ECP Combination Study

Study Overview
=================
Brief Summary
-----------------
Extracorporeal photopheresis (ECP) offers an alternative to standard immunosuppression and shows an immunomodulatory rather than an immunosuppressive effect, which is associated with less toxicities and side effects. Additionally ECP has been shown to allow tapering of steroids and immunosuppressant agents which should be a goal of GvHD therapy. ECP has been used for the management of GvHD since first described in 1994 and as its use has continued over the decades. The treatment was incorporated into a number of guidelines as a second line therapy in steroid refractory or steroid dependent GvHD patients. As well as being used in addition and after steroids, it is also used in combination with CNI Inhibitors, MMF and other immunosuppressant agents. However, despite the current widespread use of ECP in the treatment of patients with GvHD, clinical data from randomized studies is limited and small prospective and retrospective trials are the main evidence base .This is also the case for other commonly used immunosuppressant agents, which have been used in GvHD since ECP was introduced. The systematic review concluded that ECP is an effective therapy for oral, skin, and liver SR-cGVHD, with modest activity in lung and gastrointestinal SR-cGVHD. In the USA Ibrutinib is the only FDA approved agent for second line cGvHD therapy once steroid therapy has failed and Ruxolitinib had been approved in the USA for the treatment of steroid refractory GvHD. While studies have shown the effectiveness and safety of ECP in GvHD treatment, there is limited data to show how it is being used in combination with the recently approved agents. Using existing registry data targeting centres where the newer agents are being used and enhancing the capture of treatment data we believe we can undertake a larger scale study, which will include the new treatment protocols. The aim of the current study is to improve the evidence basis on the potential benefit of ECP use as treatment of GVHD.

Detailed Description
-----------------
This is a Registry Based Study (RBS) designed to collect data on the treatment behaviour of acute and chronic GvHD after HSCT. The data collection will be based on the EBMT registry, which so far consists of two questionnaires (Forms A and B), mainly covering the primary disease diagnostics, the status before and at HSCT, the type of HSCT (donor status, preparative regimen etc) and the survival status. With a new questionnaire Form C, which will be similar in design as the current forms used in the registry, we aim at collecting more information and additional data on GvHD characteristics and treatment (schedule, combination, disease states) for both chronic and acute GvHD EBMT will work with the selected sites to facilitate the collection of additional data as specified in section 4. The data collected will all be retrospective and include up to 3 years of data covering 2017 onwards, from onset of GvHD that has failed to respond to steroids with a minimum data follow up of 6 months for acute and 1 year for chronic. Centres will be asked to select patients that meet the inclusion criteria and fill in Form C retrospectively. The amount of additional data required will depend on whether the centre selected fills in the more detailed Form B or the more minimum data set in Form A. Criteria for centre selection will be based on: Centres that have expressed a willingness to participate in the study through a feasibility questionnaire that was sent out prior to the study or via Email confirmation Centres who have responded through the feasibility questionnaire Centres where there is prior knowledge of use of both Ruxolitinib/Ibrutinib and ECP or have responded as such in the feasibility questionnaire

Official Title
-----------------
Multi-centre Retrospective Study to Describe the Use and Outcomes of ECP in Combination With New Treatment Protocols in Acute and Chronic GvHD

Conditions
-----------------
Steroid Refractory GVHD

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Device: Extracorporeal photopheresis
* Drug: Ibrutinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Acute GvHD Patients Patients who develop acute SR-GvHD after first HSCT and there is a minimum of 6 months follow up data in the database Patients who initiate treatment with ECP or Ruxolitinib within 60 days of onset of SR aGvHD Grade: II-IV only at time of treatment initiation Patients who are ≥ 18 years at time of treatment initiation Chronic GvHD Patients Patients who develop chronic SR-GvHD after first HSCT and there is with a minimum of 1 year follow up data in the database Patients who initiate treatment with ECP or Ruxolitinib or Ibrutinib within I year of the onset of SR-cGvHD Severity: moderate to severe only at time of treatment initiation Patients who are ≥ 18 years at time of treatment initiation Exclusion Criteria: Acute GvHD Patients on a clinical trial for GvHD for an interventional drug to treat GvHD in the retrospective period Patient is pregnant or breastfeeding Grade I at time of SR GvHD treatment initiation Patients who receive ECP or new treatment as prophylaxis Patients initiating ECP or new treatment later than 60 days from onset on SR-aGvHD Patients < 18 years at time of treatment initiation Chronic GvHD Patients on a clinical trial for an interventional drug to treat GvHD in the retrospective period Patient is pregnant or breastfeeding Chronic GvHD : Severity mild at time of SR GvHD treatment initiation Patients who receive ECP or new treatment as prophylaxis Patients initiating ECP or new treatment after 1 year onset of SR-cGvHD Patients < 18 years at time of treatment initiation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ECP only (aGVHD patients)<br>Patients treated with ECP and other Standard Of Care treatments (SOC) | Device: Extracorporeal photopheresis<br>* As per treating physician's decision - non interventional study<br>|
| ECP and Ruxolitinib (aGVHD patients)<br>Patients treated with ECP and Ruxolitinib | Drug: Ruxolitinib<br>* As per treating physician's decision - non interventional study<br>Device: Extracorporeal photopheresis<br>* As per treating physician's decision - non interventional study<br>|
| Ruxolitinib only (aGVHD patients)<br>Patients treated with Ruxolitinib and other Standard Of Care treatments (SOC) | Drug: Ruxolitinib<br>* As per treating physician's decision - non interventional study<br>|
| ECP only (cGVHD patients)<br>Patients treated with ECP and other Standard Of Care treatments (SOC) | Device: Extracorporeal photopheresis<br>* As per treating physician's decision - non interventional study<br>|
| ECP and treatment combination (cGVHD patients)<br>Patients treated with ECP and Ruxolitinib or Ibrutinib | Drug: Ruxolitinib<br>* As per treating physician's decision - non interventional study<br>Device: Extracorporeal photopheresis<br>* As per treating physician's decision - non interventional study<br>Drug: Ibrutinib<br>* As per treating physician's decision - non interventional study<br>|
| Treatment combination only (cGVHD patients)<br>Patients treated with Ibrutinib and/or Ruxolitinib and other Standard Of Care treatments (SOC) | Drug: Ruxolitinib<br>* As per treating physician's decision - non interventional study<br>Drug: Ibrutinib<br>* As per treating physician's decision - non interventional study<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Partial or Complete response according to NIH/Glucksberg classification) at 3 months for acute GvHD since start of targeted* treatment for SR-GvHD | 3 months | 
| Overall response rate (Partial or Complete response according to NIH/Glucksberg classification) at 6 months for chronic GvHD since start of targeted* treatment for SR-GvHD |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of ECP | Organ specific response | up to one year | 
| Safety of ECP | Incidence of Complications and infections | Up to one year | 
| Safety of ECP | Steroid sparing effects (decrease of dose or percentage) | Up to one year | 
| Efficacy of ECP | overall survival (Percentage at a fixed time) | Up to one year | 
| Efficacy of ECP | Non Relapse Mortality | Up to one year | 
| Efficacy of ECP | Duration of response | Up to one year | 
| Efficacy of ECP | Failure-free survival | Up to one year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ECP, Steroid refractory GVHD, Extracorporeal photopheresis, Ibrutinib, Ruxolitinib