5. Scientific Agenda/Studies in Progress a. IS08-01 Transplant Activity Survey in the Americas (M Pasquini) (Attachment 3)

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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR INTERNATIONAL STUDIES Tampa, Florida Thursday, February 12, 2009, 6:30 am 8:30 am Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Mahmoud Aljurf, MBBS, King Faisal Hospital, Riyadh, Saudi Arabia Phone: ; Fax: ; maljurf@kfshrc.edu.sa David Gomez-Almaguer, MD, Hospital Universitario, Monterrey, Mexico Phone: ; Fax: ; dr_gomez@infosel.net.mx Phillip Rowlings, MBBS, MD, Newcastle Mader Hospital, Newcastle, Australia Phone: ; Fax: ; phil_rowlings@yahoo.com.au John Klein PhD, CIBMTR Statistical Center Phone: ; Fax: ; klein@mcw.edu Kathleen Sobocinski, MS, CIBMTR Statistical Center Phone: ; Fax: ; ksobo@mcw.edu Marcelo Pasquini, MD, MS, CIBMTR Statistical Center Phone: ; Fax: ; mpasquin@mcw.edu 1. Introduction a. Introduction of Leadership Team b. Minutes of February, 2008 meeting (Attachment 1) c. Instuctions for sign-in and voting 2. Accrual summary (Attachment 2) 3. Regional Survey/Data a. WBMT Global Survey(Helen Baldomero) d. APBMT (Yoshihisa Kodera/Yoshiko Atsuta) e. EMBMT (Syed.Zaidi/Mahmoud Aljurf) 4. Training/Data Management a. Training Data Managers b. Training Physicians for Research c. Other 5. Scientific Agenda/Studies in Progress a. IS08-01 Transplant Activity Survey in the Americas (M Pasquini) (Attachment 3) 6. Future/Proposed studies a. PROP MM in North vs South America (Milone) (Attachment 4) b. PROP AA by transplant region (Kumar) (Attachment 5) Protocol Development 1

2 Not for publication or presentation c. PROP Global Trends in HCT (Aljurf) (Attachment 6) d. PROP Racial and Geographic Differences in Allo/auto outcomes for AML t (8,21) (Almohareb) (Attachment 7) e. PROP HCT in children in Latin America (Gonzales-Llano) (Attachment 8) f. PROP NST in CML in developing countries (Ruiz-Delgado) (Attachment 9) 7. Other Business 2

3 Attachment 1 M I N U T E S CIBMTR WORKING COMMITTEE FOR INTERNATIONAL STUDIES San Diego, California Wednesday, February 13, 2008 Co-Chair: Co-Chair: Co-Chair: Statisticians: CIBMTR Sci Dir: Mahmoud Aljurf, MBBS, King Faisal Hospital, Riyadh, Saudi Arabia Phone: ; Fax: ; maljurf@kfshrc.edu.sa David Gomez-Almaguer, MD, Hospital Universitario, Monterrey, Mexico Phone: ; Fax: ; dr_gomez@infosel.net.mx Phillip Rowlings, MBBS, MD, Newcastle Mader Hospital, Newcastle, Australia; Phone: ; Fax: ; phil_rowlings@yahoo.com.au John Klein PhD, CIBMTR Statistical Center Phone: ; Fax: ; klein@mcw.edu Kathleen Sobocinski, MS, CIBMTR Statistical Center Phone: ; Fax: ; ksobo@mcw.edu Marcelo Pasquini, MD, MS, CIBMTR Statistical Center Phone: ; Fax: ; mpasquin@mcw.edu Participants: Abecasis, Manuel Aljurf, Mahmoud (Co-Chair) Atsuta, Yoshiko Fasth, Anders Ghavamzadeh, Ardeshir Gomez-Almaguer, David (Co-Chair) Keating, Armand Kernan, Nancy Lewis, Victor Milone, Gustavo Pasquini, Ricardo Rowlings, Philip (Co-Chair) Sales-Bonfim, Carmem Schouten, Harry Schultz, Kirk Seber, Adriana Suzuki, Ritsuro Szer, Jeffrey Van Biesen, Koen Vigorito, Afonso Wu, Roy Yoshimi, Ayami PORTUGAL SAUDI ARABIA JAPAN SWEDEN IRAN MEXICO CANADA USA CANADA ARGENTINA BRAZIL AUSTRALIA BRAZIL NETHERLANDS CANADA BRAZIL JAPAN AUSTRALIA USA BRAZIL USA JAPAN Staff: Pasquini, Marcelo (Scientific Director) Eapen, Mary CIBMTR CIBMTR 3

4 Attachment 1 Hari, Parameswaran Horowitz, Mary Klein, John P. Rizzo, J. Douglas Rocha, Vanderson (Visiting Professor) Watry, Paula CIBMTR CIBMTR CIBMTR CIBMTR CIBMTR CIBMTR The meeting was called to order by the Scientific Director, Dr. Marcelo Pasquini (MP), at 6:55 A.M. 1. Administrative Functions MP reported that in fall 2007 nominations were invited for three Chair positions for this committee. The CIBMTR Nominating Committee reviewed the 16 nominees and selected Dr. Mahmoud Aljurf (MA, Riyadh, Saudi Arabia), Dr. David Gomez-Almaguer (DGA, Monterrey, Mexico) and Dr. Phillip Rowlings (PR, Newcastle, Australia). The CIBMTR Advisory Committee approved these appointments and this is the first meeting managed by the new Chairs. Terms will be 5 years except for year staggering at this time to maintain continuity in the future. All other attendees introduced themselves The minutes of the February 12, 2007 meeting were approved. The first chore for the new Chairs will be to finalize the committee Charter, drafted this past year. It was reiterated that membership to this committee is open to any interested individuals. 2. Review Of Initiatives MP stated that the vision for the work of this committee is conceptualized within a network of centers which led to open discussion. Several points are highlighted. Forms Translation PR first mentioned the special challenge regarding translating the forms. He asked Dr. Yoshiko Atsuta to review activities in the Asia Pacific Blood and Marrow Transplantation Group. She noted that they first started by establishing an activity survey in Twelve interested countries in the region (not all English speaking) agreed to form a Registry and to use CIBMTR forms. English is the primary language at all business meetings and forms/manuals are published in English. There were many suggestions including: - use Europe as a model where many languages are spoken amongst member countries. - survey data managers to determine actual numbers interested and languages spoken. - have CIBMTR staff travel to member sites but have the region itself organize the training session and seek funding from local industry. - get to bosses : identify key physicians or investigators with regional influence with interest in clinical research to assist in the implementation of ISC initiatives. - pursue any funding mechanism possible to support travel grants (for data managers attending Tandem/Council) or sponsorship of CIBMTR day at other international meetings. - decentralizing approach to regional member societies to tackle language barriers All in attendance agreed: - Focus on forms translation and data manager training - Need champions within regions - Centers interested in getting data back 4

