The Role of Outcomes Registries in Blood and Marrow Transplantation Mary M Horowitz, MD, MS Cape Town, South Africa November 2014 Worldwide Network for Blood and Marrow Transplantation
Transplants A Little History. Reported Human Bone Marrow Transplants, 1958-1968 70 60 BMTs 50 40 30 20 10? 0 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 Years (Source: 1970,9:572) Mmh09_9.ppt Bortin, Transplantation, 1970 2
Transplants Transplant Activity Worldwide 1968-2014 40000 35000 Autologous Allogeneic 30000 25000 20000 15000 10000 5000 0 International Bone Marrow Transplant Registry Established '68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12 3
In the Beginning First Advisory Committee of the International Bone Marrow Transplant Registry Dirk van Bekkum Don Thomas George Mathe Bob Good Mort Bortin George Santos JJ Bergan, JL Fahey, Bob Levey, GN Rogentine Fritz Bach 4
Transplants OUTCOMES REGISTRIES A Part of the HCT Community Since the Beginning and Continuing to Grow 40000 35000 30000 25000 20000 15000 10000 5000 IBMTR 1970; EBMT - 1974 National: US, Japan, Germany, France, etc 1980s-90s International: Asian-Pacific BMT Group; Eastern Mediterranean BMT Group; Eurocord 1990s- 2000s; LABMT - emerging NMDP Established IBMTR Established NMDP & IBMTR join to form CIBMTR 0 '68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12 5
First 200 Patients Reported to IBMTR 1968-73, 11 Countries, 35 Centers 82 with Malignancy; 108 with SCID/Marrow Failure USA France Netherlands Switzerland Canada United Kingdom Denmark Germany Italy Australia Hungary
International Bone Marrow Transplant Registry - 1985 1970-1985 200 centers 1,000 transplants 35 publications Mortimer M. Bortin, MD Scientific Director Al Rimm, PhD Statistician D Etta Waldoch Sharon Nell Diane Knudsen Data Management Karen Gurgul Admin. Assistant 7
Key Contributions Transplants Can Be Done Safely and Can Cure Bortin MM, Rimm AA. ACS-NIH organ transplant registry. 2nd scientific report. JAMA. 1972 Bortin MM, Buckner CD. Major complications of marrow harvesting for transplantation. Experimental Hematology. 1983 Disease Specific Outcomes Bortin MM, Rimm AA. Severe combined immunodeficiency disease: characterization of the disease and results of transplantation. Transplantation Proceedings. 1977 Bortin MM, Rimm AA. Bone marrow transplantation for acute myeloblastic leukemia. JAMA. 1978. Bortin MM, Rimm AA. Allogeneic bone marrow transplantation for of 144 patients with severe aplastic anemia. JAMA. 1981 Gale RP, Kersey JH, Bortin MM, Dicke KA, Good RA, Zwaan FE, Rimm AA. Bone-marrow transplantation for acute lymphoblastic leukaemia. Lancet. 1983. Speck B, Bortin MM, Champlin RE, Goldman JM, et al. Allogeneic bonemarrow transplantation for chronic myelogenous leukaemia. Lancet. 1984 8
Key Contributions Risk Factors Bortin MM, Rimm AA. Factors influencing success and failure of human marrow transplantation: a review from the International Bone Marrow Transplant Registry. Experimental Hematology Today. 1979 Bortin MM, Kay HEM, Gale RP, Rimm AA. Factors associated with interstitial pneumonitis after bone-marrow transplantation for acute leukaemia. Lancet. 1982 Bortin MM, Gale RP, Kay HEM, Rimm AA. Bone marrow transplantation for acute myelogenous leukemia. Factors associated with early mortality. JAMA. 1983 HLA Associations Rimm AA, Bortin MM. HLA antigens and SCID. Lancet. 1977 D'Amaro JD, van Rood JJ, Rimm AA, Bortin MM. HLA associations in Italian and non-italian Caucasoid aplastic anaemia patients. Tissue Antigens. 1983 D'Amaro JD, van Rood JJ, Bach FH, Rimm AA, Bortin MM. HLA C associations with acute leukaemia. Lancet. 1984 9
Why are Large Registries Still Necessary? SMALL NUMBERS Annual Numbers of HCTs vs Numbers of Selected Cancers in the US Breast Pancreas HCT Ovary Stomach Brain Liver Sarcomas 0 50000 100000 150000 200000 10
Distribution of Allotransplant Volumes Among 162 US Centers Reporting Data to CIBMTR in 2012 2% 8% 52% 19% 19% <200 100-199 50-99 31-49 <30 Individual transplant centers treat relatively few patients and these patients are heterogeneous in many factors that affect outcomes 11
