University of Kansas Cancer Center from March 2014 to December 2014.

Patient eligibility criteria were reported previously (25). In brief, patients were eligible if they were 18–70 years old with non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), or multiple myeloma and were eligible for aHSCT. Inclusion criteria included a Karnofsky performance status ≥ 70% and adequate hepatic, renal, pulmonary, and cardiac function. Patients were excluded if they were pregnant or breastfeeding, had severe chronic obstructive pulmonary disease (COPD) requiring oxygen, had a history of spontaneous pneumothorax, or had certain other conditions that could increase the risk of HBO complications, such as prior ear surgeries. Only 19 patients who completed HBO treatment were included in this analysis after excluding one patient who started HBO but stopped after 14 minutes due to ear discomfort (Figure 1). Patients who received HBO were compared with a matched historical cohort of patients treated with standard-of-care aHSCT at our center. Matching was based on age category (10-year increments), sex, disease group (multiple myeloma vs. lymphoma), and conditioning regimen. The Mann–Whitney test was used for age, the chi-square test for sex, and Fisher’s exact test for diagnosis, disease status, and conditioning regimen.

Figure 1

Figure 1. Consolidated standards of reporting trials (CONSORT) diagram.

Treatment

Patients received standard conditioning myeloablative chemotherapy at the physician’s discretion, either high-dose melphalan; carmustine, etoposide, cytarabine, and cyclophosphamide; or carmustine, etoposide, cytarabine, and melphalan. HBO was delivered at 2.5 atmospheres absolute for 90 minutes as a single treatment, with patients breathing 100% supplemental O₂ in a monoplace hyperbaric chamber (Model 3200/3200R; Sechrist Industries, Anaheim, CA, USA). HBO therapy was completed 6 h before hematopoietic stem cell infusion, as previously described (24, 25).

Endpoints

The primary endpoints of the original pilot trial were safety and feasibility of HBO therapy. Secondary endpoints included the effect of HBO on engraftment, transfusion requirements, growth factor use, neutropenic fever, mucositis, and day +100 disease response. In the current study, we report long-term outcomes, including overall survival and relapse-free survival. We also evaluated the incidence of organ damage and the occurrence of secondary malignancies as captured via chart review, which are known long-term side effects in post-aHSCT patients. The definitions used to capture cardiac and renal organ damage are listed in Table 1. The incidence of autoimmune disease was obtained from chart review and was defined as any condition not present prior to transplant and potentially attributable to immune dysregulation. Conditions included (but were not limited to) vasculitis, thyroiditis, immune thrombocytopenic purpura, polymyalgia rheumatica, and antiphospholipid syndrome.

Table 1

Table 1. Definitions of organ damage.

Statistical analysis

A t-test was used to compare the number of days to neutrophil engraftment. Fisher’s exact 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. Historical cohorts received aHSCT between January 2008 and December 2012. Survival curves for overall survival (OS) and relapse-free survival (RFS) were estimated using Kaplan–Meier methods, and group differences were evaluated using a two-sided log-rank test implemented in Python NumPy and SciPy libraries. For non-relapse mortality (NRM) in the presence of the competing risk of relapse or progression, the Fine–Gray cumulative incidence estimator was used, and Gray’s weighted log-rank test was performed. All competing-risk analyses were conducted using the Python scikit-survival package.

Results

Patient characteristics

A total of 244 patients were reviewed; 19 completed HBO pretreatment and 225 did not (Figure 1). Patient characteristics of both cohorts are reported in Table 2. The median age of patients was 63 years in the HBO-treated group and 61 years in the historical cohort. There were 9 (47%) males in the HBO cohort and 148 (66%) males in the historical cohort. In the HBO-treated cohort, 2 (10.5%) patients had HD, 9 (47.4%) had multiple myeloma, and 8 (42.1%) had NHL, compared with 15 (6.7%) patients with HD, 148 (65.8%) with multiple myeloma, and 62 (27.6%) with NHL in the historical cohort. The most common conditioning chemotherapy regimen used was high-dose melphalan, administered to 9 (47.4%) patients in the HBO cohort and 148 (65.8%) patients in the historical control cohort. Disease status at transplant was first complete remission in 6 patients (31.5%) in the HBO cohort and 63 patients (28%) in the historical cohort. There was no difference in median CD34⁺ cell dose/kg between the two cohorts.

Table 2

Table 2. Patient characteristics.

