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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR LATE EFFECTS (LONG-TERM COMPLICATIONS / SECOND CANCERS) Salt Lake City, UT Friday, February 15, 2013, 2:45-4:45 pm Co-Chair: Co-Chair: Co-Chair: Scientific Director: Statisticians: David A. Jacobsohn, MD, Children s National Medical Center, Washington DC, Phone: ; DAJacobs@cnmc.org Mohamed Sorror, MD, Fred Hutchinson Cancer Center, Seattle, WA Phone: ; Fax: ; msorror@fhcrc.org Christine Duncan, MD; Dana Farber Cancer Institute, Boston, MA Phone: ; christine_duncan@dfci.harvard.edu Navneet Majhail, MD, MS, National Marrow Donor Program, Minneapolis, MN, Phone: , Fax: ; nmajhail@nmdp.org Ruta Brazauskas, PhD, CIBMTR Statistical Center Phone: , Fax: , ruta@mcw.edu Jerry (Zhiwei) Wang MS, CIBMTR Statistical Center Phone: , Fax: , zwang@mcw.edu 1. Introduction a. Minutes of February, 2012 meeting (Attachment 1) b. Introduction of incoming Co-Chair: Bipin N Savani, MD, Vanderbilt University Medical Center, Nashville, TN. bipin.savani@vanderbilt.edu 2. Accrual summary (Attachment 2) 3. Published or submitted papers a. LE09-01 Danner-Koptik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY, Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML, Jacobsohn DA. Second malignancies after autologous hematopoietic cell transplantation in children. Bone Marrow Transplantation. [Epub ahead of print] doi: /bmt Epub 2012 SEP 10. b. LE10-02 Buchbinder D, Nugent DJ, Brazauskas R, Wang Z, Aljurf MD, Cairo MS, Chow R, Duncan C, Eldjerou LK, Gupta V, Hale GA, Halter J, Hayes-Lattin BM, Hsu JW, Jacobsohn DA, Kamble RT, Kasow KA, Lazarus HM, Mehta P, Myers KC, Parsons SK, Passweg JR, Pidala J, Reddy V, Sales-Bonfim CM, Savani BN, Seber A, Sorror ML, Steinberg A, Wood WA, Wall DA, Winiarski JH, Yu LC, Majhail NS. Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research. Biology of Blood & Marrow Transplantation. [Epub ahead of print] doi: /j.bbmt Epub 2012 JUL 31. 1

2 Not for publication or presentation c. Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns LJ, Chaudhri N, Davies S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JR, Tichelli A. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant Mar;18(3): Epub 2011 Dec 13. Co-published on Bone Marrow Transplant Mar;47(3): , Rev Bras Hematol Hemoter 2012;34(2): Hematol Oncol Stem Cell Ther 2012;5(1):1-30. d. LE09-03a Loren AW, Brazauskas R, Chow EJ, Gilleece M, Halter J, Jacobsohn DA, Joshi S, Pidala J, Quinn GP, Wang Z, Apperley JF, Burns LJ, Hale GA, Hayes-Lattin BM, Kamble R, Lazarus H, McCarthy PL, Reddy V, Warwick AB, Bolwell BJ, Duncan C, Socie G, Sorror ML, Wingard JR, Majhail NS. Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients. Submitted to BMT. 4. Study proposals a. PROP The rate of aging in hematopoietic stem cells transplant patients: A frailty survival model analysis (Y Lin) (Attachment 3) b. PROP Cancer risk in HSCT recipients followed in the recent transplant era (E Engles, D Jacobsohn) (Attachment 4) c. PROP Late cardiovascular morbidity and mortality following pediatric allogeneic HSCT (KS Baker, C Duncan, M Pulsipher) (Attachment 5) d. PROP Cigarette smoking and allogeneic stem cell transplantation outcomes (S Hashmi, WK Kremers, SL Ehlers, WJ Hogan, MS Patnaik, LF Porrata, MR Litzow) (Attachment 6) 5. Study proposals submitted but dropped a. PROP Sexual dysfunctions in female survivors of allogeneic stem cell transplantation (P Stratton, B Savani) (Attachment 7) b. PROP Diabetes, congestive heart failure, stroke and renal failure in recipients older than 50 years after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (H Huang, Y Kodera, AK Lie) (Attachment 8) 6. Research opportunities through the LEWC (Attachment 9) 7. Studies in progress (Attachment 10) a. LE09-03b Review of fertility preservation practice in HSCT patients (S Joshi) b. LE07-01 Second cancer after RIC transplants (O Ringden) (attachment 11) c. LE10-01 Avascular necrosis of bone in children and adolescents after hematopoietic cell transplantation (X Li) (Attachment 12) d. LE11-01 Long-term survival following second allogeneic HCT for hematologic malignancies (C Duncan, M Sorror) e. LE11-02 Risk factors for secondary CNS tumors in survivors of pediatric HCT (M Gabriel, P Shaw) f. LE12-03 Solid organ transplant after HCT (M Gupta, P L Abt, M Levine) g. LE12-04 HCT recovery index (S Holtan, R Chandran, L Porrata) (Attachment 13) Manuscript Preparation Analysis Analysis Data File Preparation Protocol Development Data File Preparation Protocol Development 2

3 Not for publication or presentation 8. Approved studies not using active statistical resources a. LE05-01 Bronchiolitis obliterans after HCT (S Mineishi) Form Development b. LE12-01 HCT in patients who had a prior solid organ Protocol Development transplant (T Schechter-Finkelstein, D Jacobsohn, F Cossor) c. LE12-02 Late Effects after AlloHCT for very young Protocol Pending children (<3y) (L Vrooman, C Duncan) 9. Educational materials for recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation 10. Other Business 3

4 Not for publication or presentation Attachment 1 M I N U T E S CIBMTR WORKING COMMITTEE FOR LATE EFFECTS (LONG-TERM COMPLICATIONS / SECOND CANCERS) San Diego, CA Thursday, February 2, 2012, 12:15-2:15 pm Co-Chair: Co-Chair: Co-Chair: Scientific Director: Statisticians: David A. Jacobsohn, MD, Children s National Medical Center, Washington DC, Phone: ; DAJacobs@cnmc.org Mohamed Sorror, MD, Fred Hutchinson Cancer Center, Seattle, WA Phone: ; Fax: ; msorror@fhcrc.org Christine Duncan, MD; Dana Farber Cancer Institute, Boston, MA Phone: ; christine_duncan@dfci.harvard.edu Navneet Majhail, MD, MS, National Marrow Donor Program, Minneapolis, MN, Phone: , Fax: ; nmajhail@nmdp.org Ruta Brazauskas, PhD, CIBMTR Statistical Center Phone: , Fax: , ruta@mcw.edu Jerry (Zhiwei) Wang MS, CIBMTR Statistical Center Phone: , Fax: , zwang@mcw.edu 1. Introduction The meeting was called to order at 12:15pm by Dr. David Jacobsohn. Co-chairs, scientific director and statisticians were introduced to the audience. Minutes of February, 2011 meeting (Attachment 1) The minutes of February, 2011 LEWC meeting were approved. 2. Accrual summary (Attachment 2) The audience was referred to the handout for the annual accrual summary. 3. Published or submitted papers David briefly reviewed the five manuscripts published during the course of last year in the late effects working committee. In 2006, Dr. Doug Rizzo et. al. published the guidelines of screening and preventive practices for long-term HCT survivors. At its five year anniversary, it was recommended that the guidelines to be reviewed and updated. Over the last year, a large international working group consisting members from CIBMTR, ASBMT, EBMT, EMBMT, APBMT and Brazilian BMT society, led by Dr. Navneet Majhail and Dr Doug Rizzo, worked together to review and update the guidelines. The guidelines are being co-published in BMT, BBMT, Hematology-Oncology and Stem Cell Therapy and Revista Brasilieira de Hematologia e Hemoterapia. Navneet welcomed the audience for suggestions or invitations to publish the guidelines in other regional society journals. The group is also working with NMDP to develop the patients and physician versions of these guidelines available in print and online. Navneet also thanked all the members of this working group on their efforts in this project. Citation for these guidelines is listed below (#d). 4

5 Not for publication or presentation Attachment 1 a. LE00-02b Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang M J, Rizzo JD. High probability of long-term survival in 2-year survivors of autologous hematopoietic cell transplantation for AML in first or second CR. Bone Marrow Transplant Mar;46(3): PMID: , PMCID: PMC b. LE07-04 Loren AW, Chow E, Jacobsohn DA, Gilleece M, Halter J, Joshi S, Wang Z, Gupta V, Hale GA, Marks DI, Stadtmauer EA, Apperley J, Cahn JY, Schouten HC, Lazarus HM, Savani B, McCarthy PL, Jakubowski AA, Kamani NR, Hayes-Lattin B, Maziarz RT, Warwick AB, Sorror ML, Bolwell BJ, Socié G, Wingard JR, Rizzo JD, Majhail NS. Pregnancy after hematopoietic-cell transplantation: A report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant Feb;17(2): PMID: , PMCID: PMC c. LE07-03 Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, and Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol Jun 1;29(16): PMID: , PMCID: PMC d. Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns JL, Chaudhri N, Davies S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JR, and Tichelli A, Recommended Screening and Preventive Practices for Long-term Survivors after Hematopoietic Cell Transplantation. In press, Biology of Blood and Marrow Transplantation, Bone Marrow Transplantation, Hematology-Oncology and Stem Cell Therapy, Revista Brasilieira de Hematologia e Hemoterapia e. LE09-01 Danner-Koptik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY, Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML, Jacobsohn DA, Second malignancies after autologous hematopoietic cell transplantation in children. Submitted to JCO 4. Future/ Proposed studies a. PROP Evaluate the risk of squamous cell CA in patients receiving voriconazole as fungal prophylaxis following allogeneic stem cell transplantation (J Palmer) Dr. Jeanne Palmer presented this proposal. The aim of the study is to determine whether patients with squamous cell carcinoma (SCCA) of the following HCT have increased exposure to voriconazole as compared to patients without SCCA following HCT. Literature review suggested voriconazole toxicity might be linked to SCCA. During discussion, it was noted that duration of the voriconazole exposure was not captured on the data collection forms. Also pre-transplant antifungal therapy was not collected before It was also noted that individuals with inherited bone marrow failure syndromes such as Fanconi anemia may have differential risks of developing SCCA. b. PROP Sequential occurrence of new malignancies in donor-recipient pairs after allogeneic HCT: Incidence, characteristics and biologic significance for malignant evolution (G Akpek) Dr. Gorgun Akpek presented this proposal. The objectives of this study are to identify and characterize the sequential new malignancies developed after allogeneic HCT in both donors and recipients. NMDP unrelated donor follow-up form was reviewed, where post-donation 5

6 Not for publication or presentation Attachment 1 adverse events such as hematopoietic and solid malignancies were captured. CIBMTR currently does not collect data on related donor follow-up. This proposal partially overlaps with CIBMTR study DS08-01, which is looking at cytogenetic abnormalities in donor derived hematopoietic cells after unrelated donor transplants. It was noted that Dr. Mike Pulsipher s 2009 paper in Blood looked at new malignancies among unrelated peripheral blood stem cell donors, and only one donor-recipient malignancy pair was identified. NMDP donor long-term follow-up study is underway, but time will be needed to accrue data. Another comment was it will be hard to confirm the donor origin of the recipient malignancy and the PI responded that scope of the study is limited to describe the malignancy pairs only. c. PROP HCT in patients who had a prior solid organ transplant (T Schechter- Finkelstein, D Jacobsohn, H Klingemann) Dr. Tal Schechter-Finkelstein presented this proposal. The main objective of the study is to assess the outcome of HCT following solid organ transplantation. Seventeen patients who had prior solid organ transplant were identified in the CIBMTR database. Patient characteristics were reviewed. Prior solid organ transplant was not explicitly asked on the forms. The information can be reported by centers in the other specify field and reporting in this field can be highly variable based on center discretion. One member expressed that even a case series on the 17 patients would be valuable to the community. Supplement data requests may be required. While supplemental data collection is generally discouraged, if the committee feels this study is worth pursuing, we could go to the centers for more information. The possibility of using methods proposed by another study (PROP # below) to supplement this list was also discussed. The proposal below will link UNOS database to the CIBMTR database and there could be the possibility of identifying solid organ transplant recipients through this mechanism as well. Linking data to UNOS database is subject to regulatory approval by HRSA. One question was if UNOS collects HSCT as an outcome post solid organ transplantation which remains to be confirmed. d. PROP Late effects of children undergoing allogeneic HSCT at a young age (L Vrooman, C Duncan) Christine presented this proposal. The main objective of this study is to report the frequency and describe the characteristics of late effects in patients who underwent allogeneic stem cell transplant for hematologic malignancy at less than 3 years of age. The characteristics of eligible patients were shown in the handout. It was recommended that this study only focus on the organ impairments that the CIBMTR forms explicitly captured. Organ impairments reported in the other specify fields depended heavily on center reporting practice and therefore is less reliable for analysis. This study is similar to study LE10-02 in terms of study objective and outcomes. It can potentially follow the same analytical techniques used in LE Audience questioned why the proposal limited the study population to malignant diseases patients only. Christine responded that considering the malignant disease patients usually receive different chemo therapies and conditioning regimen than the non-malignant disease patients, they would like to to restrict the analysis to a population that is more homogenous in terms of treatment. Another question was why choose 3 year of age as the cut-off point. Christine responded that while there is no hard biologic reason behind it, children under 3 years of age are believed to have more neurologic impairment from irradiation than children over 3. 6

7 Not for publication or presentation Attachment 1 e. PROP Solid organ transplantation after hematopoietic cell transplantation (M Gupta, P L Abt, M Levine) Navneet presented this proposal on behalf of Dr. Gupta. The main objective is to determine the incidence of solid organ (kidney, liver, heart, lung, pancreas) transplantation among patients who underwent prior HCT and identify risk factors. CIBMTR follow-up forms do not explicitly collect solid organ transplant events. UNOS databases currently do not capture HCT event prior to solid organ transplant. This project requires merging CIBMTR database with the UNOS database. Linking the data from the two organizations is subject to HRSA approval. Patients can be potentially linked by social security numbers and dates of birth. SSN information is only available for NMDP legacy patients and patients who reported in FormsNet2 (i.e., after 2007). f. PROP Avascular necrosis of bone in adults after hematopoietic cell transplantation (L Burns, B McClune, N Majhail) Dr. Linda Burns presented this proposal. This proposal aims at describing the incidence of avascular necrosis (AVN) in adults following HCT and identifying risk factors associated with AVN in this population. Patient characteristics were briefly reviewed. Study LE10-01 looks at post-transplant AVN in children, and this proposal looks at the same condition in the adult population. A case-control design was proposed. All cases and controls will have to be confirmed with the centers. There were some limitations of the data: post-transplant AVN could be under reported in the database; the dosage and duration of immunosuppression treatment was not well captured; hormone usage of female patients after transplant was not collected; and the time of onset of AVN was not captured until after 2007 although it could be imputed based on adjacent contact dates. g. PROP Prevalence and associated risk factors for diabetes mellitus and hyperglycemia in children following hematopoietic stem-cell transplantation (J Ho, G Guilcher, T Schechter- Finkelstein) Dr. Ho presented this proposal. The aim of this study is to assess the prevalence and determine the associated risk factors of diabetes mellitus/hyperglycemia in children post HCT. Prior to 2007, adrenal insufficiency as pre-transplant comorbidity was not collected on the CIBMTR forms. Diabetes mellitus after transplant was not collected prior to 2007 either. This would limit the study population to patients transplanted after It was noted that the median follow-up of the patients was about 24 months. Longer term follow-up would be desired. A challenge of this study is to distinguish patients who had steroid treatment-related short-term hyperglycemia vs. patients who had repeated or long-term diabetes. 5. Studies in progress a. LE09-01: New malignancies after autologous hematopoietic stem Submitted cell transplantation in children (K Danner-Koptik, D Jacobsohn): David presented this study. This study was recently submitted to JCO. The study population was pediatric patients who underwent autologous transplanted before 2003 and reported to CIBMTR. Overall cumulative incidence of secondary malignancy in this cohort was 2.6% at 10 years. No association was found between secondary malignancy risk and age, gender, diagnosis, disease status, time since diagnosis, or use of total body irradiation or etoposide as part of conditioning. AHCT recipients had increased risks of developing SMNs when compared with age- and gendermatched study population. 7

