Protecting the epithelium and taming GVHD Free

In this issue of Blood, Schulz et al explore the use of high-dose palifermin for graft-versus-host disease (GVHD) prophylaxis in patients undergoing HLA-matched unrelated donor hematopoietic cell transplantation (HCT).¹ They found that palifermin can preserve epithelial integrity without directly modulating T-cell immunity, highlighting its potential as a novel approach for GVHD prophylaxis (see figure).

GVHD remains a significant complication following allogeneic HCT, particularly in cases involving peripheral blood stem cell grafts.² Effective GVHD prophylaxis with minimal toxicity that does not negatively impact the graft-versus-leukemia effect is crucial. Although lower doses of palifermin, a recombinant keratinocyte growth factor (KGF), have been ineffective in preventing GVHD in prior human studies,^3,4 preclinical models suggest that higher doses may be beneficial.⁵ 

This phase 1/2 trial used a dose-escalation approach (180-720 μg/kg) to establish the recommended phase 2 dose (RP2D), followed by an efficacy assessment. All patients received reduced-intensity conditioning with a combination of fludarabine and cyclophosphamide, alongside standard GVHD prophylaxis using tacrolimus, methotrexate, and sirolimus. Palifermin was generally well tolerated, with transient rash and pancreatic enzyme elevations being the primary adverse effects. The study found that none of the patients receiving the RP2D (720 μg/kg) developed grade 2 to 4 acute GVHD (aGVHD). However, the incidence of moderate to severe chronic GVHD (cGVHD) remained unchanged compared with historical controls.

The study takes an innovative approach by targeting tissue protection as a means of preventing GVHD. By promoting epithelial repair and maintaining thymic integrity, palifermin represents a unique intervention distinct from conventional T-cell-directed immunosuppressive strategies. The study followed a well-structured dose-escalation model, allowing for the determination of the RP2D while ensuring patient safety. The complete absence of grade 2 to 4 aGVHD at the RP2D is a remarkable finding. Given the severe morbidity associated with aGVHD, palifermin’s potential to mitigate this complication without excessive toxicity is promising. The study includes extensive immunophenotypic and biomarker analyses, providing valuable insights into potential mechanisms of action. The observed alterations in regulatory T cells (Tregs) and naive CD4⁺ T-cell dynamics may offer clues to the complex interplay between epithelial integrity and immune tolerance. Finally, palifermin was well tolerated, with only transient grade 3 to 4 adverse events such as rash and pancreatic enzyme elevation. Importantly, no unexpected safety signals or treatment-related mortality were reported, supporting its feasibility for broader clinical use.

This study highlighted the importance of appropriate dose and timing strategy of palifermin. Although 60 μg/kg per day for 3 consecutive days prior to conditioning and after cell infusion in autologous HCT has shown efficacy in preventing severe oral mucositis,^6,7 a multidose protocol with similar dose failed to show efficacy for GVHD prophylaxis in a phase 1/2 randomized, placebo-controlled trial.⁴ The study reported here used a different dosing strategy. The innovative high-dose “single shot” strategy might be the key to the efficacy in aGVHD prevention observed in this study. Given the median half-life of approximately 4.5 hours, the role and long-term effects of palifermin on aGVHD prevention shown in this study are intriguing.

Despite these strengths, the study suffers from some limitations. Although aGVHD prevention is a crucial advancement, the study did not demonstrate a significant reduction in cGVHD incidence. This suggests that although palifermin may modulate early inflammatory processes, additional interventions will be necessary to influence cGVHD pathogenesis. The trial enrolled a relatively small number of patients (n = 31) due to accrual challenges exacerbated by the COVID-19 pandemic. The single-center nature of the study also limits generalizability, necessitating multicenter validation in larger cohorts. The efficacy analysis relies on historical controls rather than a randomized comparator arm. Although this approach allows for preliminary assessment, randomized controlled trials are needed to confirm the observed effects. Although the study performed extensive temporal analysis on immune cell subsets, cytokine, and biomarkers to try to delineate the potential immunomodulatory mechanism involved in the prevention of GVHD by palifermin, the underlying mechanisms involved remain unclear. In 2006, Alpdogan et al demonstrated that exogenous KGF enhanced thymic epithelial regeneration following irradiation or chemotherapy, suggesting that thymic protection may be a key mechanism by which KGF prevents GVHD.⁸ However, in the current study, thymic size did not change prominently after use of palifermin. Meanwhile, Tregs, which require thymic epithelial cells for generation, decreased.⁹ These data do not support that thymus protection and immune tolerance played a central role. The authors proposed that reducing local exposure of the immune system to microbial antigens and damage-associated molecular patterns (DAMPs) might collectively contribute to aGVHD prevention (see figure). KGF administration has shown gut-protective effects in intestinal GVHD mouse models and reduced infection rates in patients undergoing high-dose chemotherapy and autologous HCT, although the reason for this reduction remains unclear.¹⁰ The potential gut-trophic effects of palifermin on intestinal GVHD in humans certainly needs exploration including changes in the microbiota and intestinal epithelial regeneration.

The safety of high-dose palifermin (720 μg/kg) is of critical concern. This study reported tolerability with manageable grade 3 to 4 adverse events. The self-limiting nature of the reported side effects (rash, pancreatic enzyme elevations) suggests short-term safety but long-term side effects, such as fertility issues or secondary cancer risk, requiring further investigation.

Given its observed safety and potential efficacy, future studies should explore palifermin in combination with posttransplant cyclophosphamide or other emerging GVHD prophylaxis regimens. Such combinations may enhance cGVHD prevention while preserving the benefits seen against aGVHD. This approach can also be applied to a broader range of transplantation scenarios, including haploidentical transplantation, allo-HCT with chemotherapy or total body irradiation-based myeloablative conditioning, and more. Finally, although the study reports favorable early outcomes, the long-term effects on relapse rates, immune reconstitution, and overall survival remain critical considerations. Future trials should incorporate extended follow-up to assess these parameters comprehensively.

In conclusion, this phase 1/2 trial provides compelling evidence that high-dose palifermin is safe and may effectively prevent aGVHD in the setting of reduced-intensity allogeneic HCT. Although it does not appear to significantly impact cGVHD incidence, its unique mechanism of action offers an attractive complement to existing prophylactic strategies. Larger, randomized studies are warranted to further validate these findings and determine optimal integration into clinical practice. Moving forward, combining palifermin with established GVHD prevention approaches may hold the key to maximizing its therapeutic potential.

Conflict-of-interest disclosure: Y.Y. reports no competing financial interests. M.M. reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma, and Jazz Pharmaceuticals; lecture honoraria from Celgene, Amgen, Bristol Myers Squibb, Takeda, and Pfizer; and grants from Roche, all outside the submitted work.