Prospective Outcomes of Secondline Therapy in Acute Graft-versusHost Study including ECP
POSTAGE
Chief Investigator: Emma Das-Gupta
Study Coordinator: Rohini Radia
Funder:
Sponsor :
Acute Graft-Versus-Host Disease
Nash et al 1992
Steroids as First Line Therapy of aGvHD
Response to Steroids
TRM by Response to 5 days of 2
mg/kg MP
Non-responders day 5
Responders day 5
MacMillan et al, Blood 2010
46%
23%
Van Lint et al, Blood 1998
Options and Recommendations for Second
Line Therapy of aGvHD
• BCSH/BSBMT Second line therapies (Grade 2C)
• ASBMT 6 month survival estimates does not support the
choice of any specific agent for secondary therapy of aGVHD
• EBMT/ELN No standard second- line treatment for aGVHD
ECP MMF mTOR inhibitors TNFa antibodies IL2 receptor antibodies
?Mesenchymal Stem Cells
Current Practice
• Clinician experience
• Influenced by conditioning -T cell depletion
• Potential toxicities and interactions
• Availability of second-line agents
• Variable funding arrangements
ASBMT Recommendations:
Second Line Therapy of aGVHD
Toxicity
Significant
Interactions
Viral
Reactivation
ECP
Limited
None
Not increased
Glucocorticoids
High
None
High
MMF
Cytopenia, GI
Myelosuppress.
Moderately high
Denileukin Diftitox
↑ hepatic transam.
None
High
Sirolimus
Cytopenia, HUS/TAM
CYP3A or P-glyc.
Moderate
Infliximab
None
None
Very high
Etanercept
None
None
High
Pentostatin
Myelosuppress., liver,
renal
None
Very high
Horse ATG
Anaphylaxis, cytopenia
None
Very high
Rabbit ATG
Cytopenia, infections
None
Very high
Alemtuzumab
Pancytopenia, infusion-AE None
Very high
Martin P et al, Biol Blood Marrow Transplant. 18(8):1150-63. 2012
We Need Prospective Comparative Data
• To guide treatment and improve outcomes
• To validate and develop guidelines
• To audit adherence to guidelines
– (BCSH requirement)
• To achieve funding through national commissioning
processes
POSTAGE
• A prospective longitudinal data collection (NOT a trial)
• Generate high quality comparative data on second line
therapies
– Efficacy, Cost, QOL (for UK commissioning purposes)
• This will require that participating centres:
– Use a protocol and stick to it
– Adhere to definition of when to start 2nd line
therapy
– Only use 1 second line treatment at a time
Funding and Backing
• Therakos
– Funder
– To define the role of ECP as a 2nd line therapy for
aGVHD
• NUH
– Sponsor
• BSBMT CTC, UKPS
• Peter Taylor: Rotherham, UKPS
– Funding for an MD student who will act as the
study coordinator in the UK
Collaborating Partners
• USA
– Vanderbilt University Medical Centre
• Dr Jagasia
• REDCap Database
– Mayo
• Dr Hashmi
• Dr Khera (has health economics expertise)
– University of Kansas Medical Centre
• Dr Abhyankar
• Austria
– Vienna: Dr Greinix
• Germany
– Regensburg: Dr Wolff
SPECIFIC AIMS
Aim 1: Clinical Outcome
6 Month Freedom From Treatment Failure (6M FFTF)
• Primary endpoint: 6-month freedom from treatment failure
for 2nd line therapy for acute GVHD.
– Patient being alive,
– Without relapse of underlying disease
– Without the addition of new systemic therapy for the
treatment of acute GVHD,
– Within 6 months of starting second line therapy.
• Patients receiving therapy for cGVHD will be censored at time
of developing cGVHD and will not be counted as failure of
second line therapy for aGVHD.
Aim 1: Clinical Outcome
• CR Day 28 and 56 (overall and according to organ)
• NRM, OS, relapse 1 and 2 years
• cGVHD incidence
• Compliance with BCSH guidelines
Aim 2: ECP v Other 2nd Line Therapies
• Hypothesis:
– ECP is associated with a superior 6 m FFTF as
compared to other treatment modalities
• The sample size has been calculated to examine this.