8 Not for publication or presentation Attachment 1 b. LE09-03: National survey of transplant physician practice patterns Manuscript preparation regarding fertility preservation (A Loren): This study was one of the LEWC fertility working group project. The national survey was carried out in And a supplemental survey was carried out in 2011 attempting to re-survey the nonresponders of the main survey. This project now is under manuscript preparation. A draft manuscript will be circulated to the writing committee in the next 2-3 months. c. LE09-03b: Review of fertility preservation practice in HSCT Manuscript preparation patients (S Joshi): Upon reviewing the survey results of LE09-03a, the fertility working group highlighted the need of reviewing current literatures on fertility preservation practice in HCT patients. This study was therefore proposed in June The draft manuscript is under development and will be circulated to the writing committee later this year. d. LE07-01: Second cancer after RIC transplants (O Ringden): Data file preparation This study was proposed in At that time, the RIC/NMC patient group follow-up in the arm was too short. The study was under data accrual over the past few years. In year 2011, the median follow-up of RIC/NMC patients has reached 5 years. The working committee recommended closing the accrual and starting the analysis. The study protocol was sent out late last year. Comments to the protocol were received and addressed. The study data file is being prepared for this study. e. LE10-01: Avascular necrosis of bone in children and adolescents Analysis after hematopoietic cell transplantation (X Li): This is a case-control study evaluating the risk factors of developing AVN for children after HCT. Matched cases and controls were confirmed by transplant centers. This study is currently under data analysis. Results and draft abstract will be circulated to the writing committee in a few coming months. f. LE10-02: Late effects in hematopoietic stem cell transplant Manuscript preparation recipients with non-malignant disease (D Buchbinder, D Nugent): Dr. David Buchbinder presented this study. The abstract of this study will be presented at the Tandem meeting late effects oral abstract session. The study described the late effects of 1718 patients post-hct for acquired SAA between reported to the CIBMTR. Patient characteristic and outcomes were reviewed. The risks of late effects have the trend of increase over time. This study is under manuscript preparation and the draft will be circulated to the writing committee shortly after the tandem meeting. h. LE11-01: Long-term survival following second allogeneic HCT for hematologic malignancies (C Duncan, M Sorror): Protocol development i. LE11-02 Risk factors for secondary CNS tumors in survivors of Protocol development pediatric HCT (M Gabriel, P Shaw): Study LE10-01 and LE11-02 were under protocol development last year and did not use active statistical hours. Protocols of these two studies will be circulated to the writing committee this year and the studies will move to data file preparation. 8

9 Not for publication or presentation Attachment 1 6. Approved studies not using active statistical resources (e.g. in data accrual/form development) a. LE05-01: Bronchiolitis obliterans after HCT (S Mineishi): Form Development This study is to evaluate the incidence and risk factors for post-transplant bronchiolitis obliterans. The study was proposed in At that time, the pulmonary data collected on the form was not adequate to address the question. The new pulmonary form has been finalized and was available for review in the handout. The new forms will be piloted in a few centers sometime early this year. Once implemented, it will take a few years to accrual enough data for the analysis. b. LE06-01: Single nucleotide polymorphism analysis in patients Dropped who developed AML or MDS after auto SCT for lymphoma (T Fenske): This study was to determine whether certain inherited polymorphisms of genes relevant to chemotherapy drug metabolism or leukemogenesis are more prevalent in lymphoma patients who develop t-mds/aml following auto-grafting. However, this study cannot be completed due to the issues with lack of appropriate control population and insufficient t-aml/mds cases with the necessary clinical and epidemiological data. 7. Update on LEWC projects that were initiated in response to survey of members in 2007 a. Late liver complications b. Fertility issues after transplant c. QOL pilot project d. Pulmonary function forms In 2007, the Late Effects Working Committee members were surveyed to assess areas for focus of future studies. Late liver complications, post-transplant fertility and quality of life were the three areas that the members were most interested in. Christine briefly reviewed the updates of each of the subcommittee. The liver complication forms and pulmonary forms have been finalized (available in the handout). The next step was to pilot these two new forms in a few selected US centers sometime early this year. Fertility working committee published the LE07-04 Pregnancy after HCT manuscript this year (item b in section 3) and continued to work on the other two manuscripts (LE09-03a and LE09-03b).Navneet briefly updated the QOL pilot project status on behalf of Dr. Doug Rizzo. The pilot project of collecting patient quality of life data has been carried out in eight US centers. Over the course of the next 1 to 2 years, data will be accrued. 8. Tandem Presentations a. LE10-02: Chronic health conditions in hematopoietic stem cell transplant recipients with nonmalignant disease (D Buchbinder). Oral abstract, Session K, Saturday, February 4, 4:45pm-6:45pm Christine welcomed everyone to attend the oral abstract presentation of study LE10-02 by Dr. David Buchbinder on Saturday. 9. Other Business Christine announced the new CIBMTR effort, the Forms Revision Process. All data collection forms are undergoing revision over the next two years, starting with the following: CRID (2804), Pre-TED (2400), Baseline (2000), Infectious Disease Markers (2004), HLA (2005), Infusion (2006), AML (2010/2110), ALL (2011/2111), MDS (2014/2114), JMML (2015/2115), Plasma Cell Disorders (2016/2116), Amyloidosis (2017/2117), Lymphoma (2018/2118) and Waldenstrom's Macroglobulinemia (2019/2119). The revised forms will coincide with the development of the new 9

10 Not for publication or presentation Attachment 1 FormsNet application. Members are encouraged to become a member of the Forms Revision Review Committee in order to capture all the relevant information needed to produce high-quality studies. Suggestions for forms can be forwarded to the working committee leadership or Emilie Meissner at emeissne@nmdp.org The meeting adjourned at 2:00PM. 10

11 Not for publication or presentation Attachment 2 Accrual Summary for Late Effects Working Committee Follow-up of patients after allogeneic transplant reported to CIBMTR between 1990 and 2012 Registration N (%) a Median (range) b Research N (%) a Median (range) b Variable All patients year survivors year survivors year survivors Follow-up of survivors, months 54 (<1-270) 68 (<1-270) Leukemia year survivors year survivors year survivors Lymphoma year survivors year survivors year survivors Other Malignancy year survivors year survivors year survivors Aplastic Anemia year survivors year survivors year survivors Immunodeficiency year survivors year survivors year survivors Other diseases year survivors year survivors year survivors a For categorical variables For continuous variables 11

12 Not for publication or presentation Attachment 2 Follow-up of patients after autologous transplant reported to CIBMTR between 1990 and 2012 Registration N (%) a Median (range) b Research N (%) a Median (range) b Variable All patients year survivors year survivors year survivors Follow-up of survivors, months 52 (<1-270) 78 (<1-270) Leukemia year survivors year survivors year survivors Lymphoma year survivors year survivors year survivors Breast Cancer year survivors year survivors year survivors Multiple Myeloma/Plasma Cell Disorder year survivors year survivors year survivors Other Diseases year survivors year survivors year survivors a For categorical variables For continuous variables 12

13 Not for publication or presentation Attachment 3 CIBMTR Study Proposal: Study Title: The rate of aging in hematopoietic stem cells transplant patients: a frailty survival model analysis. Yuhui Lin, PhD Student, Max Planck Institute for Demographic Research, Rostock, Germany lin@demogr.mpg.de Prof James Vaupel, Max Planck Institute for Demographic Research, Rostock, Germany vaupel@demogr.mpg.de Specific Aims: To determine whether the rate of aging differs between different hematopoietic stem cell (HSCs, hereafter) transplants. Hypothesis: Related-donor transplants will have a lower rate of aging to unrelated transplants. Abstract: Most epidemiological studies have considered survivorship and chronic diseases by risk exposures, yet only a few have considered the rate of aging. This is due to the widespread and longstanding belief that aging is an inexorable degenerative process. In aging research, the question arises whether risk exposure (e.g. radiation exposures, cigarette smoking) may modify the rate of aging. Here, I propose to use the Center for International Bone and Marrow Registry (CIBMTR) to investigate the rate of aging in transplant patients. In this context, the rate of aging is measured by the relationship between mortality rates and age. I will apply frailty survival models to the data to explore whether different HSCs transplants and the occurrence of Graft-versus Host Disease (GVHD) will alter the rate of aging in patients. Scientific Justification: Longevity is an integrative phenotypic outcome of a number of interactive factors. In a human population, individuals are consistently selected for survival. Life-history exposures to infection and organ failure can lead to long-term health consequences and premature mortality. It is therefore of interest to understand why certain individuals are not able to fend off chronic diseases and the extent to which different transplants can alter the rate of aging. In population studies, the best indicator for measuring rate of aging is age-specific mortality rates. The study of mortality rates versus age is the relationship first described by Benjamin Gompertz in 1825, μ(x)= ae bx (Gompertz 1825). Gompertz showed that mortality rate increases logarithmically in most human populations between the ages of 30 and 85 years. The slope of the equation, represented by the parameter b, has hence been considered to be an index for the rate of aging. Meanwhile the parameter a has been referred as the onset for mortality that is influenced by extrinsic risk exposures. The Gompertz equation has been applied in many human and non-human population studies, and it is one of the most firmly established concept of the aging process. Therefore, it is of strong interest to examine whether the Gompertz equation is a suitable candidate to measure the rate of aging in transplant patients. The importance of heterogeneity and individuals frailty impact on population dynamics was first described in detail by Vaupel and colleagues in 1979 (Vaupel et al. 1979). The paper has received significant attention and appraisal, where extended frailty models like shared and bivariate model were later developed. Mortality rates are weighted by the contributions of individual death. This arithmetic quantity reflects the dynamics of population aging. Separate analysis of groups of individuals can provide informative measurement of heterogenous risk for mortality. In a heterogeneous population, frail individuals will die at young ages, leaving the less frail individuals to experience selection for survival. 13

14 Not for publication or presentation Attachment 3 To account for frailty, the term z was introduced to the Gompertz equation μ(x, z)= zae bx, where the distribution for frailty was defined. Individuals with high value of z are more likely to be frail and experience death before low z -values individuals. Rapid advancement in medical care and biotechnology have an increasing impact on the outcomes of medical treatments and transplant. The introduction of health interventions, policies, and translational science research has brought remarkable decrease in infant mortality, increase in life expectancy and reduction in disease morbidity. These improvements have given individuals living today more lifesaving opportunities than before. Given this knowledge, it is likely that the highest beneficiary in mortality and morbidity risk reductions are frail individuals; creating a phenomenon of postponement in aging and an increase in heterogeneous mixing for mortality at older ages. Therefore, in survival analysis, the failure to account for heterogeneous frailty effect will lead to misleading risk estimates. In HSC transplants studies, the most common cause for mortality was relapsed of disease. In this study, there will be a focus comparing autotransplants and allotransplants. Further comparison will be made within types of allotransplants: unrelated, related and identical twin donors. The interest for unrelated and related transplants is the difference in HLA-mismatched, and for identical twin transplants it is the absence of no or minimal amount of GVHD. Initial assumption for identical twin transplants is better health and survival outcome than siblings-type transplant. However, it has been shown that co-twin recipients suffer a higher risk for relapse than patients receiving HLA-identical siblings transplants (Gale et al. 1994). In a recent study, a significant association was reported in chronic GVHD and the reduced risk for relapse (Ringden et al. 2011). In reference to the studies, the once thought inhospitable inflammatory response may exhibit some benefits to transplant patients and may be a crucial element influencing the rate of aging. This research work is of significance to the domain of aging and epidemiological research. It aims to highlight how mortality rates versus age changes in accordance to different HSCs transplants and in the presence of GVHD. There will be little doubt that GVHD increases the risk for mortality. However, it is uncertain whether the rate of aging alters. It would therefore be of interest to see if the process of newly transplanted material attacking recipients body will alter the rate of aging. The application of frailty models will account for unobserved heterogeneity effects and obtain reliable risk estimates to interpret the rate of aging in different groups of HSCs transplant patients. Patient Eligibility Population: This study will be using CIBMTR survival data on patients who has received HSCs transplant at 18 years of age or older. List of variables Date of birth: Recipient and Donor Gender Ethnicity Country of residency Types of transplant: Autotransplant or Allotransplant- related unrelated identical twins Product/ Graft-type: marrow PBSC cord blood/ multiple cord blood 14

15 Not for publication or presentation Attachment 3 others Primary disease for HSCs transplant Disease status prior transplant Year of transplant Waiting time to transplant History of malignancy Co-existing diseases or organ impairment History of smoking habit Infectious disease: fungal infection serological evidence of existing viral infection Pre-HSCT preparation: irradiation prescription of any drugs HSCT History: number of HSCT Years of remission Number of remission(s) Socioeconomic information: education achievement occupation work status type of insurance Lost to Follow-up Occurrence of GVHD and if any treatment was given Age at death Data Requirements: Due to the nature of this research work, I will require access to the following data. Form number Abr Name Rev Recipient Baseline Data Six months to two years Post-HSCT Yearly Follow-up for Greater than two years Post-HSCT Recip ltfu Lost to Follow-up Declaration Recipient Death Data 1.0 Study Design: To investigate the rate of aging in transplant patients and observe how it might differ between different types of transplants. In this context, the rate of aging is referred as the first derivative of the logarithmic mortality rate, also known as the relative change in risk for mortality. In reference to previous studies, patients should experience a higher risk for mortality than the general population. Furthermore, patients who received unrelated donor transplants should also experience a higher mortality risk than related donor transplants. However, it is uncertain how the rate of aging d(log μ(x))/dx would appear in transplant patients. The rate of aging represented by the Gompertz slope, b, indicates how fast or slow the population is aging (see Figure 1), while the constant a marks the y-intercept of the slope. 15

16 Not for publication or presentation Attachment 3 Figure 1. A sketch on the rate of aging. The force of mortality indicated as μ(x) represents the instantaneous rate of mortality at a certain age. When μ(x) is expressed in logarithmic form (log μ(x)), the relative change in mortality risk over time can be easily interpreted from the graphs. Consider two groups of transplant patients, where the solid and dotted lines represent their respective mortality risk. The relative risk is interpreted by the difference between the two hazard lines. Relative risk may change through the passage of time, x to x+n. Here are a few possible outcome characteristics: (i) when the relative risk remains constant over time, the two hazard lines will run in parallel - a proportional hazard survival model; when the relative risk changes over time, the two hazard lines either (ii) converge or (iii) diverge - a clear indication of heterogeneity. Calculations for mortality rates will be based on follow-up status of patients HSCT- and graft-type transplant. Demographic information on patients is required for descriptive and frailty survival analysis. Pre-existing infectious disease (e.g. Hepatitis's, Human Immunodeficiency virus) will be considered as a covariate during the analysis. Using the CIBMTR data, I will apply frailty survival models to obtain the survivorship s(x), force of mortality μ(x) and the relative change in mortality risk log μ(x) in groups of patients, and determine whether the rate of aging differs substantially among transplants and in the presence of GVHD. After performing a descriptive analysis and identifying potential confounding factors, I will apply multivariate analysis and finalize the model. By using frailty survival models, I will account for unobserved heterogeneity and deliver my observation on the rate of aging in transplant patients. In conjunction to this analysis, I will use the Human Mortality Database (HMD, see references) as a control group, representing the rate of aging in a general population. Data conditioning for HMD age 16

17 Not for publication or presentation Attachment 3 groups and countries will coincide with CIBMTR patients. The HMD is a multinational database providing mortality and population data. All analysis will be performed using the R-Software. In this research project, the interpretation on the rate of aging is deduced through population and groups of individuals. This generalization may be a limiting factor in representing one single rate for every individual. There will be a concern in low statistical power for identical twin transplants as the occurrence is fewer than 2 % of all marrow transplants (Bortin et al. 1992). To overcome these challenges, more sophisticated frailty models may have to be used. Dissemination: Results will be published in research journals, presented at international conferences, and available as a chapter in a PhD thesis. Concluding remarks: To my knowledge, the rate of aging has not been explored in population-based bone marrow research. The proposed work carries careful consideration of unobserved heterogeneity and the interpretation on the rate of aging. The results will justify whether accumulation of damage by inflammatory response holds the key to an increase in the rate of aging. The results will offer valuable insights to epidemiological, aging and translational research communities. References: 1. Bortin, M.M., Horowitz, M.M. & Rimm, A.A., Increasing Utilization of Allogeneic Bone Marrow Transplantation. Annals of Internal Medicine, 116(6), pp Gale, R.P. et al., Identical-Twin Bone Marrow Transplants for Leukemia. Annals of Internal Medicine, 120(8), pp Gompertz, B.T., On the Nature of the Function Expressive of the Law of Human Mortality, and on a New Mode of Determining the Value of Life Contingencies. Philosophical Transactions of the Royal Society of London, 115 IS -, pp Human Mortality Database. University of California, Berkeley (USA), and Max Planck Institute for Demographic Research (Germany). Available at or 5. Ringden, O. et al., Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. 6. Vaupel, J., Manton, K. & Stallard, E., The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography, 16(3), pp

18 Not for publication or presentation Attachment 3 Accrual of patients (age>18), reported to CIBMTR, by type of donor Variable Auto N (%) Related N (%) Unrelated N (%) Number of patients Number of centers Age at transplant, years, median (range) 49 (18-83) 37 (18-83) 42 (18-80) Age at transplant, years (10) (31) 5454 (23) (16) 9232 (27) 5021 (22) (27) 8196 (24) 5593 (24) (28) 4852 (14) 4803 (21) (17) 1318 (4) 2236 (10) >= ( 2) 82 (<1) 149 ( 1) Patient gender Male (45) (58) (58) Female (55) (42) 9795 (42) Missing Disease AML 1755 ( 6) (30) 8026 (35) ALL 257 ( 1) 4420 (13) 3197 (14) CML 271 ( 1) 8369 (24) 5125 (22) NHL 8252 (26) 2758 (8) 1602 ( 7) HD 2760 ( 9) 316 ( 1) 96 (<1) MDS/MPS 63 (<1) 2487 ( 7) 2872 (12) Other Leukemia 259 ( 1) 1080 ( 3) 1156 ( 5) Myeloma/PCD 8242 (26) 1140 ( 3) 170 ( 1) Other Cancers 9685 (31) 361 ( 1) 78 (<1) Aplastic Anemia 3 (<1) 2683 ( 8) 755 ( 3) Other Non-Malignant Diseases 114 (<1) 339 ( 1) 179 ( 1) Graft type BM 4717 (15) (66) (52) PB+-BM (85) (34) 9384 (40) CB 0 19 (<1) 1687 ( 7) Missing year survivors (49) (40) 7063 (30) 5 year survivors 9710 (31) (31) 4617 (20) 10 year survivors 3568 (11) 5420 (16) 1563 ( 7) Follow-up of survivors, months, median (range) 60 (<1-270) 84 (<1-443) 62 (<1-287) 18