5 Attachment 1 Survey of South America Dr. Sergio Giralt first asked Dr. Dietger Niederwieser to review the efforts of the new Worldwide Network for Blood and Marrow Transplantation (WBMT) group. Dr. Niederwieser reported that this evolved since the institution of activity surveys in Europe but the concept now has expanded to a global registry. The founding member groups, EBMT, CIBMTR, APBMT and WMDA, have met on several occasions. They estimate that 60,000 transplants are performed annually worldwide and it would be to everyone s benefit to share data at that level. Some issues discussed already are the challenges of regulations and also the unique identification of centers and recipients. He encourages pursuing a Latin American activity survey. He suggests the regions themselves must deal with the logistics of ID numbers but that the CIBMTR can offer substantial support to the centralization of data sharing/activity. Again there was much discussion with these highlights: - Regions must establish National Registries; they then help seek/allocate funding for data manager travel - Translate a survey document first, then use as a model for all registries - Establish a mailing distribution list ( string ) per country o Need primary contact o Consider country codes (work with EBMT/APBMT) Start with region codes o Regional alignment may be an issue for some countries - Associate with these national societies - Establish relationship with Health Ministries suggest reimburse centers only if data forms submitted as Med A (a national mandate ) o o Focus on National Registry concept; purview of regions Dr. R. Pasquini reported that when he started the Brazilian registry, 90% agreed to submit data to CIBMTR. National meetings (Latin America) were easily coordinated once established society o Key is how to get data get people who pay involved - Use CIBMTR as good standardized data registry ; can return consolidated data to centers; Societies can support regional data collection but cannot provide infrastructure for data handling/analysis - First determine who has a Society (survey); establish Directory Update on Development of Middle East/North Africa Registry MA described the survey used within this Registry. Six of 17 centers belong to either EBMT or CIBMTR. He suggests a more global survey tool could be done in stages first asking only about retrospective transplant activity; then eventually data collection tools harmonized with EBMT/CIBMTR. Perhaps a minited type of form could be designed using a pre-, post-ted model. He has had success requesting financial support from Pharma (Novartis). English and French are the most commonly spoken languages in the region so document translation has not been a large problem. 3. Scientific Agenda MP noted that one of the missions of this committee is to attract more non-us input to, and involvement in, its data collection and publication efforts. He announced that this committee has been granted full Working Committee status meaning actual statistical hours will be assigned to studies performed within this committee in the future. These studies should address regional issues having impact on the performance and/or outcome of hematopoietic stem cell transplantation. Committee structure is now in place and he challenges that we aim for a goal of four proposals submitted this year for consideration at the 2009 BMT Tandem meetings. Surveys such as those discussed at this meeting could be proposal 5

6 Attachment 1 topics. He suggests using the well established activity survey developed by Dr. Alois Gratwohl of the EBMT as the best model. Mary Horowitz said the initiatives established today should be formalized in order to get insight into problems regionally. She supports the development of two subcommittees: - International Training o Decide need for translation/training Disadvantage: they must be translated and back-translated o Decide who/where to go for training or to train o Consider developing web-based training modules - Regional Registry Support o Decide how best CIBMTR can support and share 4. International Presentations Both Drs. Adeshir Ghavamsadeh (Iran) and Julio Voltarelli (Brazil) were invited to present information about transplant activities and challenges within their respective regions. Dr. Voltarelli was unable to arrive early enough for his presentation. Dr. Ghavamsadeh gave a brief presentation about the activity of HCT in Iran. The national program was initiated in 1991 with only 6 available beds. This has been expanded to 32 beds. He presented activity in several diseases spanning from acute and chronic leukemia to non-malignant indication. He focused their experience on transplantation for Thalassemia, for which they performed 342 patients to date. The most common graft source is peripheral blood stem cells, although they started to use umbilical cord blood as a graft source in selected cases. The majority of transplants are allogeneic with HLA-match sibling donors. Conditioning regimens are mainly non-irradiation containing combinations since total body irradiation is not available. He finalized by showing a few case examples and pictures of his institution. 5. Review Of Action Items - Chairs to finalize committee Charter - CIBMTR to prepare a distribution list for Latin American countries o Carmem Sales Bonfim to distribute activity survey - CIBMTR to establish Global Directory - CIBMTR/ISC/Regional Societies to research additional funding opportunities - Chairs/ISC identify members for two subcommittees: o International Training o Regional Registry Support With no further business the meeting adjourned at 7:55 A.M. 6

7 Not for publication or presentation Attachment 2 Accrual Summary for International Studies Committee Numbers of patients and transplant centers registering with the CIBMTR between 2000 and 2006 by country within WHO regions Patients Allogeneic transplants Autologous Transplants Number of Teams N (%) N N N Country of Center Africa South Africa 451 (<1) Americas Argentina 1528 ( 1) Brazil 2842 ( 3) Canada 7218 ( 7) Chile 3 (<1) Columbia 59 (<1) Costa Rica 1 (<1) Cuba 6 (<1) Mexico 430 (<1) Panama 25 (<1) Peru 82 (<1) Uruguay 639 (<1) USA (59) Venezuela 232 (<1) Eastern Mediterranean Egypt 751 (<1) Kuwait 8 (<1) Pakistan 140 (<1) Saudi Arabia 919 ( 1) Europe Austria 640 (<1) Belgium 1030 (<1) Czechoslovakia 799 (<1) Denmark 452 (<1) England 2560 ( 2) Finland 389 (<1) France 1570 ( 1) Germany 4468 ( 4) Greece 97 (<1) Hungary 117 (<1) Iran 977 ( 1) Ireland 247 (<1) Israel 1021 ( 1) Italy 2130 ( 2) Netherlands 362 (<1) Norway 18 (<1) Poland 677 (<1)

