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Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD)

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Melhem M. Solh
Melhem M. Solh
Melhem M. Solh
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Chloe Farnham
Chloe Farnham
Chloe Farnham
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Scott R Solomon at Blood and Marrow Transplant Program at Northside Hospital
Scott R Solomon
  • Blood and Marrow Transplant Program at Northside Hospital
Asad Bashey
Asad Bashey
Asad Bashey
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Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV–, HR 2.34, CI 1.16–4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20–0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20–0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.
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ARTICLE
Extracorporeal photopheresis (ECP) improves overall survival in
the treatment of steroid refractory acute graft-versus-host
disease (SR aGvHD)
Melhem M. Solh
1
✉, Chloe Farnham
1
, Scott R. Solomon
1
, Asad Bashey
1
, Lawrence E. Morris
1
, H. Kent Holland
1
and Xu Zhang
2
© The Author(s), under exclusive licence to Springer Nature Limited 2022
Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell
transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment
related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to
identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR
aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset
of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p=0.01), DFS (p=0.008), lower relapse
(p=0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter
hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p=0.03). Multivariable analysis for OS indicated patient
CMV status (CMV+versus CMV–, HR 2.34, CI 1.16–4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20–0.75), and
the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20–0.75) were associated with OS. In summary, the use of ECP in the treatment of SR
aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not
incorporate ECP.
Bone Marrow Transplantation (2023) 58:168–174; https://doi.org/10.1038/s41409-022-01860-x
INTRODUCTION
Despite improvement in preventive measures, about 50% of
allogeneic-HSCT patients develop acute GvHD (aGvHD) [1]. Acute
GvHD has significant impact on outcomes after allogeneic-HSCT as
well as on quality of life and healthcare resource utilization [2].
Steroids remain the first-line treatment for aGvHD requiring
systemic immunosuppression. Steroid refractory acute graft-versus-
host disease (SR aGvHD) remains a major cause of morbidity and
mortality following allogeneic hematopoietic stem cell transplantation
(HSCT) [3]. Following first-line therapy with steroids, approximately
40–50% of patients do not respond or cannot tolerate weaning to a
low dose below 0.5 mg/kg daily [4]. Following failure of first-line
therapy, various second-line therapies have been utilized, including
mycophenolate mofetil, sirolimus, monoclonal antibodies such as
Infliximab, Basiliximab, and rituximab with limited success [4–7]. The
recent approval of Ruxolitinib for treatment of SR aGvHD has
exhibited some progress as a salvage therapy, however the short- and
long-term survival of patients with steroid refractory acute graft-
versus-host disease (SR aGvHD) remains dismal with 6-month overall
survival (OS) around 50% [8,9].
Extracorporeal photopheresis (ECP) therapy has been shown to
produce durable responses among patients with SR aGvHD with
low ECP related mortality [2,10–14]. ECP activates immature
dendritic cells by an inflammatory cascade, followed by expansion
of plasmacytoid dendritic cells with a stimulation of tolerogenic
mechanisms and inhibition of allospecific effectors [15–17]. Such
mechanisms include normalization of CD4+/CD8+lymphocyte
populations and a decrease in circulating CD80+, CD123+
dendritic cells [18]. Recent studies show that the effect of ECP
goes beyond antigen-presenting cells and affects T-cell subset
expression, promotes a balanced immune reconstitution and
induces immune tolerance [19–21]. Ni et al investigated the effect
of ECP on T helper cells (Th), expression of immune checkpoints
(PD-1 and Tim-3) and apoptotic molecules (Fas R) [19]. ECP
therapy was shown to increase Th22 and Tfh cells in acute GVHD
and increases of Th2-like Tfh cells in chronic GvHD and such
changes were associated with better responses [19].
Although ECP outcomes differ between acute and chronic
GvHD patients, most retrospective and prospective trials have
shown consistent benefit of ECP in the treatment of both GVHD
entities [22] In recent open-label multicenter phase 3 study,
among children and young adults with SR aGVHD, ECP induction
had an overall response of 74% by week 8 and 79% by week 12
[23]. In chronic GvHD (cGvHD) the overall response rate is
approximately 60% with a complete response rate around 20%
[24,25]. For SR aGvHD patients, the reported overall response rate
has been variable, organ dependent and ranged from 30 to 70%.
A systemic review of prospective studies on the effect of ECP in
steroid refractory acute or chronic GVHD showed that overall
response was 0.69 for acute and 0.64 for cGvHD [2]. In Acute
Received: 27 September 2021 Revised: 12 October 2022 Accepted: 17 October 2022
Published online: 9 November 2022
1
Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.