95% Confidence Intervals for Samples Drawn from a Population Receiving a Treatment Producing 50% Survival Probability, % 100 70% Publish 50 40% Don t publish 0 0 10 20 30 40 50 60 70 80 90 100 200 300 Sample Size, N 12
Transplants CIBMTR 420,000 Cases Registered, 1985-2013 > 900 Publications 450000 400000 350000 300000 250000 200000 150000 100000 50000 0 Descriptive Allogeneic Autologous Cumulative Total Multicenter Clinical Trials Technology Assessment Prognostic factors Health Services Research QOL, Long-term Follow-up Immunobiology* *NMDP Repository - Specimens for >33,000 donor-recipient pairs. '85 '87 '89 '91 '93 '95 '97 '99 '01 '03 '05 '07 '09 '11 '13 Years 13
Probability, % The Value of Outcome Registries: Identifying patients most likely to benefit from BMT 100 80 Probability of Overall Survival after HCT for AML not in Remission by CIBMTR Risk Score 60 40 20 0 Risk score = 0, N = 148, 42% (39-50) Risk score = 1, N = 326, 27% (23-33%) Risk score = 2, N = 342, 15%(11-19%) Risk score = 3, N = 321, 6%(3-9%) 0 1 2 3 Years Duval, JCO, 2010 14
The Value of Outcomes Registries: Evaluating Graft Sources 15
The Value of Outcomes Registries: Changing Practice - US Cord Blood Transplants, 1990-2011 Number of transplants 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 500 450 400 350 300 250 200 150 100 50 0 Adults Children 16
Survival The Value of Outcome Registries: Understanding the Influence of HLA Survival Survival 8/8 Match 7/8 Match 6/8 Match 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60 1.0 Early Disease Stage Intermediate Disease Stage Advanced Disease Stage 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60 0.0 0 12 24 36 48 60 Months after transplant Months after transplant Months after transplant S. Lee, et al. Blood 2007 Showed impact of single allele mismatch at A, B, C and DRB1: changed the paradigm for selecting adult donors 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 17
Survival After Unrelated Donor Transplantation Age <50 years, myeloablative conditioning, acute leukemia in remission or MDS Probability, % 100 90 80 Adjusted 1-year Overall Survival 70 60 50 40 30 20 10 Odds of 1-year survival increased by 8% per year (95% CI, 7-9%) on average between 1990 and 2011 0 Year of Transplant 18
Probability of Survival, % Adjusted Probability of Survival After Transplantation for AML, 2002-2006 100 90 80 70 100 90 80 70 60 50 40 30 20 10 7/8 MUD (N=406) 8/8 MUD (N=1,193) HLA-id Sib (N=624) 60 50 40 30 20 10 0 0 0 6 12 18 24 30 36 Months 19
CIBMTR EMMES NMDP BMT CTN Early and ongoing collaboration with cooperative groups to synergize and avoid duplication (intensified since 2005) DCC 2001 2002 Developed Infrastructure ECOG CALBG BMT CTN Steering Committee SWOG COG PUBLICATIONS Primary Outcome Safety, Secondary Outcome, or Design Submitted, Primary Outcome Total Subjects = 450 1,050 1,625 2,150 2,625 3,050 3,450 4,300 7,000 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 9 trials this grant cycle 0903: Allo for HIV-malignancy 1101: Haplo vs Double Cord 1202: Biomarker collection 1204: RIC for HLH 1102: BMT vs Chemo for MDS = Enrollment/follow-up complete = Enrollment complete; ongoing F/U = Enrollment on-going 0202 PIII follicular NHL (closed early) 0201 PIII Unrelated PBSC vs. Marrow 0101 PIII Vori vs. Fluconazole 0102 PIII Myeloma Tandem HCT 1205: Patient-friendly Consent 1304: Early vs Late BMT for MM 1203: GVHD proph in RIC BMT 1301: CNI-free GVHD proph (soon) 0301 PII Unrelated Tx for aplastic anemia 0401 PIII BEAM vs BEAM-Bexxar for Lymphoma 0302 PII AGVHD therapy + + 0303 PII T-depleted HCT for AML + 0402 PIII GVHD prophylaxis 0604 PII DCB in Adult 0603 PII Haplo in Adult 0601 PII Sickle Cell NST 0703 PII HD 0701 PII NST for NHL 0702 PIII Myeloma Follow-on 0403 PIII Etanercept for IPS (closed early) 0704 PIII MM maintenance 0502 PII NST for AML >60y 0501 III Single vs. Double CBT + + 0803 HIV+ Lymphoma 0805 Ph+ ALL 0801 P II/III CGVHD Treatment 0802 PIII AGVHD Treatment 0804 High Risk CLL 0902 Stress Mgmt 1301 1203 1102 + 1304 1205 1204 1202 1101 Haplo vs. UCB 0903 Allo HIV+ 0901 Full vs. RIC - MDS/AML 20
