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Two different treatment approaches in combination with ECP for the management of steroid refractory aGvHD: etanercept and ruxolitinib

Jun 24, 2020

Acute graft- versus-host disease (aGvHD) can develop following stem cell transplantation (SCT) with an occurrence rate of up to 50% of all allogeneic SCT (allo-SCT). Steroids are considered as the first-line treatment; however, response rates usually do not exceed 30–40% and there is no accepted standard of care for steroid refractory (SR) aGvHD. Extracorporeal photopheresis (ECP) is another approach that combines UVA light and 8-methoxypsoralen for the management of acute and chronic GvHD.

Two different studies have recently reported results using ECP in combination with other agents for the treatment of SR aGvHD. While Singh and colleagues presented their results during the 2020 ASCO Virtual Meeting evaluating etanercept with or without ECP in patients with SR aGvHD 1 , Modemann and colleagues investigated ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor in combination with ECP for the treatment of SR acute and chronic GvHD of the lower gastrointestinal (GI) tract, and have published their results in Bone Marrow Transplantation. 2

ECP with etanercept for the treatment of SR aGvHD 1

Singh and colleagues assessed the efficacy of etanercept plus ECP by analyzing the change in grade of aGvHD and death rate due to infection. Most patients had myelodysplastic syndrome as underlying disease. All patients (N = 30) received second-line etanercept treatment at a subcutaneous dose of 25 mg twice weekly for at least 4 weeks. Patient characteristics and the study design are shown in Table 1.

Table 1. Patient characteristics and study design 1

ECP, extracorporeal photopheresis


N = 30

Number of patients who received ECP, n (%)

25 (83.3)

Median age, years (range)

57.6 (19–71)


The median time from allo-SCT to steroid initiation was 39.5 days (14–183 days), and from steroid initiation to etanercept was 6 days.


Incidence of Grade 3 aGvHD was reduced from 43.3 to 11.5%, and Grade 4 from 20 to 19.2%. The outcomes are summarized in Table 2.

Table 2. Outcomes 1

aGvHD, acute graft- versus-host disease

*Responded best

Overall response rate, %


Response status at Day 56 from initiation of steroids, n (%)

aGvHD site






No response


3 (30)

4 (40)

3 (30)

3 (20)

10 (66.7)


2 (13.3)

3 (42.9)

2 (28.6)


2 (28.6)

Active infection within 6 months of transplant, %


Cause of death

Infection alone, n (%)

Infection + GvHD, n (%)

Infection + relapsed disease, n


7 (28)

7 (28)


Median overall survival, days (range)




306 (59–2005)

181 (89–261)


  • High response rates (83.3%) can be achieved using etanercept with or without ECP
  • Seven patients (26.9%) achieved a complete remission of their aGvHD
  • A high death rate due to infection in more than half of all patients is still a concern

Ruxolitinib plus ECP for SR aGvHD of the lower GI tract 2

Modemann and colleagues investigated the tolerability and efficacy of the ruxolitinib and ECP combination in patients with SR aGvHD of the lower GI tract. The objective of the study was to increase response rates compared with ruxolitinib alone, and to investigate the impact of this treatment on regulatory T cells. Patient characteristics and the study design are shown in Table 3.

Table 3. Patient characteristics and study design 2

aCML, atypical chronic myeloid leukemia; aGvHD, acute GvHD; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GI, gastrointestinal; GvHD, graft- versus-host disease; MDS, myelodysplastic syndromes; MM, multiple myeloma; MMUD, mismatched unrelated donor; MMUD, mismatched unrelated donor (9/10 HLA match); MRD, matched related donor; MUD, matched unrelated donor; PMF, primary myelofibrosis


N = 18

Median age, years (range)

58.5 (21–73)

Additional site of GvHD (to lower GI tract)

None (n = 7)



Upper GI tract

Skin and liver

Liver and upper GI tract

Underlying disease (n)


