A Randomized Trial of Thymoglobulin to Prevent Chronic ... - CBMTG

A Randomized Trial of Thymoglobulinto Prevent Chronic Graft versus Host Diseasein Patients Undergoing Hematopoietic Progenitor CellTransplantation (HPCT) from Unrelated Donors.Study CBMTG-0801Study CBMTG-0801

Appendix AIllustrations of cGVHD – Joints and LungJointRestrictionsChronic lung disease

Appendix AIllustrations of cGVHD - Oral

Appendix AIllustrations of cGVHD- Dermatological

Quality of LifeFraser CJ et al. Impact of chronic graft-versus-host disease on the health status ofhematopoietic cell transplantation survivors: a report from the Bone Marrow TransplantSurvivor Study. Blood 2006;108:2867-2873.

FinkeLancet Oncol 2009;10: 855–64BacigalupoBlood 2001;98:2942BBMT 2006;12:560ATG-Fresenius60 mg/kg totalThymoglobulinLow-dose7.5 mg/kg totalThymoglobulinHigh-dose15 mg/kg totalPrimary End-Point Death/AGVHD III-IV AGVHD III-IVPrimary End-Point NS NS 11% vs 50%, P=.001Infectious Deaths NS NS 30% vs 7%Survival NS NS NSNon RelapseMortalityChronic GVHD 30.8% vs 58.8%p

A Randomized Trial of Thymoglobulinto Prevent Chronic Graft versus Host Diseasein Patients Undergoing Hematopoietic Progenitor CellTransplantation (HPCT) from Unrelated Donors.Study CBMTG-0801Study CBMTG-0801

Administration0801 Trial Committee• Stephen Couban• Ronan Foley• Stephanie Lee• Tony Panzarella• Jean Roy• Kirk Schultz• David Schweitzer• Christopher Skedgel• Cynthia Toze• Holly Kerr• Irwin WalkerCollaboration• Paul MartinCoordinationUniversity of British Columbia• Clay Smith• Holly KerrData Safety MonitoringCommittee (DSMC)• Pediatric BMT Consortium

FundingTOTAL GRANT:CIHR:$1,245,055 (CAD)Genzyme Corporation: $800,000 (US)Total $2,045,055

HypothesisThe addition of Thymoglobulin® to the preparative regimen willresult in a decrease in the proportion† of patients with chronicgraft versus host disease, resulting in improved quality of life butwithout an increase in mortality, disease relapse or death due toinfection.† from 0.6 to 0.4

FinkeLancet Oncol 2009;10: 855–64BacigalupoBlood 2001;98:2942BBMT 2006;12:560ATG-Fresenius60 mg/kg totalThymoglobulinLow-dose7.5 mg/kg totalThymoglobulinHigh-dose15 mg/kg totalPrimary End-Point Death/AGVHD III-IV AGVHD III-IVPrimary End-Point NS NS 11% vs 50%, P=.001Infectious Deaths NS NS 30% vs 7%Survival NS NS NSNon RelapseMortalityChronic GVHD 30.8% vs 58.8%p

The Primary EndpointFreedom of chronic graft versus host disease at 12 months fromtransplantation defined as withdrawal of all systemicimmunosuppressive agents without resumption up to 12 monthsafter transplantation (this end-point is binary i.e. Yes/No).

Time to Onset of Prednisone RxMielkarek et al. Blood 2003;102:756-762

Sample Size198 Patients• To demonstrate absolute 20% decrease in need for treatment(60% to 40%).• Allowing for 2% drop out• Half will receive Thymoglobulin

Secondary End-Points• Time to engraftment• Incidence of acute GVHD• Incidence of chronic GVHD according to NIH Consensus criteria• Incidence of chronic GVHD according to Sullivan Criteria• Time to non-relapse mortality• Time to all-cause mortality• Time to relapse of leukemia• Incidence of Graft rejection or failure• Incidence of Serious infection• Incidence of CMV activation• Quality of life• Cost effectiveness• Incidence of specific organ grades (NIH) of chronic graft versus host disease• Number of months on immunosuppression up to 12 months post transplant• Proportion of patients needing immunosuppression at 24 months• Doses of immunosuppressive drugs at 12 months• Immunosuppressive therapy at time of diagnosis of cGVHD

Inclusion Criteria1. The recipient is aged between 16 and 702. The recipient has an hematologic malignancy3. The recipient will receive either a bone marrow (“HPC, Marrow”) orblood progenitor cell (“HPC, Apheresis”) graft4. The preparative regimen may be MAbl, NMAbl, or RIC5. The recipient has an unrelated donor who with high resolution typing iseither fully MHC matched at HLA-A, B, C and DRB1 with the recipient oris 1-antigen or 1–allele mismatched at A, B, C or DRB1 loci

Treatment Plan - ThymoglobulinThe experimental intervention is the addition of Thymoglobulinto the standard preparative regimen.The total dose of Thymoglobulin is 4.5 mg/kg (actual bodyweight, not effective body weight), given in divided doses asfollows:Day -2: 0.5 mg/kgDay -1: 2.0 mg/kgDay 0: 2.0 mg/kgDayDayDayDayDayDayDayDay–7–6–5–4–3–2–10 ¤Preparative Regimen(Arms A and B)Myeloablative or non-myeloablative (syn.RIC*)conditioning regimen†GraftInfusionThymoglobulin0.52.02.0(Arm B only)mg/kgmg/kgmg/kg

Treatment Plan – PreparativeRegimensMYELOABLATIVE• CY-TBI• BUCY• BUFLUNON-MYELOABLATIVE (syn. RIC)• BUFLU(ATG) - Slavin• FLU-TBI - Seattle• FLU-MELRegimens containing ATG or Campath not allowed