8 Not for publication or presentation Attachment 2 Continued. Patients Allogeneic transplants Autologous Transplants Number of Teams N (%) N N N Portugal 385 (<1) Russia 370 (<1) Scotland 423 (<1) Spain 1810 ( 2) Sweden 705 (<1) Switzerland 674 (<1) Turkey 663 (<1) SE Asia India 502 (<1) Korea 1817 ( 2) Western Pacific Australia 2627 ( 2) China 75 (<1) Hong Kong 216 (<1) Japan 788 (<1) Malaysia 118 (<1) New Zealand 304 (<1) Singapore 259 (<1) Taiwan 213 (<1) Total 110,

9 Not for presentation or publication Attachment 2 Accrual Summary for the International Studies Working Committee Characteristics of recipients of allogeneic transplants by WHO region registered with the CIBMTR between 2000 and 2006 Variable Africa Americas a Mediterranean Europe SE Asia Western Pacific Eastern Number of Patients Number of Centers Age, years 38 (<1-65) 39 (<1-93) 17 (<1-57) 35 (<1-83) 29 (<1-65) 37 (<1-82) ( 6) 4969 (15) 582 (33) 2202 (13) 344 (15) 533 (15) (14) 4071 (12) 473 (26) 2293 (13) 380 (17) 454 (12) (14) 3590 (11) 402 (22) 2558 (15) 477 (21) 461 (13) (20) 4384 (13) 220 (12) 2954 (17) 541 (24) 590 (16) (23) 6357 (19) 99 ( 6) 3348 (19) 414 (18) 719 (20) (21) 6591 (20) 14 ( 1) 2862 (17) 91 ( 4) 698 (19) ( 1) 2586 ( 8) ( 6) 15 ( 1) 181 ( 5) (<1) (<1) -- 5 (<1) Male sex 171 (63) (59) 1089 (61) 9982 (58) 1347 (60) 2165 (60) Year of Transplant (16) 4249 (13) 188 (11) 3015 (17) 316 (14) 673 (18) (19) 4063 (12) 179 (10) 3000 (17) 294 (13) 574 (16) (15) 4494 (14) 262 (15) 2822 (16) 322 (14) 542 (15) (16) 4608 (14) 261 (15) 2397 (14) 304 (13) 484 (13) (16) 4849 (15) 294 (16) 2192 (13) 362 (16) 454 (12) (11) 5128 (16) 308 (17) 2112 (12) 309 (14) 485 (13) ( 8) 5324 (16) 298 (17) 1726 (10) 355 (16) 429 (12) Primary Disease AML 565 (21) 9903 (30) 381 (21) 5207 (30) 746 (33) 1121 (31) ALL 22 ( 6) 5383 (16) 233 (13) 3182 (18) 363 (16) 706 (19) CML 47 (17) 3407 (10) 307 (17) 2568 (15) 347 (15) 440 (12) MDS 23 ( 8) 3494 (11) 83 ( 5) 1662 (10) 171 ( 8) 353 (10) 9

10 Not for presentation or publication Attachment 2 Continued. Variable Africa Americas A Mediterranean Europe SE Asia Western Pacific Eastern NHL 39 (14) 3573 (11) 18 ( 1) 1004 ( 6) 25 ( 1) 330 ( 9) HD 2 ( 1) 338 ( 1) 3 (<1) 165 ( 1) 3 (<1) 16 (<1) MM 20 ( 7) 532 ( 2) 1 (<1) 386 ( 2) 7 (<1) 82 ( 2 ) Other Malignancy 8 ( 3) 2119 ( 6) 35 ( 2) 860 ( 5) 89 ( 4) 199 ( 5) SAA 41 (15) 1776 ( 5) 295 (16) 782 ( 5) 357 (16) 149 ( 4) Other Non-malignancies 13 ( 5) 2162 ( 7) 434 (24) 1357 ( 8) 154 ( 7) 243 ( 7) Missing (<1) 91 (<1) -- 2 (<1) Graft Type Bone Marrow 15 ( 6) (35) 759 (42) 6021 (35) 1526 (67) 1344 (37) PBSC 253 (93) (55) 934 (52) (60) 642 (28) 1930 (53) Cord Blood 1 (<1) 2871 ( 9) 89 ( 5) 500 ( 3) 81 ( 4) 31 ( 8) Other/missing 2 ( 1) 449 ( 1) 8 (<1) 431 ( 2) 13 ( 1) 66 ( 2) Donor HLA-identical 193 (71) (47) 1635 (91) 9265 (54) 1504 (66) 1912 (53) sibling Other relative 16 ( 6) 2607 ( 8) 88 ( 5) 1266 ( 7) 86 ( 4) 357 (10) Unrelated 61 (23) (42) 59 ( 3) 6446 (37) 647 (29) 1283 (35) Other/missing 1 (<1) 813 ( 2) 8 (<1) 287 ( 2) 25 ( 1) 89 ( 2) a US (83) Canada 2871 ( 9) Central - S. Am 2776 ( 8) 10