AML (2), ALL (3), aCML (1), MDS (6), MM (1), PMF (5)

Donor source (n)

MUD (9), MRD (3), MMUD 9/10 (6)

Overall grade of aGvHD at start of ruxolitinib/ECP treatment (n)

III (9) IV (9)


All patients received 2 mg/kg of methylprednisolone when starting ruxolitinib or ECP. Median start dosage of ruxolitinib was 20 mg per day, given in 10 mg doses twice a day. The ECP treatment was initiated two times per week, for two weeks, and adjusted individually thereafter. While most patients received one ECP treatment per week, the number and duration of ECP ranged between 0.5 to 2.1 treatments (median, 20.5 per patient) and 0.4 to 23.4 months (median, 5.7 months), respectively.

Furthermore, calcineurin inhibitors were administered in all patients in addition to the study treatment and/or methylprednisolone; 17 patients also received mycophenolate mofetil.


A summary of study results is shown below in Table 4.

Table 4.Study results 2

CMV, cytomegalovirus

Overall response, n (%)

Complete remission

Partial remission

No response

10 (56)

8 (44)

2 (11)

8 (44)

Reasons to treatment cessation, n (%)


Complete remission status

No treatment response


8 (44) (n = 3 recovered, n = 2 died)

6 (33)

2 (7)

Reasons to treatment discontinuation, n


Vomiting and emesis






Side effects (Grade III and higher), n (%)



Increased C-reactive protein level (> 50 mg/dL)

CMV reactivation


7 (39)

9 (50)

9 (50) (led to sepsis in 3 patients)

12 (67)

Overall survival

Results from the survival analysis are presented in Table 5.

Table 5.Survival results 2

aGvHD, acute graft- versus-host disease; GI, gastrointestinal

2-year overall survival, n (%)

10 (56)

Median overall survival, months


Death events, n

Relapse of underlying disease

Severe therapy-refractory aGvHD of lower GI tract

Infection complications

8 (44%)




Immune status

Samples were analyzed before treatment, 4 weeks after treatment initiation, and 3–4 weeks after treatment cessation:

  • No significant changes in whole lymphocyte or CD4+ T helper cell counts at any of the three time points were observed
  • There was an increase in regulatory T cells during the treatment (p = 0.02), which decreased after stopping the treatment (p = 0.02)
  • High levels of regulatory T cells were also seen in patients with complete or partial response (p = 0.03)

Steroid tapering

The combination allowed tapering the dose of steroids; this was performed with a dose reduction by half in a maximum of 7 days, and by a quarter of initial dosage of methylprednisolonein a median time of 6 days (range, 1–12 days). Complete stopping of steroids was achieved in a median time of 27 days (range, 12–63).


  • A high number of responses could be achieved with the combination of ECP plus ruxolitinib resulting in improved survival, with a median overall survival rate of 18.4 months in responders, compared with 11.4 months in non-responders (p = 0.1)
  • Increased regulatory T-cell levels were measured during treatment which may be an indicator of potential efficacy in severe refractory aGvHD
  • Cytopenia was the major side effect, with anemia, thrombocytopenia, and leukopenia of all grades seen in 13/18 patients
  • After a follow-up of 887 days, five patients remained in complete remission of their aGvHD, while four maintained their partial response, and only one patient relapsed indicating long-lasting effects. However, the fact that 12 patients developed chronic GvHD is a concern


Based on the results of the two studies, combining ECP with other agents appears to be effective; however, high infection rates and the risk of chronic GvHD remain a concern that needs to be carefully monitored.

  1. Singh SRK, Malapati SJ, Neme K, et al. Etanercept with extracorporeal photopheresis (ECP) for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation. J Clin Oncol. 2020;38(15; suppl; abstr #7543).
  2. Modemann F, Ayuk F, Wolschke C, et al. Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft- versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level.  Bone Marrow Transplant. 2020:1-8. DOI: 1038/s41409-020-0952-z