Flu-Bu-ATG (Slavin) vs F-TBI (Seattle)Tandem Meeting, Orlando, 20105-year overall survival: Flu-Bu-ATG 45%F-TBI 49%

Reviews of NM/RIC Regimens• Banna GL, Aversa S, Sileni VC, Favaretto A, Ghiotto C,Monfardini S. Nonmyeloablative allogeneic stem celltransplantation (NST) after truly nonmyeloablative andreduced intensity conditioning regimens. Critical Reviews inOncology-Hematology. 2004;51:171-189.2. Pollack SM, O'Connor TP,Jr, Hashash J, Tabbara IA.Nonmyeloablative and reduced-intensity conditioning forallogeneic hematopoietic stem cell transplantation: a clinicalreview. American Journal of Clinical Oncology. 2009;32:618-628.

Benefits and Harms• BENEFITS• Less chronic graft versus host disease• Improved quality of life• Lower health care costs• HARMS• {NO increase in mortality, disease relapse or deaths due toinfection}• Post Transplant Lymphoproliferative Disorder (EBV)

Epstein Barr Virus (EBV)BACKGROUND1. Herpes virus type 4.2. Infects over 90% of worlds population, mostly unrecognized, or as IM.3. Latency, like other herpesviruses (HSV, HZV, CMV)4. Latent state in B-lymphocytes5. Highly immunogenic resulting in B-cell proliferation, occasionally malignant.6. Activation controlled by EBV-specific T-cells7. Activation can result in a spectrum of disorders collectively termed PostTransplant Lymphoproliferative Disorder (PTLD).8. Median time to document EBV activation by QPCR following HPCT is 60days (most

PTLD in Unrelated/Mismatch +ATGStudy Activation PTLD DeathsWagner 29.4% 2/46 (4.3%) vs.6/39 (15%) TCDFinke N/A 5/103 (4.9%) vs.1/98 (1%) no ATGRussell (personalcommunication)0/23/6N/A 3/91 (3.3%) 0/3Bacigalupo 0% 0/53 (0%) 0Dominietto 71% (19%>1000) 6/77 (8%) 2/6Deeg 2% (1/56) 0/66 0/0

Management of EBV• Be aware of the possibility; watch for FUO andlymphadenopathy.• Perform QPCR for EBV weekly until day 100• If QPCR shows activation, consider decreasingimmunosuppression.• If symptoms are compatible:– Have a low threshold for imaging and biopsy– Exclude alternative diagnoses– Give rituximab weekly until symptoms and copy number normalize.– Consider DLI if donor EBV antibody-positive.

Performance of QPCR test for EBVAssume prevalence of PTLD will be 3%PTLD YESPTLD NOTEST POS 3 60 PPV 3/63= 0.48%TEST NEG 0 40 NPV 40/(40+0)= 100%Sensitivity3/(3+0)= 100%Specificity40/(40+60)= 40%Rising titres adds specificity.Presence of EBV-specific CTL in blood improves specificity (To 100%?)

Shulman/Sullivan cf. NIHShulman/Sullivan• Time dependent ±100 days• Classification– Classic acute 100 days• Only Skin and Liver diagnostic• No patient centred parametersNIH• Manifestation dependent• Classifications:– Classic acute 100days– chronic any time– Overlap syndrome any time• Skin, lung, mouth, genitalia, GI,lungs, soft tissues are diagnostic• Symptoms and function added,description more detailed e.g.extent, ulceration

cGVHD Manifestions – NIHFilipovich BBMT 2005;11:945 and asbmt.orgFor each organ system manifestations are:• Diagnostic – sufficient to make a diagnosis• Distinctive – needs extra test, clinical, biopsy etc• Other – Rare, controversial, non-specific• Common (shared by both acute and chronic)Diagnostic process:• Presence of at least 1 Diagnostic OR 1 Distinctive + biopsy etc.• Distinguish from acute GVHD• Exclude other possible diagnoses

cGVHD Assessment by NIHFilipovich BBMT 2005;11:945-55 and asbmt.org• Diagnosis (Diagnostic/Distinctive)• Organ Scoring• Global Scoring• Performance Score (Function)– Walk time– Grip Strength– Karnofsky

cGVHD Case Report Form (CRF)

cGVHD Case Report Form (CRF)

cGVHD Case Report Form (CRF)

cGVHD Case Report Form (CRF)

Body Surface Area (Rule of 9)

Dermatology Work Sheet

Will CBMTG 0801 succeed?In part for sure

FinkeLancet Oncol 2009;10: 855–64BacigalupoBlood 2001;98:2942BBMT 2006;12:560ATG-Fresenius60 mg/kg totalThymoglobulinLow-dose7.5 mg/kg totalThymoglobulinHigh-dose15 mg/kg totalPrimary End-Point Death/AGVHD III-IV AGVHD III-IVPrimary End-Point NS NS 11% vs 50%, P=.001Infectious Deaths NS NS 30% vs 7%Survival NS NS NSNon RelapseMortalityChronic GVHD 30.8% vs 58.8%p

Flowers ME, Storer BE, Lee SJ, et al. Risk Factors for the Development ofAcute and National Institute of Health (NIH) Chronic Graft-Versus-Host Disease(GVHD). Blood. 2009;114 (abstr 345)

Will CBMTG 0801 succeed?In part for sureIn totality - hopefullyWill the decrease in cGVHD have meaning for patientsi.e. less immunosuppression, better quality of life, andless medicalization…. and for the administrators: noextra cost (or maybe even cost savings)?

Thank you