100 days outcomes

All 19 patients tolerated HBO therapy and were able to complete the planned treatment. The median time to neutrophil engraftment was 10 days (8–13) in the HBO cohort compared with 11 days (8–17) in the historical control cohort (p = 0.003). The median time to platelet count recovery was 16 days (14–21) for the HBO cohort versus 18 days (11–86) for the historical control cohort (p < 0.0001). There was a lower incidence of mucositis in the HBO cohort, 26.3% (5/19), compared with 64.2% (138/225) in the historical control cohort (p = 0.002). There was no significant difference between the two cohorts in transfusion burden (measured by the number of packed RBC or platelet units transfused) or in the incidence of neutropenic fever (Table 3).

Table 3

Table 3. Summary of post-transplant outcomes in secondary analyses.

Long term outcomes

After a median follow-up of 11.4 years (6–14), the median overall survival was not reached (0.29–10.1 years) in the HBO pretreatment group and was 9 years (0.05–16.3) in the historical control cohort, with no statistically significant difference (p = 0.59; Figure 2A). Median relapse-free survival was 4.2 years (0.24–9.9) in the HBO pretreatment group and 3.7 years (0.05–14.8) in the historical control cohort (p = 0.34; Figure 2B). A total of 52.6% (10/19) of patients in the HBO cohort were alive at last follow-up compared with 40% (90/225) in the historical cohort. Among patients with multiple myeloma, 66.6% (6/9) in the HBO cohort were alive compared with 30.4% (54/148) in the historical cohort. The HBO group showed a lower cumulative incidence of non-relapse mortality compared with the historical control cohort, although this did not reach statistical significance (p = 0.057; Figure 2C).

Figure 2

Figure 2. Overall survival, relapse-free survival, and non-relapse mortality. (A) The Kaplan–Meier curve for Overall Survival (Figure 2A) shows that the median survival was 9 years for the historical control group, but was not reached in the HBO group (p = 0.59). (B) shows the Kaplan–Meier analysis for Relapse-Free Survival, with a median of 4.2 years in the HBO cohort and 3.7 years in the control cohort (p = 0.34). (C) The cumulative incidence of non-relapse mortality (NRM) calculated by Fine–Gray’s test competing risk (p = 0.057).

To further investigate potential contributors to this reduction in non-relapse mortality, we reviewed the incidence of secondary malignancies. Throughout the follow-up period, excluding non-melanoma skin cancers, results were suggestive of a lower incidence of secondary malignancies in the HBO cohort (5.26% vs. 22.07%, p = 0.074; Figure 3A). One patient in the HBO cohort developed a secondary malignancy, which was hematological, compared with 49 cases in the historical control group (out of 222 patients with data available), of which 38.0% were hematological, 54.0% were non-skin solid tumors, and 8.0% were melanoma.

Figure 3

Figure 3. Long-term complications post aHSCT. (A) The rate of secondary malignancies, excluding non-melanoma skin cancers (NMSC), was (5.26%) in the HBO group compared to (22.62%) historical controls (p= 0.074). The incidence of malignancy was divided into hematologic (5.26% vs 8.56%) and solid (0.00% vs 13.51%) in the HBO and historic controls cohort, respectively. (B) The rate of cardiac damage (5.26% vs 23.9%, p = 0.03) and renal damage (15.7% vs 43.0%, p = 0.01) in the HBO and historic controls cohort, respectively.

Rates of organ damage were lower in the HBO cohort than in the historical control cohort but did not reach statistical significance (47.4% vs. 61.3%, p = 0.12). We further evaluated rates of organ-specific effects between the two cohorts. Rates of cardiac (5.3% vs. 23.9%; p = 0.046) and renal (15.8% vs. 42.8%; p = 0.016) organ damage were reduced in the HBO cohort compared with the historical control cohort (Figure 3B). Interestingly, the development of autoimmune disease after aHSCT was lower in the HBO group compared with the historical control cohort (0.0% vs. 7.69%, p = 0.14).

Discussion

Here, we report a long-term analysis of patients who received HBO therapy in a pilot clinical trial while undergoing aHSCT compared with a historical control cohort. This single 90-minute exposure to hyperbaric oxygen, delivered 6 h before autologous hematopoietic stem cell infusion, may confer durable biologic benefits that extend well beyond the initial engraftment window. Autologous hematopoietic stem cell transplantation is a widely used and effective therapy for patients with multiple myeloma and is curative for a subset of patients with Hodgkin lymphoma and non-Hodgkin lymphoma (1–6). However, aHSCT is associated with significant early and late complications. Early complications include severe pancytopenia, which increases the risk of infectious and bleeding events, as well as conditioning-related organ toxicities associated with hospitalization and increased costs to patients and the healthcare system (26, 27). Late adverse effects include secondary malignancies and organ damage, particularly cardiovascular and renal disease (28, 29). These clinical and economic pressures underscore the need for low-cost, easily deployable adjunctive therapies that can hasten hematopoietic recovery and mitigate late complications without introducing new toxicities.