Aim 3: Healthcare Burden
Incremental budget spend between therapies:
• Length of stay in transplant unit, high-dependency
unit step-down unit, intensive care unit
• High cost drugs
• Total parenteral nutrition
• Surgical procedures
UK-specific data
QoL Using FACT-BMT
• No validated QoL scoring systems for aGVHD
Eligibility: Inclusion Criteria
• Corticosteroid refractory or corticosteroid dependent
Grade II-IV aGVHD
• >18yrs age
• Enrolment within 5 days including weekends of
starting second-line therapy
• DLI induced aGVHD if for mixed chimerism
• Less than 3 weeks of corticosteroid
• No systemic therapy as part of first-line other than
corticosteroids
• Informed consent
Eligibility: Definitions
• Steroid refractory aGVHD:
– Worsening of acute GVHD after 3 days of systemic
corticosteroids (minimum dose of 1 mg/kg)
– Or no improvement after 5 days of systemic
corticosteroids (minimum dose of 1 mg/kg)
• Steroid dependent acute GVHD:
– Recurrence of acute GVHD (grade 2 or higher)
during steroid taper and prior to reaching 50% of
initial starting dose of corticosteroids
Eligibility: Exclusion Criteria
• Has received corticosteroids at 2 mg/kg or higher for 3 weeks or
greater as part of first-line therapy for acute GVHD
• Has received systemic therapy other than corticosteroids for
treatment of acute GVHD as part of first-line therapy for acute
GVHD. Simultaneous uses of topical or enteric steroids or PUVA for
first line are permitted.
• Acute GVHD after second allogeneic stem cell transplant is
excluded.
• Karnofsky Pormance status >/= 50%; ECOG PS </= 2
Eligibility: Exclusion Criteria
• Requiring mechanical ventilation or renal replacement therapy at
the time of enrollment
• Histologic or flow-cytometric evidence of relapse or progression of
underlying disease. Molecular or cytogenetic presence of disease is
permitted. Mixed chimerism is permitted.
• Current or prior diagnosis of chronic GVHD as defined by NIH
consensus criteria.
Research Electronic Data Capture
• Hosted at Vanderbilt University Medical Center in Nashville,
TN, USA
• Secure, web-based application designed to support data
capture for research studies, providing:
– An intuitive interface for validated data entry
– Audit trails for tracking data manipulation and export
procedures
– Automated export procedures for data downloads to
common statistical packages
– Procedures for importing data from external sources.
REDCap Consortium
• 734 active institutional partners from in 59 countries.
• More than 78,000 projects with over 103,000 users
• The database designed to support POSTAGE has been created
in REDCap Dr. Jagasia.
• Users at other sites will have access to REDCap, through a
password protected web interface.
• User rights are variable and will be assigned depending on the
role of the collaborator and key study personnel.
Data Schedule and Reporting
Statistics
Aim 1, Aim 3, and Aim 4: No formal statistics. Data will be
described using appropriate statistical tests.
Aim 2:
• Cumulative incidence estimates of relapse, NRM and
treatment change as causes of failure during second
line treatment will be derived, treating each event as a
competing risk for the other two.
• Rates of 6m FFTF will be estimated by subtracting rates
of total failures from 100%.
• Cox regression models will be used to identify risk
factors for failure.
Patient Accrual
• Expect to accrue 132 pts
– 76pts with Grade II
– 56pts with Grade III-IV
• To fulfill Aim 2 we require a minimum of 63 patients treated with
ECP and 42 patients treated with any other systemic therapy.
• International collaboration
• All centers will follow the same eligibility criteria.
• Data from all sites will be entered in REDCap database.
• De-identified data from all sites will be merged for purposes of
final combined data analyses.
Summary
• Ambitious project aiming to collect high quality prospective
comparative clinical data
• Timely Entry into study and prospective data entry essential
• Data Integrity Committee and study coordinator
• Several firsts:
– Health economics
– QOL
• NIHR adopted
• Funding: £500 per patient enrolled
• Open to Recruitment!
Thank You
[email protected]
[email protected]