11 Not for presentation or publication Attachment 2 Accrual Summary for the International Studies Working Committee Characteristics of recipients of autologous transplants by WHO region registered with the CIBMTR between 2000 and 2006 Variable Africa Americas Mediterranean Europe SE Asia Pacific a Eastern Western Number of patients Number of centers Age at transplant 46(<1-70) 52(<1-91) 38(18-60) 48(<1-78) 42(13-61) 51(1-83) 0-9 6( 3) 2296( 5) 258( 5) 36( 4) ( 7) 1661( 4) 1( 4) 323( 6) 7(12) 40( 4) (12) 3349( 7) 4(14) 558(10) 7(12) 91( 9) (13) 4565(10) 11(39) 715(13) 13(23) 107(11) (29) 8207(18) 9(32) 1074(20) 21(37) 193(20) (28) 13618(30) 2( 7) 1616(30) 8(14) 289(30) ( 8) 10257(22) 1( 4) 745(14) 1( 2) 189(20) ( 4) 31( 1) 14( 1) Male sex 110(61) 26361(58) 18(64) 3125(59) 39(68) 609(64) Year of transplant (18) 5922(13) 3(11) 1430(27) 10(18) 165(17) (11) 5874(13) 1126(21) 5( 9) 145(15) (21) 5988(13) 17(62) 1115(21) 11(19) 138(14) (19) 6212(14) 5(18) 626(12) 7(12) 170(18) (13) 6990(15) 1( 4) 469( 9) 5( 9) 126(13) (13) 7269(16) 2( 7) 335( 6) 8(14) 106(11) ( 6) 7374(16) 219( 4) 11(19) 109(11) 11

12 Not for presentation or publication Attachment 2 Continued. Variable Africa Americas a Eastern Mediterranean Europe SE Asia Western Pacific Primary Disease AML 13( 7) 2244( 5) 498( 9) 17(30) 69( 7) ALL 4( 2) 204(<1) 146( 3) 3( 5) 15( 2) CML 53(<1) 70( 1) 4(<1) MDS 1( 1) 71(<1) 1( 4) 33( 1) 2( 4) 7( 1) NHL 55(31) 13843(30) 9(32) 1634(31) 7(12) 383(40) HD 21(12) 5859(13) 10(36) 578(11) 1( 2) 79( 8) PCQ 74(41) 17743(39) 8(29) 1557(29) 25(44) 333(35) Other malignancy 8( 4) 5308(12) 737(14) 2( 4) 60( 6) SAA 4(<1) 1(<1) 1(<1) Other malignancy 4( 2) 285(1) 58( 1) 7( 1) Missing 15(<1) Graft type Bone Marrow 1013( 2) 160( 3) 1( 2) 13( 1) PBSC 175(97) 43500(95) 22(79) 4107(77) 7(12) 766(80) Cord Blood Other/missing 5( 3) 1116(2) 6(21) 1052(20) 49(86) 180(19) a US 38212(84) Canada 4347(10) Central - S. Am 3070( 7) 12

13 Not for publication or presentation Attachment 3 CIBMTR IS08-01 HEMATOPOIETIC CELL TRANSPLANTATION ACTIVITY SURVEY IN THE AMERICAS: WBMT GLOBAL SURVEY Study Chairs: Willem Bujan B., MD Programa Transplante de Celulas Madre S. de Hematologia, Hospital Mexico San Jose, Costa Rica Tel/ Fax: wbujan@racsa.co.cr Marcelo C. Pasquini, MD, MS CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Ave, CC5500 Milwaukee, WI USA Telephone: Fax: mpasquin@mcw.edu Helen Baldomero, MD University Hospital Hematology Petersgraben Basel Switzerland Tel.: Fax: baldomeroh@uhbs.ch Study Statistician: Kathleen Sobocinski, MS CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Ave, CC5500 Milwaukee, WI USA Telephone: Fax: ksobo@mcw.edu 13

14 Not for publication or presentation Attachment 3 Working Committee Chairs: Mahmoud Aljurf, MBBS King Faisal Hospital Riyadh, Saudi Arabia Phone: Fax: maljurf@kfshrc.edu.sa David Gomez-Almaguer, MD Hospital Universitario Monterrey, Mexico Telephone: (52) Fax: (52) dr_gomez@infosel.net.mx Phillip Rowlings, MBBS, MD Newcastle Mader Hospital Newcastle, Australia Phone: Fax: phil_rowlings@yahoo.com.au Scientific Director: Statistician: Marcelo C. Pasquini, MD, MS CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Ave, CC5500 Milwaukee, WI USA Telephone: Fax: mpasquin@mcw.edu John Klein, PhD CIBMTR Statistical Center Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: klein@mcw.edu 14

15 Not for publication or presentation Attachment OBJECTIVES: 1.1 To compile annual transplant activity in all countries in the American continents. Combine the data with transplant activity data from other regions for the WBMT World Transplant Activity Survey. 2.0 SCIENTIFIC JUSTIFICATION: Hematopoietic cell transplantation (HCT) is a specialized and high costly procedure, utilized for the treatment of a number of malignant and non malignant diseases. Presently, HCT have been incorporated as standard of care for several disease indications. Thus, the activity of transplantation worldwide increased significantly in the last two decades. Data reported to the CIBMTR, European Blood and Marrow Transplant (EBMT) group and the Asian Pacific Blood, Marrow Transplant (APBMT) registry and Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group confirms this trend in transplant numbers(1-5). Autologous HCT are done more frequently than allogeneic HCT and acute leukaemias are the most common indication for allogeneic HCT and lymphoproliferative diseases the most common indication for autologous HCT(3, 5). However, transplant activity is different depending on the country or regions. High cost of this procedure and difficult access to limited number of transplant centers in a country may contribute to differences in the overall profile of transplant practices in a country or region. The EBMT performs an annual survey to transplant centers to assess number of transplants performed during that year by indications, donor type and graft source(6). The data collection through a simple form resulted in important information on transplant trends in European countries for almost two decades. Incorporating this data with economic indexes, such as the gross national income (GNI) from the World Bank, demonstrated discrepant transplant activity depending on the per capita income in a country(7). Countries classified as low income based on this index, had a sluggish growth on transplant activity comparing to countries with intermediate and high per capita income. Regional differences where also evident based on other factors such as number and location of transplant centers in a country and difference in disease prevalence(8). This data not only demonstrate a snap shot of transplant activity in a region, which may help better allocation of resources, but also might identify important trends worth of further investigation. Transplant data in the Americas is mainly derived from the CIBMTR, which relies on voluntary reporting by transplant centers. The vast majority of data are from US, Canada, Brazil, Argentina and Mexico. However, not all centers from countries in Latin America report to the CIBMTR and thus the true transplant activity in this region is not completely known. The data in US has also differential reporting depending on transplant and donor types. Allogeneic HCT from unrelated donors are, in the vast majority facilitated by the National Donor Program (NMDP) which requires mandatory reporting. This data is shared with the CIBMTR. Allogeneic HCT from related donor for US transplant donors became mandatory in 2008 with the implementation of the Stem Cell Therapeutics Outcomes Database (SCTOD). Reporting of any autologous HCT, regardless of region, remains voluntary. Thus the CIBMTR data is under represented depending on the region and donor type. Application of the EBMT survey to the Americas would offer an opportunity to understand the transplant practices for this region, highlight difficulties with access to transplantation, be an important data for the transplant community in general and identify areas for future studies. 15