19 Not for publication or presentation Attachment 4 CIBMTR Study Proposal: Study Title: Cancer risk in HSCT recipients followed in the recent transplant era. Eric Engels, National Cancer Institute, Bethesda, MD; engelse@exchange.nih.gov Lindsay Morton; National Cancer Institute, Bethesda, MD; mortonli@mail.nih.gov Rochelle Curtis, MA, National Cancer Institute, Bethesda, MD; rcurtis@mail.nih.gov Ruth Pfeiffer, National Cancer Institute, Bethesda, MD; David A. Jacobson, MD; Children s National Medical Center, Washington, DC; dajacobs@cnmc.org Additional investigators to be named Specific Aims: 1. Characterize spectrum of malignancies after allogeneic HSCT for recipients followed after a. Describe incidence rates for cancer overall and each cancer type. b. Describe short-term cancer incidence in recent recipients, and long-term cancer incidence among recipients transplanted in earlier years. c. Compare cancer incidence in HSCT recipients with that in general population. d. Describe mortality due to cancer. 2. Assess the role of conditioning regimens in the development of subsequent malignancies in HSCT recipients followed after a. Evaluate the association between TBI and late-onset malignancies. b. Assess the relationships of specific chemotherapeutic agents with development of subsequent malignancies, with a particular focus on risks for patients treated in more recent years as treatment approaches have changed. 3. Assess whether cgvhd is a risk factor for cancer in HSCT recipients after a. Evaluate this association for specific cancers, especially SCCs of oropharynx and skin, and cancers of the GI tract, liver, and lung. b. Assess the relationship of cgvhd at specific sites with subsequent cancer risk at those sites. c. Assess the magnitude of the association of cgvhd with cancer risk in different periods of follow-up after transplantation. Scientific Justification: Hematopoietic stem cell transplantation (HSCT) provides potentially curative therapy for patients with a range of hematologic malignancies as well as selected other cancers and non-malignant conditions. The number of allogeneic HSCTs has increased over time, with approximately 4000 unrelated-donor and 3000 related-donor transplants in the U.S. in 2010 (1). Among participating centers in the CIBMTR, there were approximately 4000 allogeneic transplants among children and 12,000 among adults in (based on incomplete reporting) (1). HSCT recipients have an elevated risk for developing new cancers (i.e., differing from the malignancy that may have been the indication for transplantation) (2-4). The reasons for this increased cancer risk are multifactorial and include prior exposure to radiation and chemotherapy as part of initial therapy for the first malignancy and the conditioning for HSCT (2;4). Risk of post-transplant lymphoproliferative disorder and lymphoid malignancies is also high, due to immunosuppression and Epstein-Barr virus infection (5). Historically, patients frequently underwent total body irradiation (TBI) with a total dose of 8-15 Gy and received a variety of chemotherapeutic agents as conditioning prior to HSCT in order to eradicate malignant cells and facilitate engraftment of donor hematopoietic cells. TBI is associated with increased risk of subsequent neoplasms, particularly for patients treated at a young age (2). Other epidemiologic 19

20 Not for publication or presentation Attachment 4 studies demonstrate that elevated cancer risks related to radiation persist for decades following exposure (6), but the long-term risks for patients treated with TBI for HSCT have not been explored. Another major complication of allogeneic HSCT is chronic graft-vs.-host disease (cgvhd), which typically has onset 2-12 months post-transplant (7;8). cgvhd affects multiple organs, especially the skin, oral and gastrointestinal mucosa, liver, and lung (9). Despite prophylaxis using a variety of immunosuppressive approaches, cgvhd develops in approximately 30-70% of allogeneic HSCT recipients (7;8;10;11). Therapy for cgvhd involves intensification of immunosuppression. cgvhd causes substantial longterm morbidity, and although it may resolve over time, severe cgvhd is associated with increased mortality (12). Of note, part of the elevated cancer risk in allogeneic HSCT recipients appears related to cgvhd (2;13). Using CIBMTR data, Rizzo et al. reported a 7-fold elevation in risk for oral cavity/pharynx cancers (standardized incidence ratio [SIR] 7.01, compared with the general population), most of which were squamous cell carcinomas (SCCs) (2). In that study, the risk of SCCs overall (i.e., combining oral cavity/pharynx cancers with SCCs at other sites including skin) was significantly increased in the presence of cgvhd, during follow-up both 1-4 years after HSCT (relative risk 6.79) and 5+ years after HSCT (relative risk 4.38). Such an association is biologically plausible as a result of chronic localized immune damage of cgvhd-involved tissues (14). Liver cancer risk was also elevated (SIR 6.32) (2), and this cancer has likewise been described to arise in the setting of cgvhd (15). Curtis et al. examined the association between cgvhd and SCCs in greater detail in a case-control study nested in the CIBMTR allogeneic HSCT population (13). They observed a 2.79-fold increased risk for SCCs in association with cgvhd but no added elevation in risk associated with acute graft vs. host disease. SCC risk increased with severity of cgvhd and with the duration of immunosuppression for cgvhd prophylaxis or therapy. Despite substantial interest in understanding the development of new cancers among HSCT recipients, prior studies have left several issues unaddressed. Importantly, no cancer cases were studied by Rizzo et al. after 1996 (2). In recent years, there have been a number of important changes in allogeneic transplantation practices, including changes in the types and doses of treatments. Numerous alternative preparative regimens have been introduced, including substantially lower doses of total body irradiation (3 Gy) used in non-myeloablative transplantation, as well as the use of conditioning regimens based on chemotherapy without radiation. Although the shift to newer treatment regimens is purported to confer lower toxicity and improved survival, a direct comparison of the carcinogenic effects of myeloablative versus non-myeloablative regimens has not yet been investigated. Furthermore, with growing use of peripheral blood stem cell transplantation in adults, the incidence of cgvhd has increased (7), which may have affected cancer risk. Limited data from Rizzo et al. suggest that the risk of solid cancers increases with time since transplantation (with SIRs trending from 1.56 to 4.55 at 1-4 years after transplantation and 10+ years after transplantation, respectively) (2). Follow-up using more recent data will allow assessment of long-term cancer risk among earlier HSCT recipients. Even if cgvhd resolves over time, or recipients with the most severe cgvhd die, lingering damage from earlier cgvhd may translate into increased cancer risk among longterm HSCT survivors. Improved understanding of cancer risks associated with HSCT regimens would provide critical information regarding the long-term health of transplant recipients, as well as valuable data on risks associated with specific radiotherapy, chemotherapy, and immunosuppressive treatments. 20

21 Not for publication or presentation Attachment 4 Variables to be analyzed: Recipient baseline form: HSCT type: unrelated or related allogeneic transplant, BMT vs. HSCT vs. cord blood Country Gender Ethnicity, race Age at transplant (calculated) Year of transplant Primary disease History of malignancy other than primary disease Smoking history Preparative regimen: radiation, chemotherapy, monoclonal antibody T-cell depletion of graft Prior HSCT Forms collected at 100 days, 6 months to 2 years, greater than 2 years post-transplant: Days from transplant at contact with recipient (calculated) Vital status Did acute GVHD develop? If yes, - Day of onset relative to transplant (calculated) - Maximum overall grade - Maximum grades at each site (skin, lower GI, upper GI, liver, other) - Therapy used to treat agvhd Did cgvhd develop? If yes, - Day of onset relative to transplant (calculated) - Maximum grade - Organ involvement - Therapy used to treat cgvhd - Presence of cgvhd at last contact - Day of last use of immunosuppressive agents relative to transplant Did bronchiolitis obliterans develop? If yes, day of onset relative to transplant (calculated) New malignancy? If yes, - Type of cancer - Day of onset relative to transplant (calculated) Subsequent HSCT? If yes, day of retransplant relative to first transplant (calculated) Recipient death: Days from transplant to death (calculated) Was cause of death confirmed by autopsy? Causes of death: primary, contributing Study design: Using CIBMTR data, we will create a cohort of allogeneic HSCT recipients followed in 1997 or after. Recipients of either related or unrelated donor HSCT, and of bone marrow, peripheral blood, or cord blood HSCT, will be included. We will consider only recipients of a first transplant who were alive and under follow-up on January 1, 1997, or who received a first transplant after 1/1/1997. Follow-up will begin at first HSCT transplantat or 1/1/1997 (whichever is later) and will end at the earliest of a subsequent transplant, death, or last follow-up report to the CIBMTR. 21

22 Not for publication or presentation Attachment 4 New malignancies will be ascertained through CIBMTR follow-up reports. Cancers will be categorized as on the CIBMTR follow-up forms as: acute myeloid leukemia, other leukemia including acute lymphoblastic leukemia (specified), breast cancer, CNS tumor, gastrointestinal malignancy, genitourinary malignancy, Hodgkin lymphoma, lung cancer, lymphoma or lymphoproliferative disease, melanoma, other skin cancer (basal cell or squamous cell), myelodysplasia, oropharyngeal cancer (tongue or buccal mucosa), sarcoma, thyroid cancer, or other (specified). Oropharyngeal cancers and squamous cell skin cancers will be grouped as SCCs in some analyses. As an initial step, we will work closely with the CIBMTR to assess the quality of the data and feasibility of the project. We will review the cancer diagnoses, including any pathology reports provided to CIBMTR. We will assess completeness of follow-up reporting in CIBMTR according to transplant center, time since transplantation, and other factors (16). These results will help guide further analyses. For example, if follow-up appears to be incomplete more than 10 years after transplantation, then we will focus on recipients who underwent transplantation in more recent years and restrict analyses to shorter periods. We will also examine the completeness and quality of the CIBMTR data on conditioning regimens and cgvhd, as these are key risk factors to be evaluated for objectives 2 and 3. Before proceeding with our main analyses, we will provide a detailed interim report to CIBMTR. Statistical analyses for objective 1 For cancer overall and each type, we will describe the incidence rate (cases per 100,000 person-years) for the entire follow-up period after transplantation, as well as in defined time intervals after transplantation. For example, incidence in recipients transplanted in can be assessed approximately 5-10 years post-transplant, while recipients transplanted in can be assessed approximately years post-transplant. Incidence rates across time periods will be compared using Poisson regression, adjusting for sex, race/ethnicity, attained age, and transplant-related characteristics. Cancer incidence will be compared with that expected using the SIR = observed number of cases/expected number of cases. The expected counts will be derived by applying general population cancer rates, specific to sex, age, race/ethnicity, calendar year, to the person-time at risk among recipients. We will utilize data on general population cancer risk collected by cancer registries and published in the Cancer Incidence in Five Continents database (17). General population rates are not available for basal and squamous cell skin cancers, so expected counts for these will not be derived. Exact 95% confidence interval will be calculated for the SIR assuming a Poisson distribution for the observed count. We will classify deaths as cancer-related according to data provided on CIBMTR forms, if the specified primary or contributing cause was listed as cancer and if there was no reported relapse of a malignancy that was the indication for transplantation. We will calculate the cancer-specific mortality rate as the number of cancer-related deaths per 100,000 person-years, and also express this as a fraction of the overall mortality rate. Statistical analyses for objective 2 We will describe changes over time in use of TBI and various chemotherapy agents as part of HSCT conditioning regimens. We will assess the association between TBI and the incidence of late-onset malignancies by evaluating recipients who survived at least 10 years after transplant. These analyses will utilize Cox regression and consider follow-up to start at the latest of 1/1/1996 and 10 years posttransplant. We will assess both overall cancer as well as individual types. Similarly, over shorter periods of follow-up for more recent recipients, we will assess cancer risk related to use of newer treatment approaches (i.e., reduced doses of radiation, alternative chemotherapy regimens). Models will be adjusted for potential confounders including demographic characteristics, transplant type (i.e., donor type, source of stem cells), and other treatment-related factors. 22

23 Not for publication or presentation Attachment 4 Statistical analyses for objective 3 We will describe the prevalence of cgvhd among recipients under follow-up at defined timepoints posttransplantation. We will present incidence rates for cancer overall, SCCs, and each cancer type, in recipients with vs. without cgvhd. We will then assess the association of cgvhd with cancer risk using Cox proportional hazards models, where cgvhd is considered as a time-dependent covariate. All Cox models will be adjusted for potential confounders, including demographics, transplant type, and conditioning regimen. We will use Cox models to assess the association of cgvhd at specific sites with risk of cancer at those sites. For example, we will evaluate risk of oropharyngeal cancers in relation to oral cavity cgvhd; we would expect the association to be stronger than between skin cgvhd and risk of oropharyngeal cancers. Cox models will also be used to evaluate the time course of the association between cgvhd and cancer risk by including an interaction term for cgvhd and time since transplantation (18). For instance, cgvhd present at 2 years after transplant may be associated with cancer risk 10 years after transplant, even if cgvhd has resolved in the interim. We will therefore evaluate cgvhd at several timepoints, and consider both the most recent level of cgvhd as well as its greatest previous severity as predictors of subsequent cancer risk. Statistical power With the CIBMTR, we will review the number of cancer cases and utilize these counts to derive power calculations for the proposed statistical calculations. If the number is small, some analyses proposed in objectives 2 and 3 may not be feasible. At a minimum, however, it should be possible to provide updated estimates of cancer risk using data after 1996, thereby meeting objective 1. Specifically, these analyses would extend the report by Rizzo et al. (2) to more recent years. If long-term follow-up appears reasonably complete, we will also be able to provide improved estimates for cancer risk 10+ years after transplantation. References: 1. Pasqini, M. C. and Wang, Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides ( Rizzo JD, Curtis RE, Socie G, Sobocinski KA, Gilbert E, Landgren O et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113: Kolb HJ, Socie G, Duell T, Van Lint MT, Tichelli A, Apperley JF et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group. Ann Intern Med. 1999;131: Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336: Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM, Sobocinski KA et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113: Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M et al. Solid cancer incidence in atomic bomb survivors: Radiat Res. 2007;168: Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367: Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:

24 Not for publication or presentation Attachment Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001;344: Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005;23: Pasquini MC. Impact of graft-versus-host disease on survival. Best Pract Res Clin Haematol. 2008;21: Curtis RE, Metayer C, Rizzo JD, Socie G, Sobocinski KA, Flowers ME et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. 2005;105: Sloand EM, Pfannes L, Ling C, Feng X, Jasek M, Calado R et al. Graft-versus-host disease: role of inflammation in the development of chromosomal abnormalities of keratinocytes. Biol Blood Marrow Transplant. 2010;16: Yoshimi A, Yamamoto G, Goto T, Koike K, Kurokawa M. Hepatocellular carcinoma in cirrhotic liver with graft-versus-host disease. Ann Hematol. 2012;91: Clark TG, Altman DG, De Stavola BL. Quantification of the completeness of follow-up. Lancet. 2002;359: Parkin, D. M., Whelan, S. L., Ferlay, J., and Storm, H. Cancer incidence in five continents IARC. 18. Quantin C, Abrahamowicz M, Moreau T, Bartlett G, MacKenzie T, Tazi MA et al. Variation over time of the effects of prognostic factors in a population-based study of colon cancer: comparison of statistical models. Am J Epidemiol. 1999;150:

25 Not for publication or presentation Attachment 4 Characteristics of patients with malignant diseases receiving allogeneic hematopoietic transplantation, reported to CIBMTR <1997 >1997 Secondary Malignancy Secondary Malignancy No N (%) Yes N (%) No N (%) Yes N (%) Number of patients Number of centers Age at transplant, years, median (range) 29 (<1-72) 33 (<1-62) 38 (<1-83) 48 (<1-77) Age at transplant, years (11) 149 (12) 3411 (10) 131 ( 7) (18) 175 (14) 4224 (13) 144 ( 7) (23) 213 (17) 4797 (14) 164 ( 8) (26) 319 (26) 5464 (16) 216 (11) (18) 281 (23) 6611 (20) 400 (21) ( 4) 93 ( 8) 6377 (19) 532 (27) (<1) 5 (<1) 2613 ( 8) 322 (17) >=70 1 (<1) (<1) 26 ( 1) Missing Patient gender Male (59) 703 (57) (57) 1203 (62) Female (41) 532 (43) (43) 732 (38) Missing Disease AML 8682 (33) 363 (29) (41) 710 (37) ALL 6630 (25) 264 (21) 7055 (21) 246 (13) CML 8471 (32) 486 (39) 5437 (16) 277 (14) MDS 937 ( 4) 57 ( 5) 3157 ( 9) 358 (19) Lymphoma 1495 ( 6) 65 ( 5) 4300 (13) 344 (18) Year of transplant (20) 233 (19) (34) 395 (32) (46) 607 (49) (35) 620 (32) (40) 774 (40) (25) 541 (28) Donor type HLA-matched siblings (74) 812 (66) (35) 548 (28) Identical twins 410 ( 2) 19 ( 2) 148 (<1) 2 (<1) Other relatives 1041 ( 4) 44 ( 4) 861 ( 3) 47 ( 2) Unrelated donor 5294 (20) 360 (29) (62) 1328 (69) Missing Graft type BM (96) 1197 (97) (39) 698 (36) PB+-BM 792 ( 3) 34 ( 3) (51) 1105 (57) CB 134 ( 1) 3 (<1) 3107 ( 9) 131 ( 7) Missing

