A single centre study of the A single centre study of the efficacy of extracorporeal efficacy of extracorporeal

photopheresis in Acute Graft photopheresis in Acute Graft Versus Host DiseaseVersus Host Disease

Lynne WatsonLynne Watson

Nottingham University Nottingham University Hospital NHS TrustHospital NHS Trust

Acute Graft-Versus-Host Acute Graft-Versus-Host DiseaseDisease

Major complication of Major complication of allogeneic HSCT.allogeneic HSCT.

Triggered by Triggered by immunocompetent immunocompetent donor cells.donor cells.

Incidence 30-50% in Incidence 30-50% in sibling and up to sibling and up to 80% in MUD 80% in MUD transplantstransplants

Developent of Acute GVHD

Time (days)

200150100500

% A

cute

GV

HD

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

PBSC

BM

GVHD Syndrome After GVHD Syndrome After AllotransplantAllotransplant

Day 0 50 100 180 1 y 2 y 3 y 5 y

Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GI liver, musculoskeletal, lungs, GU

- Classic acute - Late acute - Classic chronic - Chronic overlap

Activity Damage(inflammation) i n j u r y r e p a i r (fibrosis)

AlloreactivityAutoimmunity

Immunodeficiency

Treatment of severe acute GvHDTreatment of severe acute GvHD

High dose steroids (2mg/kg/day) is standard approach High dose steroids (2mg/kg/day) is standard approach for the treatment of grade II-IV acute GvHD treatmentfor the treatment of grade II-IV acute GvHD treatment

~ 40-50% of patients with grade II-IV disease are steroid ~ 40-50% of patients with grade II-IV disease are steroid responsive responsive

Higher response rates in grade II compared to grade Higher response rates in grade II compared to grade III/IV disease and in patients with one organ involved III/IV disease and in patients with one organ involved compared to 2 or 3. compared to 2 or 3.

Responses are worse in patients receiving MUD Responses are worse in patients receiving MUD transplants. transplants.

Overall CR is only seen in 25-40% of patientsOverall CR is only seen in 25-40% of patients

Options for second line therapy for Options for second line therapy for GVHDGVHD

Extracorporealphotopheresis

Sirolimus

MycophenolateMofetil

EtanerceptAnti-TNF

CD5 Immunotoxins

Rituximab

ATG

Second LineTherapy

For AGVHD

Extracorporeal Photopheresis Extracorporeal Photopheresis (ECP)(ECP)

ECP is based upon the re-infusion of apoptotic autologous ECP is based upon the re-infusion of apoptotic autologous blood mononuclear cells which have been treated blood mononuclear cells which have been treated extracorporeally with the DNA intercalating agent 8 –extracorporeally with the DNA intercalating agent 8 –methoxypsoralen and then irradiated with PUVAmethoxypsoralen and then irradiated with PUVA

ECP has demonstrated efficacy in selected T cell diseases ECP has demonstrated efficacy in selected T cell diseases including chronic GvHD and cutaneous T cell lymphoma including chronic GvHD and cutaneous T cell lymphoma

The experience of ECP in Acute GVHD is much less than The experience of ECP in Acute GVHD is much less than that with chronic. that with chronic. Greinix et al (2006) reported a Greinix et al (2006) reported a phase II study of 59 patients treated with ECP for phase II study of 59 patients treated with ECP for steroid refractory acute GvHD using an intensive steroid refractory acute GvHD using an intensive schedule of a cycle of therapy ( 2 consecutive daily schedule of a cycle of therapy ( 2 consecutive daily treatments) weekly for 8 weekstreatments) weekly for 8 weeks

ECP Schedule for acute GVHDECP Schedule for acute GVHD

We established an ECP programme for acute We established an ECP programme for acute and chronic GVHD in Nottingham in 2006 using and chronic GVHD in Nottingham in 2006 using the Therakos XTS systemthe Therakos XTS systemPreviously we had used ATG in this setting but Previously we had used ATG in this setting but with a poor response and a high incidence of with a poor response and a high incidence of infectious complicationsinfectious complications18 consecutive patients with steroid-refractory 18 consecutive patients with steroid-refractory acute GVHD have been treated with twice acute GVHD have been treated with twice weekly ECP at weekly intervals for a planned 8 weekly ECP at weekly intervals for a planned 8 week course (Greinix schedule)week course (Greinix schedule)In 2009 we started using the new Cellex system In 2009 we started using the new Cellex system for suitable patientsfor suitable patients