16 Not for publication or presentation Attachment 3 This project will be done as collaboration among the HCT registries: CIBMTR, EBMT, APBMT and EMBMT under the auspices of the Word Blood and Marrow Transplant (WBMT). 3.0 STUDY POPULATION: The study population include all patients who received an HCT for any indication in American centers during one year. The first report will focus on patients who received an HCT in All identified transplant centers from North, South and Central America will be invited to participate independent of size or number of transplants performed. 4.0 VARIABLES TO BE ANALYZED: Data collected for the survey include transplant indications, graft type and donor type. Figure 1 include a sample of the survey and figure 2 the same survey in Spanish. Additional variables that will be included in the analysis are the number of transplant per country, number of transplant centers by the country population according to the US census and distribution of transplant centers per area by each county or region. The EBMT survey uses a measure of team distribution which refers to the number of transplant centers per 10,000 Km 2 (8). We intend to use a similar estimate for the America data. 5.0 STUDY DESIGN: The study is a survey of transplant centers using the EBMT activity survey. The data will be analyzed and summarized by descriptive statistics. Transplant centers will be identify according the the CIBMTR database, National Societies Memberships and through personal contact with transplant physicians from different countries. We will develop a comprehensive list of centers from the Americas and submit the survey for data related to transplants performed in REFERENCES: 1. Aljurf MD, Zaidi SZ, El Solh H, Hussain F, Ghavamzadeh A, Mahmoud HK, et al. Special issues related to hematopoietic SCT in the Eastern Mediterranean region and the first regional activity report. Bone Marrow Transplant. 2008;43(1): Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med Oct 11;357(15): Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A. EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplant.37(12): Kodera Y. The Japan Marrow Donor Program, the Japan Cord Blood Bank Network and the Asia Blood and Marrow Transplant Registry. Bone Marrow Transplant.42(S1):S6-S. 5. Pasquini MC, Wang Z, Schneider L. Current use and outcome of hematopoietic stem cell transplantation: part I CIBMTR Summary Slides, CIBMTR Newsletter [serial online] 2007;13(2): Gratwohl A, Schmid O, Baldomero H, Horisberger B, Urbano-Ispizua A. Haematopoietic stem cell transplantation (HSCT) in Europe Changes in indication and impact of team density. A report of the EBMT activity survey. Bone Marrow Transplant.34(10): Gratwohl A, Passweg J, Baldomero H, Horisberger B, Urbano-Ispizua A. Economics, 16

17 Not for publication or presentation Attachment 3 health care systems and utilization of haematopoietic stem cell transplants in Europe. Br J Haematol May;117(2): Gratwohl A, Baldomero H, Frauendorfer K, Niederwieser D. Why are there regional differences in stem cell transplantation activity[quest] An EBMT analysis. Bone Marrow Transplant.42(S1):S7-S10. 17

18 Not for publication or presentation Attachment 3 Figure 1: EBMT Activity survey 18

19 Not for publication or presentation Attachment 3 Figure 2: Spanish version 19

20 Not for publication or presentation Attachment 4 Study Proposal Study Title: Outcome of autologous hematopoietic progenitor cell transplantation (AHPCT) in patients with multiple myeloma, comparison of patients from North vs South America. Gustavo Milone, MD, Angelica Ocampo-Hospital and Research Center-Fundaleu Uirburu, Buenos Aires C1114AAN, Argentina Specific Aims: AHPCT is an effective therapy for patients with multiple myeloma as first or second line consolidation. Different approaches are used in different centers in different countries that induces different results. This study aims to analyze the outcome of AHPCT in patients with multiple myeloma in North vs South America. Scientific Justification: Multiple myeloma is a disease characterized by the clonal proliferation of a single clone of plasma cell inducing the production of monoclonal immunoglobulin that develop anemia, lytic bone lesion, hypercalcemia nad renal failure. At present most of the patients are consolidated with AHPCT after first line therapy as part of the induction treatment, different results are obtained in different countries, depending in different approaches, conditioning regimens and supportive care. In the absence of prospective trials, the only way to see the outcome of the patients receiving autologous transplantation in America is trougth a retrospective analyses in the group of patients reported to the CIBMTR with multiple myeloma. Patient Eligibility Criteria: Disease and transplant related data will be collected retrospectively and devided in two groups of patients from centers belonging to North and South America. The analyses will include patients characteristics, disease parameters at diagnosis, prior treatment to AHPCT, disease status at time of AHPCT, pretransplant organ function, source of stem cells and details of mobilization, conditioning regimens, cytokine support and engraftment details, non-hematopoietic toxicity information, response information, long term toxicity and quality of life. Data Collection: Data will be collected using CIBMTR initial forms for multiple myeloma and for follow-up. 20

21 Not for publication or presentation Attachment 4 Characteristics of patients who underwent autologous transplantation for Multiple Myeloma reported to the CIBMTR between 1995 and 2005, by region. North America South America Variable N (%) N (%) Number of patients Number of centers Country USA 3164 (92) 0 Canada 281 ( 8) 0 Argentina (58) Brazil 0 48 (20) Uruguay 0 54 (22) Age, median (range), years 57 (22-80) 54 (28-71) Age at transplant, years <30 9 (<1) 2 ( 1) ( 4) 14 ( 6) (19) 66 (27) (39) 97 (40) (33) 59 (24) ( 5) 7 ( 3) Male sex 2039 (59) 130 (58) Karnofsky score pre-transplant <90% 1193 (72) 82 (54) 90% 459 (28) 71 (46) Missing Durie-Salmon stage at diagnosis I 283 ( 9) 13 ( 6) II 935 (30) 58 (26) III 1931 (61) 150 (67) Missing Disease status prior to transplant Complete remission 537 (18) 55 (25) Partial remission 1822 (60) 117 (53) Minimal response 234 ( 8) 10 ( 4) No response/stable disease 354 (12) 32 (15) Relapse 18 ( 1) 2 ( 1) Progressive 57 ( 2) 4 ( 2) Missing