The Value of Global Outcome Registries: Understanding Late Effects www.ebmt.org 21
The Value of Outcome Registries: Influencing National Public Policy Most US patients 65+ years have health insurance through Medicare which did not cover BMT for MDS August 2010: Medicare, in part because of existing CIBMTR data, decided it would cover costs of BMT but ONLY if patients enrolled in an IRB-approved study that will provide CMS with data to determine the value of the procedure in the Medicare population CIBMTR used its infrastructure to open a study using EXISTING data collection mechanisms (minimal additional work of transplant centers) 22
US Allogeneic Transplants for MDS in patients older than 65, 2005-2013 250 200 150 100 50 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 23
The Value of Global Outcome Registries: Understanding Trends in Use, Practice and Outcomes Low middle high income 24
The Value of Global Outcomes Registries: Understanding Macro-Economic Influences on Survival Globally 1.0 LEUKEMIA-FREE SURVIVAL Probability 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1st percentile 2nd percentile 3rd percentile 4th percentile 5th percentile Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia (Giebel at al, Blood 2010) 0 1 2 3 4 5 6 7 8 Years after allo-hsct 25
Why Should a Registry be Considered When BMT is Just Developing in a Country or a Region?
Because to Develop a Therapy Effectively, We Need DATA Assessment identify the most important problems and most promising solutions Analysis - determine efficacy overall and for specific subgroups/regions; monitor longterm outcomes Advancing best practices - Optimize treatment strategies/improve outcome in the real world with real resource constraints Allocation of resources research and clinical care 27
Data Are Needed: At the center level Quality improvement Understanding costs and resource needs (and making the case for them to hospital and local authorities) Scientific study At the national level Understanding access, costs and resource needs (and making the case for them) To advance best practices 28
Data Are Needed: At the regional level Facilitate research relevant to regional issues The process of sharing data also creates opportunities for professional, educational and scientific collaboration in a community that faces similar challenges and affords the potential for sharing expertise and resources At the global level To understand differences and commonalities in access, practice and outcomes To advance the science and practice of HCT To communicate with regulatory and funding bodies about needs 29
It is Important to Incorporate Careful Data Collection and Analysis Early Because building a culture of evaluating and understanding outcomes is critical for effective quality management systems to improve patient care building an effective clinical research infrastructure to improve patient care When numbers of transplants in individual centers and countries are small, sharing data allows examination of important issues with greater power 30
An African Registry Could Offer Some Unique Contributions to Global Understanding of BMT High prevalence of non-malignant hematopoietic disorders Development and evaluation of regimens that ensure engraftment and minimize GVHD Studies of BMT vs non-bmt therapy; HLA-id sib vs haplo or other alternative graft sources Extremely diverse distribution of HLA and other genetic determinants of outcomes insight into permissive vs non-permissive matches/variations Examination of cost-effective approaches to both autologous and allogeneic BMT 31
Levels of Data Collection Start small but plan for growth: What are the most important questions to answer in the next 3-5 years? 5-10 years? 10-15 years? TED/MED-A level data Comprehensive Data (CRF/MED B) Simple Activity Data Basic Outcome Data 32
Thank You If you want to go fast, go alone; if you want to go far, go with others.