Our group has previously shown that transient hyperoxia downregulates EPO receptor expression on CD34+ cells, likely facilitating improved stem cell homing and engraftment alongside the establishment of a favorable niche for stem cell survival, proliferation, and differentiation (23–25). In the present study, early post-transplant HBO therapy was associated with expedited neutrophil and platelet engraftment and a lower incidence of mucositis. In contrast, there was no difference in the incidence of neutropenic fever or transfusion burden between the HBO cohort and the historical control cohort. With a median follow-up approaching 14 years, we observed no difference between cohorts in overall survival or relapse-free survival; however, we identified a trend toward reduced non-relapse mortality in the HBO group (p = 0.057). This finding was supported by a lower incidence of secondary malignancies, a well-recognized late effect of aHSCT (30–32). After excluding non-melanoma skin cancers, HBO recipients demonstrated a numerically lower incidence of secondary malignancies (5.26% vs. 22.62%, p = 0.074). In addition, the incidence of cardiac and renal events was significantly lower in the HBO cohort.

These findings are particularly encouraging in light of a multicenter Phase II randomized trial in patients with multiple myeloma, which provides mechanistic support for our observations. In that trial, patients in the HBO arm demonstrated accelerated lymphocyte recovery, improved T-cell reconstitution, and enhanced natural killer cell recovery after transplant (33).

Furthermore, a case series offers additional clinical insight into the potential immunomodulatory effects of HBO therapy in the transplant setting. Among 34 patients who received HBO therapy before transplantation, three developed transient lymphocytosis in the absence of infection or relapse, with two achieving durable remission (34). This benign immune expansion may reflect accelerated lymphocyte and NK-cell recovery, consistent with findings from the Phase II randomized trial. Faster immune reconstitution, particularly among lymphocyte subpopulations, may play a critical role in reducing mucositis, infectious complications, and chronic inflammatory injury after transplant (35–38). In addition, the role of HBO therapy before allogeneic umbilical cord transplantation has been investigated, with encouraging positive effects on transplant outcomes (24). Further studies are being planned in the allogeneic transplant setting using different donor sources to evaluate the impact of HBO on graft-versus-host disease and graft-versus-leukemia effects.

This study has limitations, including its single-center design, non-randomized allocation with comparison to a historical cohort, and the small sample size of the HBO group. Although the limited sample size warrants caution, we observed promising signals of benefit, including improved early engraftment, reduced mucositis, and potential late protective effects against organ toxicity and secondary malignancies. These effects are mechanistically plausible, as exposure to HBO, modulation of EPO signaling, and enhanced immune reconstitution at a critical juncture may protect against chemotherapy-induced tissue injury and mitigate chronic inflammation thought to drive cardiac and renal damage, as well as oncogenic processes years after transplant.

Despite these limitations, the consistency of benefit across multiple early and late endpoints and the biologic plausibility of the proposed mechanisms justify further investigation. This pilot study demonstrates that a single pre-infusion HBO session is safe, feasible, and associated with faster engraftment, reduced mucositis, and encouraging trends toward durable reductions in organ toxicity and secondary malignancies. Prospective multicenter trials powered to detect clinically meaningful reductions in non-relapse mortality and major organ toxicity are warranted to definitively evaluate this inexpensive adjunctive intervention and improve the long-term safety of autologous transplantation.

In conclusion, this pilot clinical trial is limited by the small size of the HBO cohort, which restricts statistical power and the strength of inferences that can be drawn. The study was intended as a hypothesis-generating analysis rather than to establish definitive causality.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Institutional Review Board - University of Kansas Medical Center. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

VL: Writing – review & editing, Writing – original draft. MO: Writing – original draft, Writing – review & editing. AbA: Writing – review & editing, Writing – original draft. LS: Writing – original draft, Writing – review & editing. SA: Writing – review & editing, Writing – original draft. AnS: Writing – review & editing, Writing – original draft. DA: Writing – original draft, Writing – review & editing. BA: Writing – review & editing, Writing – original draft. JM: Writing – review & editing, Writing – original draft. OA: Writing – review & editing, Writing – original draft. HA: Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Acknowledgments

We acknowledge the patients and their family who participated in the clinical trial.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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