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Front Immunol. 2023 Dec 11:14:1283034.
doi: 10.3389/fimmu.2023.1283034. eCollection 2023.

ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party

Olaf Penack 1 2 , Christophe Peczynski 2 3 , William Boreland 2 3 , Jessica Lemaitre 2 3 , Ksenia Afanasyeva 4 , Brian Kornblit 5 , Manuel Jurado 6 , Carmen Martinez 7 , Annalisa Natale 8 , Jose Antonio Pérez-Simón 9 , Lucia Brunello 10 , Daniele Avenoso 11 , Stefan Klein 12 , Zubeyde Nur Ozkurt 13 , Concha Herrera 14 , Stina Wichert 15 , Patrizia Chiusolo 16 , Eleni Gavriilaki 17 , Grzegorz W Basak 2 18 , Hélène Schoemans 2 19 , Christian Koenecke 2 20 , Ivan Moiseev 4 , Zinaida Peric 2 21

Affiliations

  • 1 Medical Clinic, Department for Haematology, Oncology and Tumorimmunology, Charité Universitätsmedizin Berlin, Berlin, Germany.

  • 2 EBMT Transplant Complications Working Party, Paris, France.

  • 3 EBMT Paris Study Office, Department of Haematology, Saint Antoine Hospital, INSERM UMR-S 938, Sorbonne University, Paris, France.

  • 4 Department of Haematology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.

  • 5 Department of Haematology, Rigshospitalet, Copenhagen, Denmark.

  • 6 Department of Haematology, Hospital Universitario Virgen de las Nieves, Granada, Spain.

  • 7 Department of Hematology, Hospital Clínic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.

  • 8 Department of Haematology, Ospedale Civile, Pescara, Italy.

  • 9 Department of Hematology, University Hospital Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain.

  • 10 Department of Haematology, SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy.

  • 11 Department of Haematology, Kings' College Hospital, London, United Kingdom.

  • 12 Department of Haematology, Universitaetsmedizin, Mannheim, Germany.

  • 13 Department of Haematology, Gazi University Faculty of Medicine, Ankara, Türkiye.

  • 14 Servicio de Hematología Hospital Universitario Reina Sofía, IMIBIC, University of Cordoba, Cordoba, Spain.

  • 15 Department of Haematology, Skane University Hospital, Lund, Sweden.

  • 16 Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore-Roma, Rome, Italy.

  • 17 Department of Haematology, Papanicolaou G. Hospital, Thessaloniki, Greece.

  • 18 Department of Hematology, Oncology and Internal Medicine, The Medical University of Warsaw, Warsaw, Poland.

  • 19 Department of Hematology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.

  • 20 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

  • 21 Department of Haematology, University Hospital Centre Zagreb, Zagreb, Croatia.

  • PMID: 38149251

  • PMCID: PMC10750400

  • DOI: 10.3389/fimmu.2023.1283034

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) stands as a vital, often curative, therapeutic option for numerous hematologic malignancies and non-malignant conditions. Despite its potential, a significant and frequently severe complication arising after this procedure is Graft-versus-Host Disease (GVHD). This complex immune-mediated disorder occurs when donor immune cells recognize and attack the recipient’s tissues, leading to widespread inflammation and organ damage. Acute GVHD (aGVHD) typically manifests within the first 100 days post-transplant, presenting a spectrum of severity from mild to life-threatening.

While corticosteroids serve as the initial standard of care for aGVHD, a substantial proportion of patients do not respond adequately to this first-line treatment or develop a dependency on steroids. This condition, known as steroid-refractory or steroid-dependent acute GVHD (SR-aGVHD), represents a major clinical challenge. SR-aGVHD is intrinsically linked to heightened morbidity and mortality rates, underscoring the urgent need for effective alternative or salvage therapies. Identifying optimal treatment strategies for these patients is paramount to improving overall post-transplant outcomes and quality of life.

For many years, extracorporeal photopheresis (ECP) has been an established immunomodulatory therapy utilized in the management of both steroid-refractory and steroid-dependent acute GVHD. The mechanism involves collecting a patient's peripheral blood mononuclear cells, treating them with a photosensitizing agent (8-methoxypsoralen), exposing them to ultraviolet A light, and subsequently reinfusing them back into the patient. This process is thought to induce regulatory T cells and dampen aberrant immune responses, thereby promoting immune tolerance and mitigating GVHD symptoms. ECP has been a valuable tool in the therapeutic arsenal against SR-aGVHD.

More recently, ruxolitinib, a potent Janus kinase (JAK) 1/2 inhibitor, has emerged as a significant advancement in the treatment landscape for SR-aGVHD. Its approval as a new standard of care is underpinned by robust data from phase III clinical trials, demonstrating its efficacy in improving response rates and survival outcomes in patients who have failed initial steroid therapy. Ruxolitinib targets key signaling pathways involved in inflammation and immune cell activation, offering a distinct mechanistic approach compared to ECP.

The advent of ruxolitinib as a highly effective option has naturally prompted clinicians to seek comparative data to inform their treatment decisions. While both ECP and ruxolitinib have individually proven their therapeutic value in managing SR-aGVHD, direct comparisons in real-world clinical settings have been limited. Such comparative analyses are essential for understanding their relative effectiveness, safety profiles, and long-term implications, thereby enabling more evidence-based and personalized treatment selection for patients facing this challenging complication.

This retrospective study, conducted by the European Society for Blood and Marrow Transplantation (EBMT) Transplant Complications Working Party, aimed to address this critical gap in comparative data. We sought to gather real-world evidence on the effectiveness of ECP versus ruxolitinib in treating SR-aGVHD grades II-IV. By analyzing outcomes from a diverse cohort of patients treated across multiple EBMT centers, our objective was to contribute to a stronger evidence base for clinical decision-making regarding these two prominent second-line therapies.