22 Not for publication or presentation Attachment 4 Continued. North America South America Variable N (%) N (%) Sensitivity of myeloma prior to transplant Sensitive 2591 (78) 205 (88) Resistant 523 (16) 18 ( 8) Untreated 36 ( 1) 0 Not evaluable 23 ( 1) 1 (<1) Unknown 120 ( 4) 7 ( 3) Missing Time from diagnosis to transplant, median (range), months 8 (<1-249) 10 (3-170) Missing 3 1 Time from diagnosis to transplant < 6 months 774 (22) 26 (11) 6-12 months 1744 (51) 125 (51) 12 months 918 (27) 99 (38) Missing 9 1 Graft type BM 14 (<1) 2 ( 1) PBSC+-BM 3431 (99) 243 (99) Year of transplant ( 8) 40 (16) (16) 54 (22) (16) 49 (20) (23) 64 (26) (21) 29 (12) (16) 9 ( 4) Median follow-up of survivors, median (range), months 48 (1-143) 63 (1-132) 22

23 Not for publication or presentation Attachment 5 Study Proposal Study Title: Comparison of the effect of stem cell source on the outcome of HLA-matched sibling donor transplants for severe aplastic anemia based on transplant region. Rajat Kumar 1, Matthew Seftel 1, Donna Wall 1, Manoranjan Mahapatra 2, Tulika Seth 2 1 University of Manitoba, Winnipeg, Canada, 2 All India Institute of Medical Sciences, New Delhi, India Specific Aims: (a) To determine the preferred source of stem cells for patient with severe aplastic anemia (SAA) undergoing HLA-matched sibling hematopoietic stem cell transplantation (HSCT) in countries with limited resources and high risk of graft failure. (b) To detect differences in outcome of HSCT using two different graft sources in different regions of the world. Scientific Justification: Question - Are the recommendations for stem cell source in SAA, which are based predominately on data from North American and European centers, valid in countries with limited facilities such as in Asia and Africa? Literature: A recent analysis of the outcome of 692 HLA-matched sibling transplants for SAA concluded that use of peripheral blood stem cells (PBSC) resulted in a worse outcome and more chronic GVHD in patients younger than 20 years (1). In patients older than 20 years, overall survival was lower with PBSC, though not statistically significant. The study data covered transplants performed from 1995 to 2003 (1). This suggests that bone marrow (BM) is the preferred source for HSCT in SAA. Aplastic anemia is more common in Asia and other developing countries compared to the West. There is frequently considerable delay from diagnosis to transplantation. As a result patients are often multiply transfused, frequently without leucodepletion, putting them at greater risk of graft rejection. Additionally, patients are often infected pre-hsct. Thus, the type of SAA coming to transplant in the developing countries has a different pretransplant risk profile. Any risk benefit analysis of transplant needs to include the fact that in the developing countries graft failure usually ends in fatality as resources to support such patients are limited. Also transfusion support and resources to manage prolonged neutropenia are a greater issue. A number of centers in Asia and Africa have reported success rates of 70-80% in aplastic anemia using predominantly PBSC as a source. GVHD does not appear to be a major problem in these centers. In recent years, use of ATG in conditioning, improvement in GHVD prophylaxis and treatment may have influenced these outcomes. Results from two centers in India (2,3), three in Pakistan (4) and one in Egypt (5) suggest excellent survival after PBSCT for SAA (Table). Most of these centers are reporting their results to CIBMTR. Country No. of PBSCTs No. of BMTs Survival Ref India % (2) India 28 7 (G-CSF stimulated) 82.8% (3) Pakistan PBSCT + BMT = % (4) Egypt 62 82% (5) 23

24 Not for publication or presentation Attachment 5 The rationale for using PBSC over bone marrow are: (a) faster engraftment (b) higher progenitor and T cell dose with lower risk of graft rejection (c) rapid immunologic recovery (d) lower blood component and antimicrobial requirement (e) less hospitalization costs. These advantages seem to outweigh the higher risk of chronic GVHD in certain regions. If PBSC transplants performed in developing countries are compared to BM transplants performed in advanced centers, it is likely that BM would have better outcome because of the superior facilities of the centers rather than a function of the graft. It is therefore important to compare the results of BM versus PBSC as a graft source for transplants performed in the same region. Patient Eligibility Population: Data on patients who have undergone their first PBSC and BM HLA-matched sibling transplantation for SAA from will be analysed. Patients who receive transplants in centers with a minimum follow up of 12 months will be included. A comparison between the outcomes of BM vs PBSC will be made overall and region-wise: North America; South America; Europe; Africa; Asia; Australia. Data will include the following - Patient characteristics - Country of transplant - Interval from diagnosis to transplant - Transfusion status prior to transplant - Infections one week prior to conditioning - Prior immunosuppressive therapy - Prior Androgens - Years of Transplant - Conditioning regimen - GVHD prophylaxis - Donor-recipient sex match - Neutrophil recovery - Platelet recovery - Primary graft failure - Secondary graft failure - Acute GVHD - Chronic GVHD - Mortality - Survival Data Collection: The data available with CIBMTR will be used for analysis. Study Design (Scientific Plan): The CIBMTR data base would provide data for the variables of interest. A cohort of patients who have undergone HSCT from HLA identical siblings for SAA will be identified. By comparing the difference in outcomes using the two different graft sources, it will be possible to determine any differences in the early and late outcomes of transplantation. An analysis by region would help to determine if the outcome remain the same irrespective of the region where the transplant is performed. If the outcomes are the same in all regions, the better source of stem cells should be used universally. If there are regional differences, it might justify the use of different graft sources in different regions. This study would also permit analysis of the factors responsible for the differences. Statistical methods: The probability of overall survival will be calculated using the Kaplan-Meier method. Death from any cause will be considered an event and surviving patients will be censored at last follow- 24