26 Not for publication or presentation Attachment 4 Continued. <1997 >1997 Secondary Malignancy Secondary Malignancy No N (%) Yes N (%) No N (%) Yes N (%) Type of Secondary malignancy No new malignancy Clonal cytogenetic abnormality (not Leukemia or MDS) 0 3 (<1) 0 4 (<1) AML/ANLL 0 29 ( 2) ( 6) Other leukemias 0 13 ( 1) 0 42 ( 2) MDS/MPS 0 11 ( 1) 0 78 ( 4) Lymphoma or PTLD ( 9) (16) Hodgkin disease 0 4 (<1) 0 7 (<1) AML/MDS (NMDP legacy) 0 11 ( 1) 0 61 ( 3) Other cancer (57) (63) Diagnosis missing - to be checked (28) 0 88 ( 5) Follow-up of survivors, months, median (range) 130 (<1-436) 193 (18-432) 60 (<1-187) 73 (3-175) 26

27 Not for publication or presentation Attachment 5 CIBMTR Study Proposal: Study Title: Late cardiovascular morbidity and mortality following pediatric allogeneic HSCT K. Scott Baker, MD, FHCRC, Fred Hutchinson Cancer Research Center, Seattle, WA ksbaker@fhcrc.org, Christine N. Duncan, MD, Dana-Farber Cancer Institute, Boston, MA, Christine_duncan@dfci.harvard.edu Michael Pulsipher, MD, University of Utah Medical School, Salt Lake City, UT, Michael.pulsipher@hsc.utah.edu Specific Aims: 1. To establish the incidence of cardiovascular (CV) related adverse outcomes (myocardial infarction, stroke, congestive heart failure, hypertension, or cardiac-related death) in patients transplanted at age 18 years or less for a malignant disease and who have survived at least two years after transplant and compare to age/sex matched population data 2. To examine the incidence of risk factors associated with CV disease including obesity, diabetes, and dyslipidemia in survivors after childhood HSCT and their impact on the development of CV related events and/or mortality 3. To determine how various patient (age at HCT, cancer diagnosis, gender, race) and treatment related factors (pre-transplant chemotherapy exposure, pre-transplant radiation, HCT conditioning regimen and intensity, stem cell source and type, acute/chronic graft versus host disease) influence the development of CV risk factors and CV-related adverse outcomes in survivors after HCT in childhood Scientific Justification: Late CV complications are a leading cause of treatment-related morbidity and mortality in long-term survivors of childhood cancer [5, 8-11]. A great deal has been learned about chemotherapy-related late CV complications in pediatric cancer survivors. However, little is known regarding the incidence and risk factors for CV toxicity following HCT in childhood. Potential risk factors that are unique to transplant include exposure to high-dose chemotherapy and total body irradiation. In addition, HCT survivors are at increased risk of developing CV risk factors such as hypertension, lipid abnormalities, and diabetes due, in part, to exposure to irradiation, prolonged immunosuppressive therapy, obesity, or other health conditions such as hypothyroidism or growth hormone deficiency. The influence of these risk factors on the development of CV late effects following HCT in childhood has not been fully investigated. Studies performed in adult survivors of HCT have shown an increased risk of CV related death compared to the general population and reports have demonstrated a risk that is increased 2.3 times that of the general population [1]. Little is known about the potential risk of premature CV death in survivors of childhood HCT. The etiology of CV risk and subsequent death following adult HCT is largely unknown, although development of metabolic syndrome (a constellation of obesity, insulin resistance, glucose intolerance, lipid abnormalities, and hypertension, that is associated with an increased risk for type 2 diabetes mellitus and coronary artery disease) has been suggested to play a contributing role [2]. The concern over time is that HCT survivors who develop metabolic syndrome will be at heightened risk for developing significant CV related events and/or early death. The Bone Marrow Transplant Survivor Study examined diabetes, hypertension, and CV events in 1089 primarily adult patients who survived two or more years after HCT [3]. At an average age of 39 years and with an average follow-up after HCT of nearly 9 years, survivors of allogeneic HCT were 3.6 times more likely to report diabetes than siblings and 2 times more likely to report hypertension. Exposure to irradiation, often a part of the transplant treatment regimen, was also associated with an increased risk of diabetes. Rates of CV outcomes also 27

28 Not for publication or presentation Attachment 5 have been examined among nearly 1,500 transplant survivors treated in Seattle from compared to a population of non-transplant patients matched for age, year, and sex [4]. Transplant survivors experienced increased rates of cardiovascular death and had an increased incidence of ischemic heart disease, cardiomyopathy/heart failure, stroke, vascular diseases, and cardiac rhythm disorders. Survivors also had an increased cumulative incidence of related conditions that predispose towards more serious CV disease: hypertension, kidney disease, lipid abnormalities, and diabetes. The vast majority of investigations of the role of late CV morbidity have been in survivors of adult transplant. There are significant knowledge gaps in regard to late CV toxicity following childhood HCT and this proposal will address the limitations in that knowledge. Patient Eligibility Population: Patients who have survived disease-free two years or greater following HCT for a malignant disease HCT at age 18 years or less Autologous transplant or allogeneic transplant with related or unrelated donor All stem cell sources All conditioning regimens Follow-up data available regarding survival, disease status, and CV and metabolic late effects HCT performed in the United States Data Requirements: Patient-Related Variables Age in years at transplant Sex Race Ethnicity Underlying disease Pre-transplant Variables Cumulative dose of anthracycline exposure (will require supplemental data collection) Pre-transplant radiation site and total dose (will require supplemental data collection) Baseline hypertension requiring the use of medication (at time of HCT) (will require supplemental data collection) Baseline medication use for dyslipidemia (at time of HCT) (will require supplemental data collection) Hyperglycemia requiring insulin or diabetes prior to HCT Height/weight/body mass index at time of conditioning Tobacco use (will require supplemental data collection) Transplant-Related Variables Year of transplant Type of transplant: allogeneic, autologous Donor type (allogeneic patients): matched sibling, other related donor, unrelated donor Stem cell source: bone marrow, peripheral blood stem cells, or umbilical cord Conditioning regimen: Cy/TBI, Bu/Cy, Cy/other, other Conditioning type: reduced intensity, myeloablative, non-myeloablative GVHD prophylaxis (allogeneic patients): T-cell depleted, calcineurin inhibitor/methotrexate, calcineurin inhibitor/methotrexate/corticosteroid, calcineurin inhibitor/mycophenolate mofetil 28

29 Not for publication or presentation Attachment 5 Post-transplant related variables: current survival, disease status, and CV-late effects Date of current status Cause of death when applicable Chronic GVHD status: present or absent Disease status: in remission or not in remission Height at two years and at last follow-up Weight at two years and at last follow-up CV-related late effects and potential predictors Tobacco use post-transplant (will require supplemental data collection) Hormone replacement therapy (gonadal, growth hormone, thyroid hormone) (will require supplemental data collection) 1. Year at start of therapy 2. Source 3. Year at last therapy 4. Present prior to transplant Hypertension (will require supplemental data collection) 1. Year at diagnosis 2. Year at start of therapy (if applicable) 3. Year at last therapy (if applicable) Dyslipidemia (triglycerides >150, HDL cholesterol <40, or on lipid lowering medication) (will require supplemental data collection) 1. Year at diagnosis 2. Year at start of therapy (if applicable) 3. Year at last therapy (if applicable) Other conditions: present or absent 1. Type 2 diabetes (if on medication and type of medication) 2. Coronary artery disease 3. Myocardial infarction 4. Stroke 5. Cardiomyopathy/congestive heart failure Sample Requirements: This protocol will not use biologic samples. Study Design: Pediatric transplant patients who developed post-hsct CV-related complications will be compared to control patients who did not develop such problems. The investigation will use data currently available from CIBMTR forms and the collection of supplemental data. Survivors of childhood transplant who have CV-related late effects will be identified through existing CIBMTR data. Additional data related to potential risk factors and predictors of CV toxicity will be collected with supplemental forms sent to individual transplant centers. Additionally, we will compare the incidence of specific CV-related late effects between HCT survivors and the general population matched for age, sex, and nationality. Initial review of the CIBMTR database will indicate the patients who will require collection of supplementary data forms to ascertain which of those patients will meet the definition of a case for this case-control study. The supplemental forms will collect additional data pertinent to baseline case characteristics not collected on the standard forms, and likewise, the post-transplant forms will collect 29

30 Not for publication or presentation Attachment 5 more detail on post-transplant factors such as hormone replacement that are not a standard part of form collection. Descriptive statistics will be presented for the patient-related variables. Frequencies and percentages will be calculated for the CV-related late effects listed below. The prevalence of each late effect will be compared between HCT survivors and the matched general population. Multivariate Cox regression analysis will be used to evaluate for potential risk factors for CV-disease and death. The CIBMTR has published extensively in the area of late effects as evidence by the recent investigation of the late effects following allogeneic transplant for aplastic anemia [5]. The investigators in conjunction with the CIBMTR have applied to the Jeff Gordon Children s Foundation for $250,000 to support this project. If successfully funded the resources would be used to help facilitate the collection of supplemental data and analysis. We believe that this funding, the record of late effects investigations, and CIBMTR study team and database make this project feasible. References: 1. Bhatia S, Francisco L, Carter A, et al, Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood Nov 15;110(10): Nieder ML, McDonald GB, Kida A, et al, National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction. Biol Blood Marrow Transplant Nov;17(11): Baker KS, Ness KK, Steinberger, et al, Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood Feb 15;109(4): Narici, MV and Maffulli N, Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull. 2010;95: Buchbinder D, Nugent DJ, Brazauskas R, et al, Late effects in hematopoietic cell transplant recipients with acquired severe Aplastic Anemia: a report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant Dec;18(12):

31 Not for publication or presentation Attachment 5 Post-transplant cardiovascular information collected on CIBMTR/NMDP forms IBMTR 095/098 CORE/Fu Before 2007 After 2007 IBMTR NMDP NMDP FN 002 Legacy V7 Legacy V yrs Core/Fu yrs >2 yrs (2200) FN >2 yrs (2300) Seizure Y Y OS Y Y Y Myocardial infarction OS Y Y OS Y Y Diabetes OS OS OS OS Y Y Congestive heart failure OS OS OS OS Y Y Y=Asked explicitly yes vs. no. OS=Not asked, but can be reported under other specify. Characteristics of patients with age<18 years old transplanted for malignant diseases in the United States between , reported to CIBMTR with 2 year CRF follow-up forms available (excluding patients with 2nd tx within 2 years of the first transplant) Variable Allo N (%) Auto N (%) Number of patients Number of centers Age at transplant, years, median (range) 9 (<1-18) 5 (<1-18) Age at transplant, years <5 490 (30) 147 (53) (27) 51 (18) (28) 37 (13) (15) 41 (15) Patient gender Male 981 (59) 165 (60) Female 669 (41) 111 (40) Missing 1 0 Disease AML 488 (30) 6 ( 2) ALL 709 (43) 0 CML 121 ( 7) 0 MDS/MPS 199 (12) 0 Other leukemias 66 ( 4) 0 NHL 59 ( 4) 6 ( 2) HD 2 (<1) 31 (11) Solid cancers 7 (<1) 233 (84) Donor type Auto HLA-matched siblings 238 (15) 0 Other relatives 28 ( 2) 0 Unrelated donor 1372 (84) 0 Missing

32 Not for publication or presentation Attachment 5 Continued. Allo N (%) Auto N (%) Variable Graft type BM 820 (50) 13 ( 5) PB+-BM 265 (16) 259 (95) CB 564 (34) 1 (<1) Missing 2 3 Post-transplant cardiovascular events a Myocardial infarction 2 (<1) 0 Seizures 123 ( 7) 15 ( 6) Diabetes mellitus 73 ( 4) 1 (<1) Congestive heart failures 12 ( 1) 0 Follow-up of survivors, months, median (range) 62 (24-149) 54 (24-147) a The count below included events reported in the first two years post-transplant. Year of transplant Myocardial Breakdown of number of events by year of transplant Allo Congestive heart failure Myocardial Congestive infarction Seizures Diabetes infarction Seizures Diabetes heart failure Total Auto 32

33 Not for publication or presentation Attachment 6 CIBMTR Study Proposal: Study Title: Cigarette smoking and allogeneic stem cell transplantation outcomes. Shahrukh Hashmi MD MPH;Von Liebig Transplant Ctr, Mayo Clinic Rochester, hashmi.shahrukh@mayo.edu Walter K. Kremers, PhD; College of Medicine; Mayo Clinic Rochester, Kremers.walter@mayo.edu Shawna L. Ehlers, PhD, LP; College of Medicine, Mayo Clinic Rochester, ehlers.shawna@mayo.edu William J. Hogan, MB, BCh; College of Medicine; Mayo Clinic Rochester, hogan.william@mayo.edu Mrinal S. Patnaik, MBBS; College of Medicine; Mayo Clinic Rochester, patnaik.mrinal@mayo.edu Luis F. Porrata, MD; College of Medicine; Mayo Clinic Rochester, Rochester, porrata.luis@mayo.edu Mark R. Litzow MD; College of Medicine; Mayo Clinic Rochester, litzow.mark@mayo.edu Specific Aims: 1. Primary Objective: To evaluate the impact of cigarette smoking on the incidence of development of secondary solid tumors in adult patients with hematologic malignancies who underwent allogeneic stem cell transplantation (ASCT). 2. Secondary Objective: To analyze the association of smoking with post-asct overall survival. Scientific Justification: Cigarette smoking is responsible for a third of all cancer deaths in Western countries 1. It is a known contraindication for recipient enrollment in the organ transplant recipient registries (absolute contraindication for heart and lung transplants, relative for rest of the organ transplants), unless enrolled in a smoking cessation program or discontinuation for at least 6 months. No such formal contraindication or guidelines exist for a potential ASCT recipient. Many single institution studies have reported adverse post-asct outcomes; however the external validity of the studies is questionable, not only due inherent selection biases, but also due to difference in definitions of smoking exposure used, and due to variability in the primary outcomes measured. A study assessing the relationship of smoking with outcomes of ASCT utilizing CIBMTR data was undertaken 2, and found an inverse association of smoking with 5 year overall survival, however only patients with chronic myeloid leukemia were evaluated; which amongst the hematologic malignancies, has currently become one of the least common indication for stem cell transplants, due to the availability of tyrosine kinase inhibitors. 3 The 2 outcome domains of smoking which have been well studied are pulmonary toxicities and survival [OS and/or relapse free survival (RFS)], with somewhat conflicting results. While a two-fold increase in pack years smoked was found to be associated with increased risk of respiratory failure within 100 days of ASCT in one study 4. Smoking was noted to have no independent association with the risk of development of severe pulmonary toxicity within 60 days of SCT s in another single institution study 5. A strong inverse association of smoking with survival (either RFS or OS) has been reproduced in many single institution studies. The risk of leukemia relapse has been reported to increase by x1.7 with each pack years smoked pre-asct 6. Our group has reported an inferior OS and an increase in the number of days of hospitalization post-asct in current smokers compared to non-smokers 7. In all these studies, besides heterogenous study populations, the measurement of smoking exposure varied significantly. Besides the well-recognized associations of smoking with acute pulmonary toxicities and survival, certain late secondary outcomes e.g. solid malignancies and cardiovascular (CVS) effects of ASCT may also be related to smoking. An European Group of Blood and Marrow Transplantation (EBMT) analysis recently published the results of late CVS outcomes in ASCT survivors, in which the cumulative incidence of arterial events post ASCT was found to be significantly higher in patients with high global CVS score (smoking, DM, HTN, physical inactivity, BMI, dyslipidemia) compared to those with a lower score (17% vs 4%) 8. Persistent smoking was associated with high incidence of CVS events alone (3%) or in combination with at least one other CVS risk factor (17%) in this study. 33