2
Center for Clinical and Translational Sciences, University of Texas Health Science Center at
Houston, Houston, TX, USA. ✉email: msolh@bmtga.com
www.nature.com/bmt
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Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease
Article
Full-text available
  • Apr 2022
  • ONCOLOGIST
Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT) and is associated with significant morbidity and mortality. For many years, there have been few effective treatment options for patients with GVHD. First-line systemic treatment remains corticosteroids, but up to 50% of patients will develop steroid-refractory GVHD and the prognosis for these patients is poor. Elucidation of the pathophysiological mechanisms of acute and chronic GVHD has laid a foundation for novel therapeutic approaches. Since 2017, there have now been 4 approvals by the US Food and Drug Administration (FDA) for GVHD. Ruxolitinib, an oral selective JAK1/2 inhibitor, received FDA approval for the treatment of steroid-refractory acute GVHD in 2019 and remains the only agent approved for acute GVHD. There are currently 3 FDA approvals for the treatment of chronic GVHD: (1) ibrutinib, a BTK inhibitor traditionally used for B-cell malignancies, was the first agent approved for chronic GVHD after failure of one or more lines of systemic therapy, (2) belumosudil, an oral selective inhibitor of ROCK2, for patients with chronic GVHD who received at least 2 prior lines of treatment, and (3) ruxolitinib for chronic GVHD after failure of one or two lines of systemic therapy. In this review, we highlight the clinical data which support these FDA approvals in acute and chronic GVHD with a focus on mechanism of actions, clinical efficacy, and toxicities associated with these agents.
View
View
Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Article
Full-text available
  • Jun 2021
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1 mg/kg at day 28 and <0.5 mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n = 51) or steroids alone (n = 30). Median age was 54 years (range: 17–75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
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A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease
Article
Full-text available
  • Sep 2019
  • BIOL BLOOD MARROW TR
Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = .42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.
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A Prospective, Multicenter Study of Closed System Extracorporeal Photopheresis for Children With Steroid-Refractory Acute Graft-Versus-Host Disease
Article
  • Feb 2022
Background: Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) therapy involves intensive immunosuppression, which is associated with significant infectious risk. Extracorporeal photopheresis (ECP) is used to treat SR-aGvHD and is considered to be more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multi-step ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. Objective: To prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGvHD. Study design: Open-label, multicenter, phase 3 study of the THERAKOS® CELLEX® Photopheresis System in children/young adults aged 1 to 21 years with SR-aGvHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGvHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving overall response (OR) at day 28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). Results: Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. Mean steroid dose decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved >50% steroid dose reduction at week 4 and 75% achieved >50% steroid dose reduction at week 12. Of 168 TEAEs reported among 25 patients (86%), 28 (17%) events were infections and 14 (8%) events were considered to be probably treatment related (all nonserious). Of 627 ECP treatments administered in children/young adults, 68% required blood priming. Treatment-related AEs, including hypotension, hypocalcemia, central line infection, and catheter-site bruising, were rare (1 event each). Three deaths occurred and were deemed unrelated to ECP by the investigators. Conclusion: Use of the THERAKOS® CELLEX® Photopheresis System was effective in children with SR-aGvHD, with more than half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.
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Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells
Article
  • Oct 2021
  • CYTOTHERAPY
Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4⁺CD8⁺ T cells. Additionally, Tim-3–expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.
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Refractory acute graft-versus-host disease: A new working definition beyond corticosteroid refractoriness
Article
  • Aug 2020
  • BLOOD
Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyper-adhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or intravenous infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.
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Extracorporeal Photopheresis in Graft-versus-Host Disease
Article
  • May 2020
Background and summary: Extracorporeal photopheresis (ECP) is a leukapheresis-based procedure used in the therapy of acute and chronic graft-versus-host disease (aGvHD, cGvHD) and other diseases. Based on the substantial efficacy and the excellent safety profile in the absence of immunosuppression ECP has established itself as a major treatment form for steroid-refractory GvHD. Here we review the current literature on ECP as a treatment option for patients with aGvHD as well as cGvHD. Key messages: ECP is a well-established second-line therapy for cGvHD. Its role in the treatment of aGvHD is less clear but also points towards an effective second-line therapy option. In the future ECP could play a role in the prevention of GvHD. More experimental and randomized controlled trials are needed to define the best patient selection criteria, settings, and therapy regimens for GvHD.
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Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
Article
  • Apr 2020
Background Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. Methods We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator’s choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. Results A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). Conclusions Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.)
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Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study
Article
  • Oct 2000
Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation has been shown to be effective in the treatment of selected diseases mediated by T cells, rejection after solid organ transplantation, and chronic graft-versus-host disease (GVHD). We present 21 patients with a median age of 38 years who developed steroid-refractory acute GVHD grades II to IV after stem cell grafting from sibling or unrelated donors and were referred to extracorporeal photochemotherapy (ECP). Three months after initiation of ECP 60% of patients achieved a complete resolution of GVHD manifestations. Complete responses were obtained in 100% of patients with grade II, 67% of patients with grade III, and 12% of patients with grade IV acute GVHD. Three months after start of ECP complete responses were achieved in 60% of patients with cutaneous, 67% with liver, and none with gut involvement. Adverse events observed during ECP included a decrease in peripheral blood cell counts in the early phase after stem cell transplantation (SCT). Currently, 57% of patients are alive at a median observation time of 25 months after SCT. Probability of survival at 4 years after SCT is 91% in patients with complete response to ECP compared to 11% in patients not responding completely. Our findings suggest that ECP is an effective adjunct therapy for acute steroid-refractory GVHD with cutaneous and liver involvement. However, in patients with acute GVHD grade IV or gut involvement other therapeutic options are warranted.
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