Our methodology involved soliciting participation from various EBMT centers to contribute de-identified patient data. From a total of 31 centers (representing 14% of surveyed institutions) that responded positively, we meticulously collected detailed information for patients who underwent allogeneic stem cell transplantation between January 2017 and July 2019. This specific timeframe was chosen to capture contemporary treatment practices and outcomes. The data was compiled using a standardized data form, Med-C, designed to capture comprehensive details essential for robust analysis.

The Med-C form facilitated the collection of granular information on each included patient, encompassing aspects such as GVHD grading, specific therapy details (including the type of treatment, ECP or ruxolitinib), exact dosing regimens, treatment response, and any associated complications. This detailed data collection was crucial for enabling meaningful comparisons between the two treatment arms. From the participating centers, we identified and included 53 patients who received ECP and 40 patients who received ruxolitinib for the management of SR-aGVHD, specifically those presenting with grades II-IV disease.

To ensure a comprehensive and statistically sound comparison, we conducted multivariate analyses. These analyses were rigorously adjusted for critical confounding variables, including the initial severity of GVHD grading and the specific type of SR-aGVHD (differentiating between steroid-dependent and truly steroid-refractory cases). This adjustment helps to minimize bias inherent in retrospective studies and provides a more accurate assessment of the treatment effects. The primary endpoint for efficacy was overall response at day +90 following the initiation of second-line treatment for SR-aGVHD.

Beyond the primary endpoint, our study also assessed several crucial secondary outcomes to provide a holistic view of treatment impact. These included overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and relapse incidence. By evaluating these various endpoints, we aimed to gain a deeper understanding of how ECP and ruxolitinib compare not only in immediate response but also in their long-term effects on patient survival and disease control after SR-aGVHD therapy.

Our findings revealed no statistically significant differences in overall response at day +90 after the initiation of treatment for SR-aGVHD. Specifically, the odds ratio for achieving an overall response in the ruxolitinib group versus the ECP group was calculated at 1.13, with a 95% confidence interval ranging from [0.41; 3.22]. This result, accompanied by a p-value of 0.81, indicates that any observed differences in response rates between the two groups were not statistically significant, suggesting comparable short-term efficacy.

Consistently with the overall response findings, our analyses detected no statistically significant differences across the secondary endpoints of overall survival, progression-free survival, non-relapse mortality, and relapse incidence between the ECP and ruxolitinib treatment groups. This suggests that, from a retrospective perspective, neither treatment conferred a distinct long-term survival advantage or improved disease control over the other within the study population. The comparable outcomes across these critical measures provide valuable insights into their real-world effectiveness.

It is imperative to acknowledge the inherent limitations of this study, primarily stemming from its retrospective design. Retrospective studies are susceptible to various biases, such as selection bias and confounding factors that may not be fully captured in existing patient records, which can influence the comparability of treatment groups despite statistical adjustments. Therefore, the clinical significance of these findings, while informative, is constrained by the nature of the study design.

Despite these limitations, the current data serves as a valuable contribution to the accumulating body of evidence supporting ECP as an effective therapeutic option for SR-aGVHD. While ruxolitinib has become a new standard of care based on prospective trials, our findings suggest that ECP remains a viable and comparable treatment choice in many real-world scenarios. The results underscore the importance of individualized patient management, considering factors beyond statistical significance when making treatment decisions.

In conclusion, this retrospective analysis by the EBMT Transplant Complications Working Party provides important comparative data on ECP and ruxolitinib for steroid-refractory acute GVHD. Our findings indicate that both therapies demonstrate comparable efficacy in terms of overall response and long-term outcomes, including survival, progression-free survival, non-relapse mortality, and relapse incidence, when adjusted for key patient characteristics. While prospective studies are still needed to solidify the evidence, these results reinforce ECP’s standing as a robust and effective treatment modality for SR-aGVHD, offering clinicians additional support for its continued use alongside ruxolitinib.

Keywords: ECP; GvHD; allogeneic stem cell transplantation; ruxolitinib; steroid-refractory.
Copyright © 2023 Penack, Peczynski, Boreland, Lemaitre, Afanasyeva, Kornblit, Jurado, Martinez, Natale, Pérez-Simón, Brunello, Avenoso, Klein, Ozkurt, Herrera, Wichert, Chiusolo, Gavriilaki, Basak, Schoemans, Koenecke, Moiseev and Peric.

Conflict of interest statement

Author OP has previously received honoraria from Mallinckrodt Pharmaceuticals, but not for the current project. Author OP has received honoraria or travel support from Gilead, Jazz, MSD, Novartis and Pfizer. He has received research support from Incyte and Priothera. He is member of advisory boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Sanofi, Shionogi and SOBI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from Mallinckrodt Pharmaceuticals. The funder had the following involvement with the study: study design was done by EBMT experts and was approved by the funder; interpretation of data was discussed by EBMT experts and was communicated with the funder. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Univariate outcome graphs showing overall survival (A) , progression-free survival (B) , relapse incidence (C) and non-relapse mortality (D) in patients with SR-aGVHD after initiation of treatment with ECP (black lines ――) or Ruxolitinib (orange lines ――).
See this image and copyright information in PMC

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Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Graft vs Host Disease* / drug therapy
  • Graft vs Host Disease* / etiology
  • Hematopoietic Stem Cell Transplantation* / adverse effects
  • Humans
  • Prospective Studies
  • Retrospective Studies
  • Steroids / therapeutic use

Substances

  • ruxolitinib
  • Steroids

Original written by from https://pubmed.ncbi.nlm.nih.gov/38149251/