34 Not for publication or presentation Attachment 6 A 40% increased incident rate of secondary cancers compared to the general population ( , P =.01) has been reported in leukemia patients who underwent ASCT with a non-total body irradiation (TBI) based regimen 9 ; among the 5 most commonly occurring secondary solid cancers reported in this cohort, 3 of the cancers have an established causal relationship with smoking i.e. Lung, esophagus and oral cavity. In this study, smoking prior to ASCT compared to non-smokers, was associated with relative risk of 11.6 (p=0.02) for the development of respiratory tract cancers. Although many investigators have hypothesized the association of biologic plausibility of these cancers with either graft versus host disease (GVHD), with immunosuppression (IST), or with conditioning (particularly with TBI), whether smoking exposure increases the risk of these cancers, or whether it has a multiplicative or additive interaction with GVHD, IST,TBI or chemotherapy is unknown. To our knowledge, an analysis to evaluate the strength of association of pre-transplant baseline smoking (measured by a strictly defined exposure), with overall survival, acute chronic pulmonary toxicities, secondary solid cancers, and late cardiovascular effects, (with adjustment for known confounders and effect modifiers) has not been undertaken. CIBMTR has been collecting information on the some smoking variables since 1990: recently more variables have been included in the database: ever smoker/never smoker; smoking within a year of ASCT/ smoking prior to a year of ASCT; number of years smoked and amount of packs per day (also has decimal units for this variable). This categorization is based on self-reported responses extracted from medical notes by data managers completing the CIBMTR forms. Besides the baseline health parameters, also contained within the database is the information on overall survival, malignancy relapse, secondary cancers, pulmonary complications captured at 100 days, 1 year and then annually until death. Besides cigarette smoking, other tobacco use is not captured within this database. Thus we propose to analyze the association of cigarette smoking with survival, pulmonary toxicities and secondary cancers, by comparing these variables between 2 groups: smokers and non-smokers (defined as below in methods). Patient Eligibility Population: Inclusion Criteria: 1st Allogeneic Hematopoetic stem cell transplant (subsequent transplants may increase the risk of both mortality and the incidence of secondary cancers due to GVHD or conditioning) Age>18 years (pediatric populations have different survival statistics and the prevalence of smoking is very different in this group compared to adults) Hematologic malignancies (patients transplanted for autoimmune diseases, genetic disorders and solid tumors have different survival outcomes, variable pulmonary toxicities and different incidences of development of solid malignancies post ASCT) Patients enrolled in the CIBMTR database between (at least 3 years of follow-up) Exclusion Criteria: Donor lymphocyte infusions (different survival outcomes) Patients with history of bone marrow failure syndromes (increased risk of solid tumors post -ASCT especially with Fanconi s anemia) Prior autologous or syngeneic stem cell transplants (different survival outcomes) Unavailable pre-asct data on FEV1 and DLCO (cannot adjust for baseline lung function). Unavailable data on smoking as follows from the CIBMTR form : Unknown to Q136, Q137 or Q138 Study Design: Study Type: Observational retrospective analysis of consecutively selected patients from the CIBMTR database who fulfill the selection criteria. 34

35 Not for publication or presentation Attachment 6 Primary outcome variable: Overall survival (OS) defined as survival from the day of stem cell infusion until death. Secondary outcome variable: Pulmonary toxicity, Secondary Cancers, late cardiovascular (CV) events. Acute Pulmonary toxicities- Within 100 days of ASCT: ARDS, Interstitial Pneumonitis, Intubation, Pulmonary hemorrhage, Bronchiolitis Obliterans, Pneumonia, as captured in Q in CIBMTR form Secondary Cancers: All invasive solid cancers captured in Q in the CIBMTR form Late CV events: Myocardial infarction captured in Q197 from CIBMTR form Hypothesis: OS of ever smokers is significantly lower than that of never smoker. Ever smokers would include both the current smokers (smoking within a year of ASCT) and the non-current smokers (smoking prior to 1 year of ASCT). Secondarily, an association of the numbers of pack years smoked on a continuous scale will be analyzed for the primary and secondary outcome variables. This would require - firstly investigating the numerical relationship of smoking exposure to OS by a spine fit model, which would suggest an appropriate transformation (e.g. log2 or square root transformation, cutoff points in case of a segmented regression, etc.) and then quantifying the relationship between fitted model and the appropriately transformed variables. All P values will be 2 sided, with a significance level of 95%. Patient, disease, and transplant-related variables for patients in both the groups will be compared using chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. Variables for adjustment: Recipient age (linear term vs. a separate stratified analysis based on age cutoffs based on decades e.g , 29-38, 39-48, etc for the secondary cancers will be considered; an interaction analysis will also be performed between age and secondary cancers), conditioning type (stratification groups TBI vs non-tbi, and sub group analysis of myeloablative versus non-ablative regimens, and also for busulfan versus non-busulfan containing regimens), type of malignancy (including molecular and cytogenetic risk sub-types), acute GVHD, chronic GVHD, Karnofsky performance status, gender, BMI, immunosuppression type and duration, types of chemotherapy patient has received prior to ASCT (including a sub-group analysis for the number of chemotherapies received prior to ASCT and for those patients treated with Bleomycin). Probabilities of OS, acute pulmonary toxicities, secondary cancers and CV events would be analyzed via the cumulative incidence function method (proportional hazards regression). For survival, cox proportional hazards models will used to adjust for patient-related, diseaserelated, and transplant-related covariates. Biologic Sample Requirements: None Study Benefits: If a significant association of smoking exposure with OS, secondary cancers, pulmonary toxicities or CV outcomes is found, we would suggest prospective studies for comprehensive evaluation of smoking pretransplant by validated scales with long term follow-up for relevant outcomes, and this may help in establishing guidelines for smoking cessation or enrollment in a smoking cessation program in our patient populations pre-transplant. References: 1. Sasco AJ, Secretan MB, Straif K. et al. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer Aug;45 Suppl 2:S Marks DI, Ballen K, Logan BR et al. The effect of smoking on allogeneic transplant outcomes. BBMT Volume 15, Issue 10, October 2009, Pages

36 Not for publication or presentation Attachment Tran BT, Halperin A, Chien JW et al. Cigarette smoking and outcomes after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant Jul;17(7): Epub 2011 Mar Ho VT, Weller E, Lee SJ et al. Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(4): Chang G, Orav EJ, McNamara T et al. Depression, cigarette smoking, and hematopoietic stem cell transplantation outcome. Cancer Aug 15;101(4): Ehlers SL, Gastineau DA, Patten CA et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant Feb;46(2): Epub 2010 May Tichelli A, Passweg J, Wójcik D et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica Aug;93(8): Epub 2008 Jun Majhail NS, Brazauskas R, Rizzo JD et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood Jan 6;117(1): Epub 2010 Oct 6. 36

37 Not for publication or presentation Attachment 6 Characteristics of patients with hematologic malignant diseases receiving allogeneic HCTs , reported to CIBMTR Smoking history Never Variable smoked Smoked Unknown Number of patients Number of centers Age at transplant, years, median (range) 42 (18-83) 50 (18-78) 46 (18-79) Age at transplant, years (24) 448 (11) 1857 (20) (20) 599 (15) 1618 (17) (23) 1003 (25) 2177 (23) (23) 1231 (31) 2412 (26) (10) 646 (16) 1149 (12) >=70 38 ( 1) 42 ( 1) 68 ( 1) Patient gender Male 3324 (52) 2650 (67) 5294 (57) Female 3071 (48) 1319 (33) 3987 (43) Missing Disease AML 2547 (40) 1789 (45) 3916 (42) ALL 1114 (17) 419 (11) 1569 (17) CML 1089 (17) 510 (13) 1150 (12) MDS/MPS 816 (13) 642 (16) 1506 (16) NHL 771 (12) 569 (14) 1071 (12) HD 60 ( 1) 40 ( 1) 69 ( 1) Donor type HLA-matched siblings 3951 (62) 2407 (61) 937 (10) Identical twins 48 ( 1) 33 ( 1) 16 (<1) Other relatives 197 ( 3) 117 ( 3) 39 (<1) Unrelated donor a 2150 (34) 1371 (35) 8243 (89) Missing Graft type BM 1547 (24) 725 (18) 3061 (33) PB+-BM 4525 (71) 3065 (77) 5824 (63) CB 323 ( 5) 175 ( 4) 384 ( 4) Missing Year of transplant (19) 797 (20) 1824 (20) (20) 716 (18) 1917 (21) (24) 826 (21) 2451 (26) (18) 688 (17) 2796 (30) (19) 942 (24) 293 (3) Smoked within past year prior to transplant No (18) 0 Yes (12) 0 Unknown (70)

38 Not for publication or presentation Attachment 6 Continued. Smoking history Never Variable smoked Smoked Unknown Smoked prior to but not during past year No (26) 0 Yes (37) 0 Unknown (37) 9281 Years smoked < (10) (13) (14) (10) ( 4) 0 >= ( 1) 0 Unknown (47) 9281 Packs per day <1 pack/days (16) pack/days (36) 0 2 packs/days ( 9) 0 Unknown (39) 9281 Secondary malignancy No 6126 (96) 3727 (94) 8635 (93) Yes 271 ( 4) 242 ( 6) 646 ( 7) Clonal cytogenetic abnormality Not Leukemia or MDS 1 (<1) 0 0 AML/ANLL 23 (<1) 17 (<1) 22 (<1) Other leukemias 7 (<1) 7 (<1) 10 (<1) MDS/MPS 6 (<1) 3 (<1) 8 (<1) Lymphoma or PTLD 46 ( 1) 26 ( 1) 77 ( 1) Hodgkin disease 1 (<1) 4 (<1) 0 AML/MDS (NMDP legacy) (<1) Other cancers/solid cancers 175 ( 3) 178 ( 4) 476 ( 5) Dx missing - to be checked 12 (<1) 7 (<1) 13 (<1) Follow-up of survivors, months, median (range) 49 (<1-151) 49 (<1-147) 71 (<1-149) a Smoking history information on NMDP legacy patients was collected since 2002 but it is not currently in the data retrieval. Smoking dose information (packs/day and years of smoking) were not collected for NMDP legacy patients (patients transplanted before 2008). 38

39 Not for publication or presentation Attachment 7 CIBMTR Study Proposal: Study Title: Sexual dysfunction in female survivors of allogeneic stem cell transplantation. Pamela Stratton, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD, ps79c@nih.gov Bipin Savani, MD, Vanderbilt University, Nashville, TN, bipin.savani@vanderbilt.edu Clarisa Gracia, MD, University of Pennsylvania, Philadelphia, PA, cgracia@obgyn.upenn.edu Elizabeth McGee, MD, Virginia Commonwealth University, Richmond, VA, eamcgee@vcu.edu Melissa Merideth, MD, National Human Genome Research Institute, NIH, Bethesda, MA, mmeridet@mail.nih.gov Specific Aims: To determine the clinical factors associated with sexual dysfunction in women post-transplant. Scientific Justification: Sexual dysfunction affects 80% of female survivors of allo-hsct long-term and evidence suggests that women do not experience significant improvement in sexual function five years post-transplant [1]. Issues with sexual activity often persist even when other measures of physical and emotional well-being return to normal after treatment [1, 2]. Thus, most women are at increased risk of sexual dysfunction[3, 4] with the youngest transplant patients with ovarian failure most likely to report an impaired sense of well-being and lower quality of life scores [5]. Sexuality is a central aspect of an individual s self-esteem and identity. While intimacy and sexuality can decrease emotional distress and improve psychological response to a life-threatening disease and complications after treatment [6, 7], sexual response may be negatively altered by psychosocial factors such as anxiety, depression, body image changes, concurrent life stress, decreased self-confidence, fear of disease recurrence and concerns related to infertility [6, 8]. The impact of a serious illness on sexuality is often not a concern expressed by patients undergoing HSCT; additionally, sexual health, while important, may be overlooked by the health care team during recovery following treatment[9]. In fact, discussion of sexual functioning has often been a taboo subject in the healthcare setting. The long-term sexual complications after transplant include decreased libido, vaginal alterations like scarring or genital tract atrophy, premature ovarian insufficiency, dysfunction in sexual hormones, dyspareunia and infertility [6, 9-11]. In particular, sexual dysfunction in long-term female survivors of allo-hsct may be related to ovarian failure, genital chronic graft-versus-host disease, medication use, or psychosocial factors like depression and self-consciousness. Acute or chronic GVHD are among the major determinants of sexual dysfunction in allo-hsct patients [1, 11]. GVHD manifests anywhere in the body. In general, systemic GVHD and treatment with high-dose corticosteroids may result in extensive changes in physical appearance such that sexuality and body image are seriously affected. Not only does systemic GVHD contribute to fatigue and perception of unattractiveness, but the occurrence of genital GVHD can contribute to dysfunction. Both vulvar and vaginal GVHD may contribute to dyspareunia through genital mucosa changes, ulcers, or scarring. Female genital GVHD affecting the vulva and vagina is common, reported in 25 to 49% of allo-hsct survivors [12, 13]. While vulvovaginal chronic GVHD (cgvhd) presents a median of 7 to 10 months after allo-hsct [12-14], vaginal GVHD can develop years later [14-16] and can lead to vaginal scarring and stenosis. Female genital cgvhd is more common after peripheral blood stem cell transplantation (PBSCT) than bone marrow transplantation (BMT)[17]. Vaginal synechiae, severe genital cgvhd, is associated with sclerotic skin cgvhd, the most severe type of skin GVHD[14]. Identification and treatment of genital cgvhd has been hampered by underreporting of symptoms, management directed at presumed infectious 39

40 Not for publication or presentation Attachment 7 or menopausal etiologies without gynecologic examination[18] or severe illness interfering with gynecology referral and assessment. Most women undergoing allo-hsct are in their reproductive years, and more than 90% of these women experience ovarian failure after radiation and myelo-ablative conditioning chemotherapy for HSCT [19, 20]. The likelihood of permanent ovarian failure depends on the patient s age, pubertal status, conditioning chemotherapy, and radiation dose and location [20-22]. High-dose or alkylating agent chemotherapy and total-body irradiation not only are toxic to gonadal function, but they can contribute to genital atrophy, scarring or tract sensitivity[23]. For those whose menses return months or years after treatment, transient ovarian failure is common in the first year after treatment [5, 24]. Not only does ovarian dysfunction along with other endocrine dysfunction arise after chemotherapy, but chronic disease and use of immunosuppressant agents to prevent GVHD also likely contribute both to ovarian insufficiency and to sexual dysfunction. Ovarian damage may ultimately result in premature menopause (before the age of 40), even among those who resume menses; risk factors for premature menopause are similar to those for acute ovarian failure[25, 26]. There is no clear recommendation for the management of ovarian failure and contraception in women after allo-hsct: the risks and benefits of hormone therapy are individualized based on the severity of menopausal symptoms, underlying disease status, contraindications to hormones, such as history of clot or active liver disease[5]. Women under age 35 have not yet reached peak bone mass and may benefit from hormone therapy to acquire bone mass. Given the young age of many transplant patients, higher doses of estrogen and progesterone may be needed to reach physiologic levels compared to women who undergo naturally-occurring menopause. Hormone therapy is likely to be continued for many years in these young women. Hormone replacement therapy (HRT) in long-term survivors with ovarian failure improves vasomotor and urogenital menopausal symptoms, and increases measures of psychological well-being, but has little effect on sexual desire and dissatisfaction[27-29]. Testosterone failed to increase libido in cancer survivors who were not on estrogen therapy [29]. The patient s psychological status and the quality of her relationship with her partner have a large effect on sexual function [30]. Behavioral therapies that encourage communication and expression of patient s fears of feeling unattractive or rejected, and directly address relationship conflicts can play a significant role in improving sexual function. Little is known about sexual changes and their consequences experienced by patients following allogeneic HSCT. It is important to draw attention to the impact that HSCT has on the sexuality and sexual functioning in patients after HSCT. Sexual functioning is an important aspect of quality of life and needs further research. We propose a cross-sectional study that will examine the association among various psychosocial, demographic, clinical, and health factors as they pertain to sexual function of women post HSCT in order to improve options for preventive or therapeutic interventions in this field. We hypothesize that all domains of sexual dysfunction, particularly libido and pain, will be worse in those Who underwent myeloablative transplant/more intensive conditioning compared to those underwent non-myeloablative transplant with worse, prolonged GVHD compared to those without GVHD with genital GVHD compared to those without genital GVHD with ovarian failure not on hormone therapy compared to those with normal ovarian function those on hormonal therapy compared to those with normal ovarian function those with depression and anxiety compared to those without depression or anxiety 40

41 Not for publication or presentation Attachment 7 We hypothesize those who underwent PBSCT will have similar sexual functioning as those after BMT after controlling for myeloablation/intensity of conditioning regimen, general GVHD, ovarian function, hormone therapy, depression, anxiety, and genital GVHD. Outcome Data: The primary endpoint will be to assess sexual function overall, and assess various domains of sexual function including desire, arousal, orgasm and sexual pain. Overall sexual function and specific domains of sexual function will be compared between groups as described above. The secondary endpoints are: To compare subjects who were sexually active and reasons for stopping sexual activity. Patient Eligibility Population: The study population will include all female patients who are over age 18 and who received allogeneic HCT transplant for the treatment of underlying hematologic or other conditions and malignancies, between 1990 and 2009 such that women will have undergone transplantation at least 3 years ago. Data Requirements: Variables: Patient related: Age at transplant Current age Gender: female Medical history related: Reason for transplant Prior treatment before transplant Transplant related: Year of transplant Graft type: BM vs. PBSC vs. cord Conditioning regimen: Myeloablative vs. reduced intensity vs. non-myeloablative GvHD prophylaxis Post transplant complications: Major infectious complications in the last year Current GVHD treatment GVHD NIH status current (or other scoring system) Need to create a form that captures: Marital and relationship status before, during and after transplant Heterosexual versus same-sex partner Sexually active prior to transplant Children prior to or after transplant Currently sexually active Use of contraceptives barriers, IUD, hormones Gynecologic history Menopausal status prior to transplant 41