25 Not for publication or presentation Attachment 5 up. The 95% confidence interval (CI) will be calculated using log transformation. Cox proportional hazards regression models will be constructed. Results will be expressed as relative risk (RR), that is relative occurrence of the event with transplantation of BM compared with that of PBSCs. Variables considered will be as shown above in section IV: neutrophil recovery, platelet recovery, primary graft failure, secondary graft failure, acute and chronic GVHD, mortality, gender, interval from diagnosis to transplant, conditioning regimen, GVHD prophylaxis, year of transplant, pre-transplant characteristics, country of transplant. References: 1. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood 2007; 110(4): Kumar R, Naithani R, Mishra P, Mahapatra M, Seth T, Dolai TK, et al. Allogeneic hematopoietic SCT performed in non-hepa filter rooms: initial experience from a single center in India. Bone Marrow Transplant 2008; Sep 15 [Epub ahead of print] 3. George B, Mathews V, Viswabandya A, Kavitha ML, Srivastava A, Chandy M. Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia. Bone Marrow Transplant 2007; 40(1): Shamsi T, Hashmi K, Adil S, Ahmad P, Irfan M, Raza S, et al. The stem cell transplant program in Pakistan--the first decade. Bone Marrow Transplant 2008; 42 Suppl 1S114-S Mahmoud H, El-Haddad A, Fahmy O, El-Emary M, Nassar A, Abdel-Mooti M, et al. Hematopoietic stem cell transplantation in Egypt. Bone Marrow Transplant 2008; 42 Suppl 1S76- S80. 25

26 Not for publication or presentation Attachment 5 Characteristics of recipients of HLA-identical sibling HSCT between 1995 and 2006 for SAA by graft type BM PBSC N (%) a N (%) a Variable Median (range) b Median (range) b Number of patients Number of transplant teams Age at transplant 19 (<1-82) 24 (4-66) (18) 15 ( 5) (36) 86 (27) (24) 98 (31) (13) 59 (19) ( 6) 35 (11) ( 2) 18 ( 6) (<1) 5 ( 2) (<1) -- Male sex 768 (60) 177 (56) Year of transplant (13) 4 ( 1) (11) 20 ( 6) (11) 23 ( 7) (10) 23 ( 7) ( 7) 28 ( 9) ( 8) 23 ( 7) ( 7) 49 (16) ( 6) 32 (10) ( 6) 25 ( 8) ( 8) 34 (11) ( 7) 33 (10) ( 6) 22 ( 7) Subdisease SAA unknown 64 ( 5) 21 ( 7) SAA idiopathic 1095 (86) 261 (83) SAA secondary to hepatitis 69 ( 5) 14 ( 4) SAA secondary to toxin 44 ( 3) 20 ( 6) Follow-up One year or more 942 (74) 185 (59) Three years or more 616 (48) 93 (29) Five years or more 423 (33) 44 (14) 26

27 Not for publication or presentation Attachment 5 Continued. Variable BM PBSC WHO Region of Team Africa 6(<1) 23 ( 7) Americas 663 (52) 85 (27) US Canada 60 6 South and Latin America Eastern Mediterranean 110 ( 9) 29 ( 9) Europe 215 (17) 103 (33) SE Asia 216 (17) 48 (15) Western Pacific 62 ( 5) 28 ( 9) a For categorical variables For continuous variables 27

28 Not for publication or presentation Attachment 5 Numbers of transplant centers and recipients of HLA-identical sibling transplants for severe aplastic anemia by country within WHO regions. Number (%) Patients Bone Marrow Number of Teams Peripheral Blood Number (%) Patients Number of Teams Country of center Africa South Africa 6 (<1) 2 27 ( 7) 3 Americas Argentina 19 ( 1) 4 4 ( 1) 3 Brazil 291 (23) Canada 60 ( 5) 11 6 ( 2) 6 Chile 1 (<1) Costa Rica 11 ( 1) 1 4 ( 1) 1 Mexico 7 (<1) 1 14 ( 4) 2 Uruguay 10 (<1) 3 4 ( 1) 2 USA 257 (20) (16) 29 Venezuela 7 (<1) 1 4 ( 1) 1 Eastern Mediterranean Pakistan 2 (<1) 1 27 ( 9) 1 Saudi Arabia 108 ( 8) 3 2 (<1) 1 Europe Belgium 6 (<1) 2 7 ( 2) 2 Czechoslovakia 15 ( 1) 4 3 ( 1) 2 Denmark 9 (<1) England 28 ( 2) 4 12 ( 4) 5 Finland 1 (<1) 1 2 (<1) 1 France 14 ( 1) Germany 22 ( 2) 4 4 ( 1) 4 Greece 1 (,1) Hungary 1 (<1) Iran 21 ( 2) 1 45 (14) 1 Ireland 18 ( 1) Israel 1 (<1) 1 12 ( 4) 1 Italy 5 (<1) Netherlands 1 (<1) 1 1 (<1) 1 Poland 17 ( 1) 2 2 (<1) 1 Portugal 7 (<1) 1 3 ( 1) 1 Russia 9 (<1) 2 2 (<1) 1 Scotland 3 (<1) 2 2 (<1) 2 Spain 15 ( 1) 7 6 ( 2) 2 Sweden 9 (<1) Switzerland 3 (<1) Turkey 5 (<1) 2 2 (<1) 1 Yugoslavia 4 (<1) SE Asia India 21 ( 2) 3 11 ( 3) 2 Korea 195 (15) 3 37 (12) 2 28

29 Not for publication or presentation Attachment 5 Continued. Number (%) Patients Bone Marrow Number of Teams Peripheral Blood Number (%) Patients Number of Teams Western Pacific Australia 25 ( 2) 4 9 ( 3) 6 China 3 (<1) 1 2 (<1) 1 Hong Kong 4 (<1) 1 6 ( 2) 1 Japan 5 (<1) 3 2 (<1) 1 Malaysia 7 (<1) New Zealand 14 ( 1) 4 3 ( 1) 1 Singapore ( 2) 1 Taiwan 4 (<1) 2 1 (<1) 1 29