ECP for Acute GVHDECP for Acute GVHD

18 consecutive patients with steroid-refractory acute 18 consecutive patients with steroid-refractory acute GVHD post BMT (n=11) or DLI therapy (n=7) GVHD post BMT (n=11) or DLI therapy (n=7) GVHD was grade II in 2, grade III in 6 and grade IV in 10 GVHD was grade II in 2, grade III in 6 and grade IV in 10 patients. patients. 66% of patients had 2 or 3 organ involvement66% of patients had 2 or 3 organ involvementPatients had been on steroids (2mg/kg) for a median of Patients had been on steroids (2mg/kg) for a median of 14 days (7-88 days) before starting ECP.14 days (7-88 days) before starting ECP.The aim was to achieve a rapid steroid taper in The aim was to achieve a rapid steroid taper in responding patientsresponding patients

Results – Response at 8 weeksResults – Response at 8 weeks

Primary end point of the analysis was the Primary end point of the analysis was the response after 8 weeks of ECP therapy. response after 8 weeks of ECP therapy. CR was arbitrarily defined as resolution of CR was arbitrarily defined as resolution of features of acute GvHD with a reduction of features of acute GvHD with a reduction of prednisolone dose to 10mg/day or lessprednisolone dose to 10mg/day or less12/18 patients have completed 8 weeks of ECP12/18 patients have completed 8 weeks of ECP 6 died of progressive GvHD prior to completing 6 died of progressive GvHD prior to completing their 8 weeks of allocated ECP therapy.their 8 weeks of allocated ECP therapy.

Overall Response to ECPOverall Response to ECP

All of the 12 /18 (66%) patients who completed 8 All of the 12 /18 (66%) patients who completed 8 weeks of therapy have responded.weeks of therapy have responded.

In the 12 patients who have completed the 8 weeks In the 12 patients who have completed the 8 weeks of therapy CR was achieved in 8.of therapy CR was achieved in 8.

4 patients achieved a partial response but remained 4 patients achieved a partial response but remained on higher dose of steroids than 10mg/day at 8 on higher dose of steroids than 10mg/day at 8 weeks.weeks.

Response was dependent upon severity and extent Response was dependent upon severity and extent of GvHD.of GvHD.

Example of Bilirubin Response Example of Bilirubin Response Rates to ECPRates to ECP

Wk 1Wk 1

494494

Wk 2Wk 2

396396

Wk 3Wk 3

313313

Wk 4Wk 4

283283

Wk 5Wk 5

426426

Wk 6Wk 6

252252

Wk 7Wk 7

187187

Wk 8Wk 8

142142

Wk 1Wk 1

235235

Wk 2Wk 2

103103

Wk 3Wk 3

8888

Wk 4Wk 4

6969

Wk 5Wk 5

4444

Wk 6Wk 6

2424

Wk 7Wk 7

2121

Wk 8Wk 8

1515

UpdatedUpdated Outcome on Responding PatientsOutcome on Responding Patients

Median follow-up is now 2 years.Median follow-up is now 2 years.

8 patients have developed chronic GvHD and remain 8 patients have developed chronic GvHD and remain on some immunosuppression. This includes 2 patients on some immunosuppression. This includes 2 patients with major relapse of liver GVHD 4-6 months after with major relapse of liver GVHD 4-6 months after stopping ECP. Both patients responded to re-starting stopping ECP. Both patients responded to re-starting ECP therapy.ECP therapy.3 patients have no GvHD and are off all 3 patients have no GvHD and are off all immunosuppression.immunosuppression.1 patient who had a PR to ECP died of HHV 6 1 patient who had a PR to ECP died of HHV 6 encephalitis.encephalitis.Only 1 patient has had relapsed of their disease.Only 1 patient has had relapsed of their disease.

Summary Summary

12/18 patients with grade II - IV steroid-refractory acute 12/18 patients with grade II - IV steroid-refractory acute GvHD completed their scheduled 8 weeks course of GvHD completed their scheduled 8 weeks course of intensive ECP intensive ECP All patients responded with 8 achieving CR and 4 PRAll patients responded with 8 achieving CR and 4 PRExcellent and rapid responses were seen in patients Excellent and rapid responses were seen in patients with isolated skin or liver GvHD . The response rate was with isolated skin or liver GvHD . The response rate was lower in patients with 3 organ involvementlower in patients with 3 organ involvement5/7 patients who developed GVHD post DLI responded5/7 patients who developed GVHD post DLI responded8 patients survive >12 months post completion of ECP 8 patients survive >12 months post completion of ECP and 3 patients are off all immunosuppressionand 3 patients are off all immunosuppression2 patients have had significant relapse of liver GVHD 2 patients have had significant relapse of liver GVHD and both responded again to re-introduction of ECPand both responded again to re-introduction of ECP8 patients survive >12 months post completion of ECP 8 patients survive >12 months post completion of ECP