42 Not for publication or presentation Attachment 7 Menstrual regularity prior to transplant Menstrual function/hormone assessment during and after transplant Last menstrual period Genital GVHD by signs or symptoms Current treatment of Genital GVHD; history of surgery for genital GVHD Gynecologic surgery - does she still have uterus and ovaries Other questionnaires to be administered: Sexual function questionnaire SFQ (Syrjala) or CFSQ or CFSQ-14 [31, 32] Depression assessment CES-D, Becks, or Promis Anxiety - ZUNG or Promis Quality of life assessment - SP-36 or QLACS Medications: Hormone use before during and after transplant Including vaginal estrogens Hormone use currently Current GVHD treatment Current antidepressants Use of lubricants Use of Replens, probiotics, other medications for vulvar pain Sample Requirements:* No need. Study Design: The study proposed here will assess self-reported sexual function in the context of key clinical parameters such as ovarian function, current GVHD status, occurrence of genital GVHD, current hormone use, depression, anxiety, and overall quality of life. Multivariable regression analyses will be performed to identify variables that are associated with the occurrence of sexual dysfunction. References: 1. Syrjala, K.L., et al., Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years. Blood, (3): p Schover, L.R., Premature Ovarian Failure and Its Consequences: Vasomotor Symptoms, Sexuality, and Fertility. Journal of Clinical Oncology, (5): p Chiodi, S., et al., Quality of life in 244 recipients of allogeneic bone marrow transplantation. Br J Haematol, (3): p Claessens, J.J., C.C. Beerendonk, and A.V. Schattenberg, Quality of life, reproduction and sexuality after stem cell transplantation with partially T-cell-depleted grafts and after conditioning with a regimen including total body irradiation. Bone Marrow Transplant, (9): p Fish, J.D., Part 1: Hormone replacement for survivors of childhood cancer with ovarian failure-- when is it worth the risk? J Pediatr Adolesc Gynecol, (2): p Thygesen, K.H., I. Schjodt, and M. Jarden, The impact of hematopoietic stem cell transplantation on sexuality: a systematic review of the literature. Bone marrow transplantation, (5): p Wimberly, S.R., et al., Perceived partner reactions to diagnosis and treatment of breast cancer: impact on psychosocial and psychosexual adjustment. Journal of consulting and clinical psychology, (2): p

43 Not for publication or presentation Attachment 7 8. Barton-Burke, M. and C.J. Gustason, Sexuality in women with cancer. The Nursing clinics of North America, (4): p ; vi. 9. Tierney, D.K., Sexuality following hematopoietic cell transplantation. Clin J Oncol Nurs, (1): p Socie, G., et al., Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. The New England journal of medicine, (1): p Syrjala, K.L., et al., Prevalence and predictors of sexual dysfunction in long-term survivors of marrow transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, (9): p Spinelli, S., et al., Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica, (10): p Zantomio, D., et al., Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management. Bone Marrow Transplant, (8): p Stratton, P., et al., Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstet Gynecol, (5): p Riera, C., Y. Deroover, and M. Marechal, Severe vaginal chronic graft-versus-host disease (GVHD): two cases with late onset and literature review. European journal of gynaecological oncology. 31(6): p Klepac Pulanic, T., et al., Female genital chronic graft versus host disease, in 57th Annual Meeting of the Society for Gynecologic Investigation2010: Orlando, FL. 17. Flowers, M.E., et al., Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood, (2): p Norian, J.M. and P. Stratton, Labial fusion: a rare complication of chronic graft versus host disease.. Obstet Gynecol, in press. 19. Sanders, J.E., et al., Ovarian function following marrow transplantation for aplastic anemia or leukemia. J Clin Oncol, (5): p Schimmer, A.D., et al., Ovarian function after autologous bone marrow transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, (7): p Warne, G.L., et al., Cyclophosphamide-Induced Ovarian Failure. New England Journal of Medicine, (22): p Jadoul, P., et al., Clinical and biologic evaluation of ovarian function in women treated by bone marrow transplantation for various indications during childhood or adolescence. Fertility and sterility, (1): p e Apperley, J.F. and N. Reddy, Mechanism and management of treatment-related gonadal failure in recipients of high dose chemoradiotherapy. Blood reviews, (2): p Tauchmanovà, L., et al., Endocrine disorders during the first year after autologous stem-cell transplant. The American Journal of Medicine, (6): p Sklar, C.A., et al., Premature Menopause in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. Journal of the National Cancer Institute, (13): p Rutter, M.M. and S.R. Rose, Long-term endocrine sequelae of childhood cancer. Curr Opin Pediatr, (4): p Balleari, E., et al., Hormone replacement therapy and chronic graft-versus-host disease activity in women treated with bone marrow transplantation for hematologic malignancies. Ann N Y Acad Sci, : p Tauchmanova, L., et al., Estrogen-progestin therapy in women after stem cell transplant: our experience and literature review. Menopause, (2): p

44 Not for publication or presentation Attachment Heinonen, H., et al., Gender-associated differences in the quality of life after allogeneic BMT. Bone marrow transplantation, (5): p Watson, M., et al., Severe adverse impact on sexual functioning and fertility of bone marrow transplantation, either allogeneic or autologous, compared with consolidation chemotherapy alone: analysis of the MRC AML 10 trial. Cancer, (7): p Meston, C.M. and L.R. Derogatis, Validated instruments for assessing female sexual function. Journal of sex & marital therapy, Suppl 1: p Keller, A., E.L. McGarvey, and A.H. Clayton, Reliability and construct validity of the Changes in Sexual Functioning Questionnaire short-form (CSFQ-14). Journal of sex & marital therapy, (1): p

45 Not for publication or presentation Attachment 8 CIBMTR Study Proposal: Study Title: Diabetes, congestive heart failure, stroke and renal failure in recipients older than 50 years after reducedintensity conditioning allogeneic hematopoietic stem cell transplantation. He Huang, MD, PhD; The First Affiliated Hospital, School of Medicine, Zhejiang University, China hehuangyu@126.com Yoshihisa Kodera, MD; Aichi Medical University School of Medicine, Aichi, Japan, ykodera@river.ocn.ne.jp Albert Kwok-Wai LIE, MD; Queen Mary Hospital, the University of Hong Kong, China akwlie@hkucc.hku.hk Specific Aims: 1. To compare diabetes, congestive heart failure, stroke and renal failure between myeloablative and reduced-intensity allogeneic hematopoietic stem cell transplantation (allo-hsct) in older recipients 2. To determine patient-, donor-, disease-, and transplant- related factors associated with late complications including diabetes, congestive heart failure, stroke and renal failure 3. To reduce late complications and improve life quality in old patients after allo-hsct. Scientific Justification: Myeloablative allo-hsct usually consists of the combination of cyclophosphamide and high-dose total body irradiation (TBI) or high-dose busulphan 1. A serious limitation of these regimens is an unacceptable transplantation-related mortality (TRM) partly due to the direct organ toxicity of the conditioning regimen in patients over 50 years of age. Recently reduced-intensity conditioning (RIC) allo-hsct is being used increasingly for patients who are considered the poor candidates for myeloablative condition because of their advanced age or other concurrent medical conditions 2. RIC regimen mostly consists of lower doses of alkylating agents or TBI, usually in combination with fludarabine. Decreased dosages of TBI and chemotherapy have reduced acute side effects of the conditioning and nonrelapse mortality (NRM). RIC allo-hsct also demonstrated successful engraftment but increased incidence of relapse compared with myeloablative conditioning regimens 3. Several retrospective comparisons of outcomes between myeloablative and RIC regimens have shown similar overall survival (OS) rates of efficacy with RIC allo-hsct 4-6. To date, investigators have begun to recognize that long-term allo-hsct recipients are at greater risk for the metabolic syndrome which is associated with a substantially increased risk for dyslipidemia, hypertension, diabetes and cardiovascular 7-8. The direct consequence of the conditioning regimen partly contributed to these complications. Agents applied in conditioning regimen are known to be cardiotoxic, most notably radiation therapy and common chemotherapeutic agents such as anthracyclines, cyclophosphamide and busulfan. Anthracyclines exposure was demonstrated to cause cardiotoxicity which may become apparent within one year of the completion of treatment (early onset chronic cardiotoxicity) or many years after chemotherapy has been completed (late onset chronic cardiotoxicity) 9. Swain et al. demonstrated that 5.1% of patients had evidence of congestive heart failure or a significant decline in left ventricular function and confirmed the cumulative dose-dependence of doxorubicin cardiotoxicity 10. Treatment with cyclophosphamide has been related to cardiac toxicity and other types of tissue damage, e.g., hemorrhagic cystitis. Soon after the introduction of cyclophosphamide in conditioning regimen, the onset of cardiotoxicity was reported by several authors. Moreover, several investigations have shown a positive correlation between the dose of cyclophosphamide and severity of cardio toxicity. Busulphan, on the other hand, has not been associated with vascular toxicity. Nevertheless, it has been suggested that busulphan can be a possible cause for pericardial fibrosis 11. Previous studies identified an association between TBI and diabetes and dyslipidemia. Baker et al found that TBI may play 45

46 Not for publication or presentation Attachment 8 a role in the development of insulin resistance, which may predispose patients to the subsequent development of diabetes 7. Insulin resistance is also linked in the causal pathway leading to the cardiovascular effects of the metabolic syndrome because of its clinical association with increased rates of macrovascular disease and subsequent cardiovascular morbidity and mortality 12. The risk was estimated to be 5-6 times higher when single dose instead of fractionated TBI is applied 13. Indirect consequence of the conditioning regimen is another important factor related to these late complications. Decreased growth hormone secretion, or hypothyroidism (heamatologica) caused by conditioning regimen leads to dyslipidemia, glucose intolerance and arterial hypertension after allo-hsct 14 while RIC regimen has less toxicity to organs such as lower risk complications of endocrine dysfunctions and loss of fertility. Additionally, renal problems are common after allo-hsct, with the cumulative incidence of acute kidney injury and chronic kidney disease being 30 50% and 20 60% of cases, respectively As a result, renal failure requiring dialysis occurs in a high proportion of these patients and leads to a high mortality rate. Stronger conditioning regimens in the form of both chemotherapy and radiation therapy are one of the main causes. So far, there has been nearly no study on diabetes, congestive heart failure, stroke and renal failure in long-term survivors after RIC allo-hsct. We hypothesize that RIC allo-hsct has lower risks of the late effects due to the reduced preparative regimen. Furthermore, it is of interest to analyze if certain RIC regimens are associated with an increased risk of these late effects. If so, such protocols may be avoided and other protocols with similar outcomes and a lower probability of late effects may be preferred. A large data source such as CIBMTR will be required to answer some of these questions. The outcomes of this study will assist a transplant physician to make guided decisions in the allo-hsct treatment of old patients and provide useful information for the design of future prospective clinical trials. Patient Eligibility Population: Inclusion criteria (should meet all the criteria): 50 years of age or older at the time of transplantation First allogeneic transplant Survival of at least 2 years after allo-hsct Exclusion criteria: Syngeneic transplants Cord blood transplantation Clinical Outcomes: Acute and chronic graft-versus-host disease Non-relapse mortality Disease relapse or progression Progression-free survival Overall survival Late complications including diabetes, congestive heart failure, stroke and renal failure Data Requirements: All data requested will be provided by existing data collection forms and no supplemental data will be required. 46

47 Not for publication or presentation Attachment 8 Variables to be Analyzed: Patient-related prior to conditioning regimen: Age Sex Race/Ethnicity Karnofsky performance score Body mass index History of smoking cigarettes Disease status including diabetes, cardiovascular events and renal failure Primary disease-related: Disease type Disease stage Time from diagnosis to transplantation Disease status before transplantation Transplant-related: Donor type: HLA identical sibling versus well matched URD vs. others (partially matched URD, other related and mismatched URD) Donor sex Donor age Donor race/ethnicity Conditioning regimen: myeloablative versus reduced intensity; TBI versus chemotherapy Source of stem cells: bone marrow versus peripheral blood stem cells Mononucleated cell dose CD34 cell dose GVHD prophylaxis: ATG or without ATG agvhd and cgvhd complications Sample Requirements:* No sample requirement Study Design: Patient-, disease-, and transplant-related variables for patients receiving RIC and myeloablative allo- HSCT will be described. Median and range for continuous variables and percent of total for categorical variables will be listed. Comparative analyses of the two groups myeloablative allo-hsct and RIC allo- HSCT will use Chi-square test for categorical variables and Wilcoxon two-sample test for continuous variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. The probability of overall survival and progression-free survival will be calculated using the Kaplan- Meier estimator, with the variance estimated by Greenwood s formula. Non-relapse mortality, relapse or progression, as well as the incidence of acute and chronic GVHD will be estimated using cumulative incidence estimates to accommodate for competing risks. Cumulative incidence of each late complication was calculated with death as competing risk. The time to each late complication was computed starting one year post-hsct to the date of disease onset, date of last contact, or date of death, whichever came first. If a late complication developed prior to HCT, or if the onset date for the late complication was within one year of HSCT, the event was left-censored at the one year time point. The Gray method was used to compare the 47

48 Not for publication or presentation Attachment 8 various sub-populations, which takes into consideration competing risk of death for left-censored data. When evaluating risk factors associated with late complications in recipients after RIC allo-hsct, chest radiation (yes, no) gender, race/ethnicity (non-hispanic white, other), age at HCT(<55 years, years, years 65years), body mass index (BMI: <30 kg/m2, 30 kg/m2), History of smoking cigarettes (Yes, No), conditioning exposure (chemotherapy, chemotherapy + TBI), chronic GVHD (none, any) were included as variables in the regression model. References: 1. Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transplant. 2012;47(1): Chevallier P, Szydlo RM, Blaise D, Tabrizi R, Michallet M, Uzunov M, Fegueux N, Guilhot F, Lapusan S, Gratecos N, Cahn JY, Socié G, Yakoub-Agha I, Huynh A, Francois S, Bay JO, Maury S, Buzyn A, Contentin N, Mohty M. Reduced-intensity conditioning before allogeneic hematopoietic stem cell transplantation in patients over 60 years: a report from the SFGM-TC. Biol Blood Marrow Transplant. 2012;18(2): Luger SM, Ringdén O, Zhang MJ, et al. Similar outcomes using myeloablative vs reducedintensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012;47(2): Horwitz ME. Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia. Curr Opin Oncol. 2011;23(2): Brown JR, Kim HT, Armand P et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia Aug 14. doi: /leu [Epub ahead of print] 6. Lioure B, Béné MC, Pigneux A et al. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood. 2012;119(12): Baker KS, Ness KK, Steinberger J et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2007;109(4): Chow EJ, Mueller BA, Baker KS et al. Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation. Ann Intern Med. 2011;155(1): Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7(4): Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin. Cancer 2003; 97(11): Al-Hashmi S, Boels PJ, Zadjali F et al. Busulphan-cyclophosphamide cause endothelial injury, remodeling of resistance arteries and enhanced expression of endothelial nitric oxide synthase. PLoS One. 2012;7(1):e Tichelli A, Bucher C, Rovó A et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007;110(9): Armenian SH, Sun CL, Vase T et al. Cardiovascular risk factors in hematopoietic cell transplantation (HCT) survivors: role in development of subsequent cardiovascular disease. Blood Oct 3. [Epub ahead of print] 14. Tichelli A, Passweg J, Wójcik D et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93(8):

49 Not for publication or presentation Attachment Piñana JL, Valcárcel D, Martino R et al. Study of kidney function impairment after reducedintensity conditioning allogeneic hematopoietic stem cell transplantation. A single-center experience. Biol Blood Marrow Transplant. 2009;15(1): Kang SH, Park HS, Sun IO et al. Changes in renal function in long-term survivors of allogeneic hematopoietic stem-cell transplantation: single-center experience. Clin Nephrol. 2012;77(3): Select post-transplant organ impairment information collected on CIBMTR/NMDP forms IBMTR 095 CORE/Fu IBMTR 002 Core/Fu Before 2007 After 2007 NMDP NMDP Legacy FN Legacy V7 V yrs yrs >2 yrs (2200) FN >2 yrs (2300) Conditions Seizure Y Y OS Y Y Y Diabetes OS OS OS OS Y Y Renal failure requiring dialysis Y Y Y Y Y Y Congestive heart failure OS OS OS OS Y Y Y=Asked explicitly yes vs. no. OS=Not asked, but can be reported under other specify. 49

50 Not for publication or presentation Attachment 8 Characteristics of patients age>50 years old receiving allogeneic transplanted for malignant hematologic diseases between , reported to CIBMTR with 2 year CRF follow-up forms available. (excluding patients with 2nd tx within 2 years of the first transplant) Myeloablative Nonmyeloablative Variable N (%) N (%) Number of patients Number of centers Age at transplant, years, median (range) 55 (50-72) 59 (50-79) Age at transplant, years (87) 1019 (55) (12) 798 (43) >=70 4 (<1) 51 (3) Patient gender Male 779 (57) 1150 (62) Female 582 (43) 718 (38) Disease AML 569 (42) 655 (35) ALL 109 (8) 60 (3) CML 196 (14) 95 (5) MDS/MPS 290 (21) 339 (18) Other leukemias 67 (5) 293 (16) NHL 97 (7) 389 (21) HD 1 (<1) 3 (<1) Multiple myeloma/pcd 32 (2) 34 (2) Donor type HLA-matched siblings 591 (44) 659 (35) Other relatives 15 (1) 23 (1) Unrelated donor 748 (55) 1179 (63) Missing 7 7 Graft Type BM 389 (29) 205 (11) PB+-BM 972 (71) 1663 (89) Year of transplant (17) 109 (6) (17) 350 (19) (29) 625 (33) (37) 784 (42) Post-transplant conditions a Seizures/stroke 39 (3) 50 (3) Diabetes mellitus 123 (9) 173 (9) Congestive heart failure 18 (1) 42 (2) Renal failure requiring dialysis 69 (5) 91 (5) Follow-up of survivors, months, median (range) 61 (24-172) 56 (24-169) a Conditions reported within the first two years of transplant are included in the count. 50