30 Not for presentation or publication Attachment 6 Study Proposal Study Title: The Global Trends in Hematopoietic Stem Cell Transplantation: A Collaboration of Projects for the Worldwide Blood and Marrow Transplantation (WBMT) Network Mahmoud Aljurf. King Faisal Specialist Hospital and Research Center, Riyadh. Saudi Arabia Specific Aims: Identify global and regional trends in hematopoietic stem cell transplantation which will be very instrumental in: - Anticipation of hematopoietic stem cell transplantation rates in the upcoming years - Identification of global and regional trends - Future determination of needed medical resources including staffing and other logistics - Budgetary implications - Identifying special opportunities for patient care and research - Highlighting needed growth in alternate donor registries - The analysis also will be of special importance for bio-industry Scientific Justification: The recently performed A Global Survey in HSCT which reflected the global transplant performance for the year 2006, had revealed significant discrepancies in HSCT practice in the different regions of the world in relation to indications, types of transplant, source of stem cells, in addition to many other variables. The proposed continuation project is more likely to accurately reflect the worldwide and regional trends over a decade and will be more instrumental in future HSCT related healthcare planning and research. Proposed Study Period: - The goal is to study the global trends for the decade between Jan1995 -Dec Alternatives will include limiting the analysis to 5 (consecutive) years - Other alternative is to study 5 non-continuous years, with equally spaced intervals (Such as ). This can also give an idea about trends (perhaps With more flexibility to stretch the total observation period) Obviously all depends on data availability Data Source and Collection: The same data source (and methods) used for the Global Survey in BMT 2006 will be used namely, registry data from CIBMTR, EBMBT, ABMTRR, EMBMT, Japan, Brazil, and others Estimated Time for Completion of the Project: Based on our preliminary experience with the Global Survey in BMT, it is estimated that this project will require.. years for completion. Variables to be Examined (changing trends, global and regional): This will include but not limited to: - HSCT indications trends - Trends for allogeneic and autologous transplantation performance - Utilization of the different alternate donor transplantation sources - Trends for utilization of peripheral blood versus bone marrow as a stem cell source - Age trends (demographic shift to older population) - Treatment related mortality trends (age adjusted) - Survival (if possible) 30

31 Not for presentation or publication Attachment 6 - Others ( inclusion of defined minority patients,etc) Limitations of the Analysis: - Analysis may not be inclusive for all centers in the countries being reviewed. Additionally, some centers could have been added and some centers have dropped out during the analysis time being reviewed. - The potential of new therapies to replace the role of hematopoietic stem cell transplantation. Typical recent example is Gleevec and perhaps more recently, the potential of new therapies for myeloma. - New indications for HSCTmay emerge in the future including using hematopoietic stem cells for cellular therapy (tissue replacement and regenerative therapy). - Unanticipated global or regional economic and political changes may put some limitations on the predictability of this analysis. 31

32 Not for publication or presentation Attachment 7 Study Proposal Study Title: An Analysis of Racial and Geographic Differences in Outcome Following Allogeneic and Autologous HSCT for Acute Myeloid Leukemia with t(8;21) Syed Osman Ahmed, Fahad Al-Mohareb,Mahmoud Aljurf. King Faisal Specialist Hospital and Research Center, Riyadh. Saudi Arabia Specific Aims: To analyze outcomes of autologous and allogeneic stem cell transplantation in patients from different racial groups in CR1 and CR2 to assess the impact of transplantation on survival and relapse risk in different races. Scientific Justification: While AML with t(8;21) is recognized as a favorable risk subtype with superior overall survival, reduced relapse risk and improved DFS and OS with repetitive cycles of high dose Ara-C (Grimwade et al 1998; Byrd 1999), racial and regional differences in outcome have been reported. A CALGB analysis of patients with t(8;21) demonstrated a hazard ratio of failure to achieve remission of 5.7 among non-white patients when compared to white patients (Marcucci 2005). There were also observed differences in overall survival. Data from our institution reveals that among Middle Eastern patients treated with chemotherapy with high dose Ara-C consolidation alone, 87% suffered relapses compared to only 21% who received an allograft in 1 st CR (submitted for publication). Results from Korean and Chinese populations similarly indicate that AML with t(8;21) are not favorable risk in the respective populations, and do not have superior outcome to other cytogenetic groups when treated with high dose Ara-C (Lee 2004, Chen 2007). A study in Korean patients (n=22) showed poor outcome in AML with t(8;21) receiving allogeneic transplantation after relapse (Lim et al 2008). Outcome differences by ethnicity have also been reported in pediatric AML unselected for cytogenetic subgroup (Aplenc et al 2006). Currently, there isn t sufficient evidence to recommend allogeneic stem cell transplantation for t(8;21) in CR1 (Oliansky 2008), though the evidence base for these recommendations may at least in part be attributable to the ethnicity of the majority of patients in these studies. A European study demonstrated similar outcomes with either autologous or allogeneic transplantation in AML with inv. 16 or t(8;21), though the impact of ethnicity on outcome was not studied (Gorin et al 2008). It is likely that the observed differences in outcome reflect true difference in disease biology possibly related to variability in the fusion protein, other high risk molecular aberrations (e.g., KIT, RAS, FLT3,others), differences in pharmacogenomics and possibly other factors. The study is intended to investigate the differences in outcome with stem cell transplant in AML t(8;21) in different geographic regions and racial groups. It is possible that high dose chemotherapy and auto or allo HSCT may attenuate or eliminate the observed racial and geographic differences in the risk of disease recurrence after conventional chemotherapy. The importance of this study lies in the need to provide optimum post-remission therapy that is tailored to groups that apparently differ in their disease biology. Patient Eligibility Criteria: The study population will include adult patients (age to be defined) on whom data on race is available and are registered as having t(8;21) by cytogenetic methods or AML1/ETO fusion protein by molecular methods and who have received autologous or allogeneic stem cell transplantation in CR1 or CR2. 32