51 Not for publication or presentation Attachment 9 Quality of life Late Effects Working Committee Published Studies 1. Andrykowski MA, Bishop M, Hahn EA, Cella D, Beaumont JL, Brady M, Horowitz M, Sobocinski K, Rizzo JD, Wingard JR. Long-term health-related quality of life, growth, and spiritual well-being following hematopoietic stem cell transplantation. J Clin Oncol 23: , Bishop MM, Beaumont JL, Hahn EA, Cella D, Andrykowski MA, Brady MJ, Horowitz MM, Sobocinski KA, Rizzo JD, Wingard JR. The late effects of cancer and hematopoietic cell transplantation on spouses or partners compared with survivors and survivor-matched controls. J Clin Oncol 25: , Bishop MM, Lee SJ, Beaumont JL, Andrykowski MA, Rizzo JD, Sobocinski KA, Wingard JR. The preventive health behaviors of long-term survivors of cancer and hematopoietic stem cell transplantation compared to matched controls. Biology of Blood & Marrow Transplantation 16: , Wingard JR, Huang IC, Sobocinski KA, Andrykowski MA, Cella D, Rizzo JD, Brady M, Horowitz MM, Bishop MM. Factors associated with self-reported physical and mental health after hematopoietic cell transplantation. Biology of Blood & Marrow Transplantation 16: , Secondary malignancies 5. Curtis RE, Metayer C, Rizzo JD, Socié G, Sobocinski KA, Flowers MED, Travis WD, Travis LB, Horowitz MM, Deeg HJ. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: An international case-control study. Blood 105: , Cogle CR, Theise ND, Fu DT, Ucar D, Lee S, Guthrie SM, onergan J, Rybka W, Krause DS, Scott EW. Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells 25: , Rizzo JD, Curtis RE, Socié G, Sobocinski KA, Gilbert E, Landgren O, Travis LB, Travis WD, Flowers MED, Friedman D, Horowitz MM, Wingard JR, Deeg HJ. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 113: , Landgren O, Gilbert ES, Rizzo JD, Socié G, Banks PM, Sobocinski KA, Horowitz MM, Jaffe ES, Kingma DW, Travis LB, Flowers ME, Martin PJ, Deeg HJ, Curtis RE. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 113: , Majhail NS, Brazauskas R, Rizzo JD, Sobecks RM, Wang Z, Horowitz MM, Bolwell B, Wingard JR, and Socie G. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117(1), Danner-Koptik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY, Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML, Jacobsohn DA. Second malignancies after autologous hematopoietic cell transplantation in children.. Bone Marrow Transplantation. [Epub ahead of print] doi: /bmt Epub 2012 SEP

52 Not for publication or presentation Attachment 9 Long term survivals 11. Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang M-J, Rizzo JD. Long- term survival and late relapse in 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and non-hodgkin-lymphoma. Br J Haematol 147: , Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang M J, Rizzo JD. High probability of long-term survival in 2-year survivors of autologous hematopoietic cell transplantation for AML in first or second CR. Bone Marrow Transplant Mar;46(3): Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, and Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol Jun 1;29(16): Late effects and organ toxicities 14. Santo Thomas LH, Loberiza Jr. FR, Klein JP, Layde PM, Lipchik RJ, Rizzo JD, Bredeson CN, Horowitz MM. Risk factors from bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest 128: , Marks DI, Ballen K, Logan BR, Wang Z, Sobocinski KA, Bacigalupo A, Burns LJ, Gupta V, Ho V, McCarthy PL, Ringdén O, Schouten HC, Seftel M, Rizzo JD, The effect of smoking on allogeneic transplant outcomes. Biol Blood Marrow Transplant Oct;15(10): Loren AW, Chow E, Jacobsohn DA, Gilleece M, Halter J, Joshi S, Wang Z, Gupta V, Hale GA, Marks DI, Stadtmauer EA, Apperley J, Cahn JY, Schouten HC, Lazarus HM, Savani B, McCarthy PL, Jakubowski AA, Kamani NR, Hayes-Lattin B, Maziarz RT, Warwick AB, Sorror ML, Bolwell BJ, Socié G, Wingard JR, Rizzo JD, Majhail NS. Pregnancy after hematopoietic-cell transplantation: A report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant Feb;17(2): Buchbinder D, Nugent DJ, Brazauskas R, Wang Z, Aljurf MD, Cairo MS, Chow R, Duncan C, Eldjerou LK, Gupta V, Hale GA, Halter J, Hayes-Lattin BM, Hsu JW, Jacobsohn DA, Kamble RT, Kasow KA, Lazarus HM, Mehta P, Myers KC, Parsons SK, Passweg JR, Pidala J, Reddy V, Sales- Bonfim CM, Savani BN, Seber A, Sorror ML, Steinberg A, Wood WA, Wall DA, Winiarski JH, Yu LC, Majhail NS. Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research.. Biology of Blood & Marrow Transplantation. [Epub ahead of print] doi: /j.bbmt Epub 2012 JUL 31. Recommendations and guidelines 18. Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, Burns LJ, Davies SM, Ferrara JLM, Socié G. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: Joint recommendations of the European Bone Marrow Transplant Group, Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 12: , Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns LJ, Chaudhri N, Davies S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JR, Tichelli A. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant Mar;18(3): Epub 2011 Dec 13. Co-published on Bone Marrow Transplant Mar;47(3): , Rev Bras Hematol Hemoter 2012;34(2): Hematol Oncol Stem Cell Ther 2012;5(1):

53 Not for publication or presentation Attachment 10 TO: FROM: RE: Late Effects Working Committee Members Navneet Majhail, MD, MS; Scientific Director for the Late Effects WC Studies in Progress Summary LE07-01: Second cancers after allogeneic non-myeloablative hematopoietic cell transplantation (O Ringden) This study will determine the cumulative incidence of secondary malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation using reduced intensity conditioning. Risk of secondary malignancies in these patients will be compared with those receiving myeloablative conditioning. Preliminary results were submitted as an abstract to the 2013 EBMT meeting. This study is under final multivariate analysis. LE09-03: Review of fertility preservation practice in HSCT patients (S Joshi): This study reviews the pathophysiology of infertility, variables that affect reproductive potential, gaps in our understanding of fertility, and suggest an approach to managing patients with reproductive issues in the setting of HCT. Ethical nuances that surround the clinician and patient are also identified and discussed. Manuscript preparation is in progress. LE10-01: Avascular necrosis of bone in children and adolescents after hematopoietic cell transplantation (X Li) This study proposes to describe characteristics of pediatric patients who develop avascular necrosis (AVN) of the bone following transplantation and will identify risk factors associated with AVN in this pediatric population. This study is under data analysis stage. LE11-01: Long-term survival following second allogeneic HCT for hematologic malignancies (C Duncan, M Sorror) This study proposes to determine the survival rates of patients with ALL, AML, and MDS/JMML following second allogeneic transplant who have survived at least one year from transplant and to determine if and when the mortality rates of patients who have undergone two allogeneic transplants return to that of the general population matched for age, sex, and nationality. This study is under protocol development. LE11-02: Risk factors for development of secondary central nervous system (cns) tumors in survivors of pediatric bone marrow transplantation (M Gabriel, P Shaw) The aims of this study is to evaluate the incidence of secondary CNS tumors in survivors of pediatric BMT and identify risk factor for the development of secondary CNS tumors in survivors of pediatric BMT. This study is under data file preparation. LE12-03: Solid organ transplant after hematopoietic cell transplantation (M Gupta, P L Abt, M Levine) This study will determine the cumulative incidence of end-stage organ failure and waitlisting for or receipt of solid organ (kidney, liver, heart, lung, pancreas) transplant; identify potential risk factors and predictors of organ failure leading to waitlisting for or receipt of solid organ transplant in the HCT population; and report on outcomes of solid organ transplantation in HCT recipients and compare survival with non-hct solid organ transplant recipients and waitlisted subjects alone. This study is under data file preparation. 53

54 Not for publication or presentation Attachment 10 LE12-04: The Hematopoietic Cell Transplant Recovery Index (HCT-RI) (S Holtan, R Chandran, L Porrata) This study aims to determine the association of lymphopenia, monocytopenia, and thrombocytopenia at the day +100 evaluation with long-term, post-allogeneic HCT clinical outcomes (severe chronic GVHD, relapse, and overall survival) at 2 years and 10 years post-hct and to compare Cox models to a machine learning technique (support vector machines) in development of a prognostic Hematopoietic Cell Transplant Recovery Index (HCT-RI), based on the day+100 elements of hematopoietic recovery. Studies previously proposed, but not initiated LE05-01: Incidence of bronchiolitis obliterans after reduced intensity hematopoietic cell transplantation (S Mineishi): This study proposes to determine the incidence of brochiolitis obliterans among patients who have received reduced intensity hematopoietic cell transplantation, and will compare their incidence with that of myeloablative transplantation. A new version of CIBMTR form that will collect detailed information on post-transplant lung complications is under development. The data will be collected once the new forms are incorporated into the FormsNet 2 system. LE12-01: Outcome of hematopoietic stem-cell transplantations following solid organ transplantations (T Schechter-Finkelstein, D Jacobsohn, F Cossor) This study is to assess the outcome of hematopoietic stemcell transplantation (HSCT) following solid organ transplantation, to determine the incidence of infectious complication following the above transplantations, and to evaluate the cumulative incidence of lymphoproliferative disease for HSCT following solid organ transplantation. LE12-02: Late Effects of Children Undergoing Allogeneic HSCT at a Young Age (L Vrooman, C Duncan) This study is to report the frequency of late effects in patients who underwent allogeneic stem cell transplant for hematologic malignancy (ALL, AML, CML, JMML) at very young age (less than 3 years of age); to report the frequency of organ impairment, chronic GVHD and new malignancy in this study population. 54

55 Not for publication or presentation Attachment 11 LE07-01 Abstract submitted to EBMT 2013 Second solid cancers in patients treated with allogeneic hematopoietic cell transplantation using reduced intensity/non-myeloablative conditioning regimens: A Center for International Blood and Marrow Transplant Research study Olle Ringden, Ruta Brazauskas, Zhiwei Wang, Christine N Duncan, David A Jacobsohn, Jonas Mattsson, Mohamed L Sorror, Navneet S Majhail Hematopoietic cell transplant (HCT) survivors are at risk for second solid cancers. Non-myeloablative (NMC) and reduced-intensity conditioning (RIC) has allowed HCT as treatment for patients who are otherwise ineligible for HCT using myeloablative conditioning (MAC) because of advanced age or comorbidities. In patients with leukemia receiving chemotherapy, less chemotherapy is associated with lower risk of second cancers. It is therefore of importance to analyze the risk of second solid cancers in recipients treated with RIC/NMC compared to MAC. Patients treated with HCT for acute/chronic leukemia and lymphoma from and reported to CIBMTR were studied (RIC/NMC=4,274, MAC=18,810 patients). Median followup for RIC/NMC and MAC cohorts was 6 and 7.6 years. RIC/NMC recipients were older, had longer interval from diagnosis to HCT, less often received TBI, more often received PBSC and more often had received a previous autograft. Median age was 53 years in the RIC/NMC and 34 years in the MAC group. Analyses were stratified by diagnosis (leukemia and lymphoma). Among patients with leukemia, cumulative incidence of second solid cancers (excluding non-melanoma skin cancers) at 10 years after HCT was 3.6% (95% CI, ) in the RIC/NMC group and 2.3% ( ) in the MAC group. The corresponding incidences for patients with lymphoma were 3.0% ( ) and 2.8% ( ), respectively. Table shows the standardized incidence ratios (SIR) for solid cancers compared to age-, gender- and race-matched general populations. RIC/NMC recipients with leukemia had significantly higher risks than the general population for cancers of the lip (SIR 14, P=0.02), other oropharynx (47, P=<0.001), bone (24, P<0.01), soft tissue (13, P<0.001) and vulva (19, P=0.01) and skin melanoma (3, P=0.02). RIC/NMC recipients with lymphoma had significantly higher risks of cancers of other oropharynx (67, P<0.001), and skin melanoma (4, P=0.03). Multivariable analyses are underway to compare the risks of solid cancers among RIC/NMC recipients with MAC recipients, while taking into account age, exposure to TBI, and other disease and treatment related factors. Our preliminary results show that the cumulative incidence of second solid cancers among RIC/NMC recipients continues to increase over time, similar to what is seen among MAC recipients. However, their risks are comparable to age- and gender- matched general population, unlike MAC recipients who have significantly higher risks. Table: Standardized incidence ratios (observed/expected) for second solid cancers (excluding nonmelanoma skin cancers) among RIC/NMC and MAC recipients compared to age-, gender- and racematched general population Diagnosis/conditioning Observed Expected SIR (95% P-value CI) Leukemia, RIC/NMC ( ) 1.0 Leukemia, MAC ( ) <0.001 Lymphoma, RIC/NMC ( ) 0.75 Lymphoma, MAC ( ) <

56 Not for publication or presentation Attachment 12 CIBMTR LE10-01 AVASCULAR NECROSIS OF BONE IN CHILDREN AND ADOLESCENTS AFTER HEMATOPOIETIC CELL TRANSPLANTATION PROTOCOL Study Chair: Study MS Statistician: Study PhD Statistician: Scientific Director: Working Committee Chairs: Xiaxin Li, MD, PhD Cardon Children s Medical Center, Mesa, AZ Telephone: xiaxin.li@bannerhealth.com Zhiwei Wang, MS CIBMTR, Milwaukee, WI Telephone: , Fax: zwang@mcw.edu Ruta Brazauskas, PhD CIBMTR, Milwaukee, WI Telephone: , Fax: ruta@mcw.edu Navneet Majhail MD MS National Marrow Donor Program, Minneapolis, MN Phone: , Fax: nmajhail@nmdp.org David Jacobsohn, MD Children s National Medical Center, Washington DC Phone: Fax: dajacobs@cnmc.org Mohamed Sorror, MD Fred Hutchinson Cancer Center, Seattle, WA Telephone: , Fax: msorror@fhcrc.org Christine Duncan, MD Children s Hospital Boston, Boston, MA Telephone: Fax: christine_duncan@dfci.harvard.edu 56

57 Not for publication or presentation Attachment 12 Specific Aims: This study will: (1) Describe characteristics of patients developing avascular necrosis (AVN) of the bone in children and adolescents following hematopoietic cell transplantation (HCT) reported in the CIBMTR database, and (2) identify risk factors associated with AVN in this pediatric population. Scientific Justification: Avascular necrosis (AVN) of the bone is a painful and debilitating condition that is associated with significant morbidity and often requires surgery [1]. Among all the skeletal locations, the femoral head is most susceptible to damage. AVN has been reported in childhood acute lymphoblastic leukemia after conventional chemotherapy, particularly after exposure to dexamethasone between the ages of 10 and 20 years [2]. AVN is also observed in patients following hematopoietic cell transplantation (HCT) [3] or other organ transplantation [4]. Atkinson et al first identified AVN in 5 of 50 patients post HCT in the late 80s and other reports have appeared since [3, 5-11]. The incidence of AVN varies from 2.9% following autologous HCT [4] to 19% following allogeneic HCT [7]. Reported AVN-associated risk factors include: a primary diagnosis of acute leukemia, TBI based conditioning regimens, acute and chronic GvHD, exposure to calcineurin inhibitors (CSA and FK506), and prolonged high-dose steroid treatment [3, 6-11]. Nevertheless, several clinical questions remain to be elucidated. First, the prevalence of AVN in pediatric patients is unclear after HCT because the reported data are based primarily on adults. So far there is no large cohort study in this patient population. Second, the age and sex distributions of AVN patients are controversial in previous studies [6, 9]. In addition, previous studies did not consider the different velocity of bone growth in children and adolescents as compared to adults. Specifically, fast growing and immature bones are expected to be more susceptible to develop AVN when exposed to osteotoxic agents including steroids, calcineurin inhibitors or chemotherapy agents. Indeed, adolescents are at higher risk for AVN after prolonged steroids treatment than younger children [2]. Also, the role of endocrine abnormalities in AVN in patients following HCT needs to be clarified; insufficiency of sex hormone, growth hormone or/and thyroid hormone has been linked to bone density loss [11-12]. Finally, it would be interesting to examine whether the reduced intensity or non-myeloablative conditioning would decrease the prevalence of AVN in pediatric population following HCT. Taken together, the CIBMTR database provides a unique opportunity to determine the risk-factors of AVN in children and adolescents following HCT. Patient Eligibility Population: Inclusion criteria: - Age 21 years at transplant - United States patients only - Survival 6 months after transplant - First allogeneic HCT - Any conditioning regimen (myeloablative or reduced-intensity/non-myeloablative) - Year of transplant from 1990 to 2008 Identification Of Cases And Controls: Cases: Cases will include patients who meet the eligibility criteria listed above and for whom centers have also reported AVN as a post-transplant complication. AVN in transplant patients is diagnosed by radiological evidence or surgical report(s). Controls: Patients who have received their transplant at centers where AVN cases were identified will be used to select controls. Controls will also meet the eligibility criteria listed above. We will request centers to confirm AVN related information for cases and controls. From the pool of controls, for every case, three controls matched year of transplant (+/- 1 year), follow up duration post-transplant (follow-up of controls no less than the interval from transplant to onset of AVN of the cases) and center (if a control from the same center is available) will be selected randomly. 57

58 Not for publication or presentation Attachment 12 Data Collection: The CIBMTR database will be used for this study. For control patients, we will send a query to the centers requesting confirmation that the control did not have a history of AVN prior to and after transplantation. Variables To Be Described: Patient related: - Age at transplant: 0-9 vs vs year old (AGE) - Sex: male vs. female (SEX) - Karnofsky/Lansky performance score at transplant: < 90 vs. 90 (K90) - Race: White vs. non-white (RACEGP2) Diseases related: - Diseases: AML/MDS vs. ALL vs. CML vs. Lymphoma vs. SAA vs. Other (DISTYPE) - Disease status of malignancies: early vs. intermediate vs. advanced vs. Unknown vs. Nonmalignant diseases (DISTATGP3) - Time from diagnosis to transplant in patients (INTXDX) - Year of transplant: vs vs vs (YEARGP) Preparative regimens: (May need to combine these variables) - Myeloablative (with TBI) vs. Myeloablative (no TBI) vs. Reduced Intensity or nonmyeloablative vs. non-malignant disease (REGITYPE) - TBI dose: No TBI vs. < 1200 vs CGy (TBIDOSE TBIDGP) Hematopoietic cell sources: - BM vs. PBSC vs. cord blood (GFTYPE) Type of transplant: - Matched siblings vs. Other related vs. Matched unrelated (DNRGP) GvHD related: - GvHD prophylaxis/treatment (GVHDGP) - History of GVHD prior to AVN: acute only vs. Chronic +/- acute GvHD (GVHDHISTORY) Variables To Be Matched On The Case-Control Model: - Year of transplant (+/- 1 year) (YEARTX) - Follow-up time (follow-up of controls no less than the interval from transplant to onset of AVN of the cases) (INTXAVN) - Center (if a control from the same center is available) (DCCN) Variables To Be Analyzed As Risk Factors In The Model - Age at transplant: 0-9 vs vs years old (AGE, AGEGP) - Disease status of malignancies: early vs. intermediate vs. advanced vs. Unknown vs. Nonmalignant diseases (DISTATGP3) - Myeloablative (with TBI) vs. Myeloablative (no TBI) vs. Reduced Intensity/nonmyeloablative (REGITYPE) - Matched siblings vs. other related or Matched unrelated (DNRGP) - History of GvHD prior to AVN: acute only vs. chronic +/- acute GVHD (GVHDHISTORY, AGVHD, CGVHD, INTXAGVHD, INTXCGVHD) 58

59 Not for publication or presentation Attachment 12 Study Design (Scientific Plan): The goal of this study is to assess potential risk factors for developing necrosis of the bone (AVN) in children and adolescents following HCT. A nested case-control study design will be used to identify the risk factors. Patients with AVN will be matched with three controls without AVN. The matching variables will include year of transplantation and follow-up time and center. A transplant recipient is considered for selection as a control for a given case patient only if alive without AVN and prior to second transplant at the time of the case s AVN event. Sampling of a control for every case will be carried out independently both of the sampling of other controls and of any later AVN event or censoring of controls. The characteristics of case and control patients will be described in a univariate table. Multivariate analysis will be performed using conditional logistic regression on all matched sets. References: 1. Lafforgue P. pathophysiology and natural history of avascular necrosis of bone. Joint Bone Spine 2006; 73: Mattano LA Jr, et al. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children s Cancer Group. J Clin Oncol 2000; 18: Tauchmannova L, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation. A single center experience and a review. Cancer 2003; 97: Hawking KM, et al. Avascular necrosis of bone after renal transplant [letter]. N Eng J Med 1976; 294: Atkinson K, et al. Avascular necrosis of the femoral head secondary to corticosteroid therapy for graft-versus-host disease after marrow transplantation: effective therapy with hip arthropasty. Bone Marrow Transplantation 1987; 2: Campbell S, et al. Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 2009; 115: Torri Y, et al. Osteonecrosis of the femoral head after allogeneic bone marrow transplantation. Clin Orthop 2001; 382: Enright H, et al. Avascular necrosis of bone: a common serious complication of allogeneiec bone marrow transplantation. Am J Med 1990; 89: Socie G, et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM). Br J Haematol 1997; 97: Fink JC et al. Avascular necrosis following bone marrow transplantation: a case-control study. Bone 1998; 22: Stern JM, et al. Bone density loss after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: Canalis E, et al. Glucocorticoid-induced osteoporosis: pathogenesis and therapy. Osteoporos Int 2007; 18:

60 Not for publication or presentation Attachment 12 Table 1. Characteristics of confirmed case and control patients, matched by gender, disease, year of transplant, transplant center and year of transplant a No AVN Confirmed AVN Variables N (%) N (%) P-value c Number of patients Number of centers Age at transplant, years, median (range) 10 (<1-21) 15 (2-21) Age at transplant, years < (51) 11 (11) (23) 39 (38) (26) 52 (51) Sex (matched variable) -- Male 114 (52) 49 (48) Female 105 (48) 53 (52) Karnofsky/Lansky score prior to transplant 0.73 <90 26 (13) 13 (14) >= (87) 77 (86) Missing Patient race 0.45 White 189 (86) 85 (83) Non-white 30 (14) 17 (17) Disease (matched variable) -- AML/MDS 106 (48) 47 (46) ALL 73 (33) 34 (33) CML 23 (11) 11 (11) NHL 3 ( 1) 2 ( 2) SAA 6 ( 3) 4 ( 4) Other non-malignant diseases b 8 ( 4) 4 ( 4) Disease risk prior to transplant 0.64 Early (CR1, CP1, RA, RARS) 87 (40) 37 (36) Intermediate (CR2+/CP2+/AP) 82 (37) 40 (39) Advanced (Not in remission, BP, RAEB/RAEBT/CMML) 27 (12) 15 (15) Unknown 9 ( 4) 2 ( 2) Non-malignant diseases 14 ( 6) 8 ( 8) Interval from diagnosis to transplant, months (39) 39 (38) (20) 24 (24) >=12 86 (39) 37 (36) Unknown 4 ( 3) 2 ( 2) Year of transplant (matched variable) ( 3) 3 ( 3) ( 8) 6 ( 6) (44) 39 (38) (45) 54 (53) Total TBI dose, cgy, median (range) 1260 ( ) 1200 ( ) 60

61 Not for publication or presentation Attachment 12 Table 1. Continued. No AVN Confirmed AVN Variables N (%) N (%) P-value c Total TBI dose, cgy 0.38 No TBI 79 (36) 30 (30) <1200 cgy 8 ( 4) 7 ( 7) >=1200 cgy 132 (60) 64 (63) Missing 0 1 Conditioning regimen intensity 0.86 Myeloablative (with TBI) 134 (61) 65 (64) Myeloablative (no TBI) 54 (25) 21 (21) RIC 17 ( 8) 8 ( 8) Non-malignant diseases 14 ( 6) 8 ( 8) Graft type BM 114 (52) 57 (56) PB+-BM 41 (19) 30 (29) CB 64 (29) 15 (15) Donor type HLA-matched Siblings 20 ( 9) 18 (18) Other related 13 ( 6) 7 ( 7) Unrelated 186 (85) 77 (75) GvHD prophylaxis -- Ex vivo T-cell depletion alone 7 ( 3) 0 Ex vivo T-cell depletion + post-tx immune suppression 10 ( 5) 5 ( 5) CD34 selection + post-tx immune suppression 1 (<1) 1 ( 1) FK506 + MMF +- others 10 ( 5) 8 ( 8) FK506 + MTX +- others (except MMF) 45 (21) 20 (20) FK506 + others (except MTX, MMF) 3 ( 1) 3 ( 3) FK506 alone 0 3 ( 3) CSA + MMF +- others (except FK506) 18 ( 8) 9 ( 9) CSA + MTX +- others (except FK506, MMF) 78 (36) 39 (38) CSA + others (except FK506, MTX, MMF) 35 (16) 9 ( 9) CSA alone 8 ( 4) 3 ( 3) Other GVHD prophylaxis 2 ( 1) 0 Unknown 2 ( 1) 2 ( 2) History of GvHD prior to AVN (or last follow up for non- -- AVN) agvhd only 39 (18) 14 (14) cgvhd+/-agvhd 101 (46) 57 (56) No GvHD 79 (36) 31 (30) Follow-up of survivors, months, median (range) 72 (24-209) 71 (11-187) a Cases and controls were confirmed with the center at the time of study. AVN in transplant patients was diagnosed by radiological evidence or surgical reports. Patients are matched by sex, disease, year of transplant (+/- 1 year), length of follow-up (follow-up of controls were no less than the follow-up of the cases). Patients from the same centers were given priority when matching. Each case was matched by up to 3 controls. b Other diseases: Inherited abnormalities of erythrocyte differentiation or function (Case N=1, Control N=2), Disorder of the immune system (Case N=1, Control N=2), Inherited disorder of metabolism (Case N=2, Control N=3). c P-values were produced by using conditional logistic regression. 61

62 Not for publication or presentation Attachment 12 Supplemental Table 1. Characteristics of study cases vs. unconfirmed cases Confirmed AVN Unconfirmed AVN Variable N (%) N (%) P-value Number of patients Number of centers Age at transplant, years, median (range) 15 (2-21) 15 (1-21) 0.61 Age at transplant, years (11) 11 (22) (38) 11 (22) (51) 29 (57) Sex 0.21 Male 49 (48) 30 (59) Female 53 (52) 21 (41) Karnofsky/Lansky score prior to transplant 0.69 <90 13 (14) 8 (17) >=90 77 (86) 39 (83) Missing 12 4 Patient race 0.65 White 85 (83) 41 (80) Non-white 17 (17) 10 (20) Disease 0.09 AML/MDS 47 (46) 18 (35) ALL 34 (33) 18 (35) CML 11 (11) 3 (6) NHL/HL 2 ( 2) 0 SAA 4 ( 4) 8 (16) Other non-malignant diseases 4 ( 4) 4 ( 8) Disease risk prior to transplant 0.07 Early 37 (36) 17 (33) Intermediate 40 (39) 13 (25) Advanced 15 (15) 7 (14) Unknown 2 ( 2) 3 ( 6) Non-malignant diseases 8 ( 8) 11 (22) Interval from diagnosis to transplant, months, 8 (<1-184) 8 (<1-111) 0.82 median (range) Year of transplant < ( 3) 7 (14) ( 6) 11 (22) (38) 16 (31) (53) 17 (33) Total TBI dose, cgy, median (range) 1200 ( )1200 ( ) 0.83 Total TBI dose, cgy 0.28 No TBI 30 (30) 11 (22) <1200 cgy 7 ( 7) 7 (14) >=1200 cgy 64 (63) 32 (64) Missing

63 Not for publication or presentation Attachment 12 Table 1. Continued Confirmed AVN Unconfirmed AVN Variable N (%) N (%) P-value Conditioning regimen intensity 0.04 Myeloablative (with TBI) 65 (64) 32 (64) Myeloablative (no TBI) 21 (21) 5 (10) RIC 8 ( 8) 2 ( 4) Non-malignant diseases 8 ( 8) 11 (22) Missing 0 1 Graft type 0.15 BM 57 (56) 36 (71) PB+-BM 30 (29) 8 (16) CB 15 (15) 7 (14) Donor type 0.76 HLA-matched Siblings 18 (18) 10 (20) Other related 7 ( 7) 5 (10) Unrelated 77 (75) 36 (71) GvHD prophylaxis 0.49 Ex vivo T-cell depletion + post-tx immune supression 5 ( 5) 5 (10) CD34 selection + post-tx immune supression 1 ( 1) 1 ( 2) FK506 + MMF +- others 8 ( 8) 2 ( 4) FK506 + MTX +- others (except MMF) 20 (20) 8 (16) FK506 + others (except MTX, MMF) 3 ( 3) 3 ( 6) FK506 alone 3 ( 3) 0 CSA + MMF +- others (except FK506) 9 ( 9) 2 (4) CSA + MTX +- others (except FK506, MMF) 39 (38) 19 (37) CSA + others (except FK506, MTX, MMF) 9 ( 9) 7 (14) CSA alone 3 ( 3) 3 ( 6) Other GVHD prophylaxis 0 1 ( 2) Unknown 2 ( 2) 0 Follow-up of survivors, months, median (range) 71 (11-187) 68 (13-228)

64 Not for publication or presentation Attachment 12 Supplemental Table 2. Characteristics of study controls vs. unconfirmed controls Unconfirmed No AVN No AVN Variable N (%) N (%) P-value Number of patients Number of centers Age at transplant, years, median (range) 10 (<1-21) 9 (<1-21) 0.40 Age at transplant, years (51) 99 (57) (23) 42 (24) (26) 34 (19) Sex 0.81 Male 114 (52) 89 (51) Female 105 (48) 86 (49) Karnofsky/Lansky score prior to transplant 0.31 <90 26 (13) 16 (10) >= (87) 147 (90) Missing Patient race <.001 White 189 (86) 125 (71) Non-white 30 (14) 50 (29) Disease <.001 AML/MDS 106 (48) 61 (35) ALL 73 (33) 63 (36) CML 23 (11) 12 ( 7) NHL/HL 3 ( 1) 3 ( 2) SAA 6 ( 3) 24 (14) Other non-malignant diseases 8 ( 4) 12 ( 7) Disease risk prior to transplant <.001 Early 87 (40) 48 (27) Intermediate 82 (37) 61 (35) Advanced 27 (12) 28 (16) Unknown 9 ( 4) 4 ( 2) Non-malignant diseases 14 ( 6) 34 (19) Interval from diagnosis to transplant, months, median 8 (<1-129) 14 (<1-118) 0.10 (range) Year of transplant ( 3) 13 ( 7) ( 8) 21 (12) (44) 78 (45) (45) 63 (36) Total TBI dose, cgy, median (range) 1260 ( ) 1320 ( )

65 Not for publication or presentation Attachment 12 Table 2. Continued Unconfirmed No AVN No AVN Variable N (%) N (%) P-value Total TBI dose, cgy <.001 No TBI 79 (36) 48 (28) <1200 cgy 8 ( 4) 26 (15) >=1200 cgy 132 (60) 100 (57) Missing 0 1 Conditioning regimen intensity <.001 Myeloablative (with TBI) 134 (61) 101 (59) Myeloablative (no TBI) 54 (25) 30 (17) RIC 17 ( 8) 7 ( 4) Non-malignant diseases 14 ( 6) 34 (20) Missing 0 3 Graft type BM 114 (52) 121 (69) PB+-BM 41 (19) 21 (12) CB 64 (29) 33 (19) Donor type <.001 HLA-matched Siblings 20 ( 9) 46 (26) Other related 13 ( 6) 5 ( 3) Unrelated 186 (85) 124 (71) GvHD prophylaxis 0.07 Ex vivo T-cell depletion alone 7 ( 3) 13 ( 7) Ex vivo T-cell depletion + post-tx immune supression 10 ( 5) 13 ( 7) CD34 selection alone 0 4 ( 2) CD34 selection + post-tx immune supression 1 (<1) 1 ( 1) FK506 + MMF +- others 10 ( 5) 7 ( 4) FK506 + MTX +- others (except MMF) 45 (21) 42 (24) FK506 + others (except MTX, MMF) 3 ( 1) 4 ( 2) FK506 alone 0 1 ( 1) CSA + MMF +- others (except FK506) 18 ( 8) 4 ( 2) CSA + MTX +- others (except FK506, MMF) 78 (36) 53 (30) CSA + others (except FK506, MTX, MMF) 35 (16) 26 (15) CSA alone 8 ( 4) 5 ( 3) Other GVHD prophylaxis 2 ( 1) 2 ( 1) Unknown 2 ( 1) 0 Follow-up of survivors, months, median (range) 72 (24-209) 73 (15-247)

66 Not for publication or presentation Attachment 13 CIBMTR LE12-04 THE HEMATOPOIETIC CELL TRANSPLANT RECOVERY INDEX (HCT-RI): IDENTIFYING PATIENTS AT RISK FOR POOR OUTCOMES BASED UPON HEMATOLOGIC RECOVERY AT DAY DRAFT PROTOCOL Study Co-Chairs: Shernan G. Holtan, MD Knight Cancer Institute Oregon Health & Sciences University Portland, OR Rekha Chandran, MD Legacy Health System Vancouver, WA Luis F. Porrata, MD Mayo Clinic Graduate School of Medicine Rochester, MN Todd Leen, PhD Oregon Health & Science University Portland, OR Study Statistician: Zhiwei Wang, MS CIBMTR Statistical Center 9200 W. Wisconsin Avenue Milwaukee, WI Telephone: , Fax: