b. Welcome new Co-Chair Bronwen Shaw, MD, PhD; Anthony Nolan Research Institute, London, UK;

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1 Not for publication or presentation AGENDA CIBMTR WORKING COMMITTEE FOR DONOR HEALTH AND SAFETY Salt Lake City, UT Thursday, February 14, 2013, 2:45 pm - 4:45 pm Co-Chair: David Stroncek, MD, National Institutes of Health Telephone: ; Fax: ; dstroncek@dtm.cc.nih.gov Co-Chair: Steven Goldstein, MD; University of Michigan Telephone: ; Fax: ; stevengo@med.umich.edu Co-Chair: Paul O Donnell, MD; Fred Hutchinson Cancer Research Center Telephone: ; Fax: ; podonnel@fhcrc.org Statisticians: Ying Shan, MS, CIBMTR Minneapolis Telephone: ; Fax: ; yshan@nmdp.org Pintip Chitphakdithai, PhD,-CIBMTR Minneapolis Telephone: ; Fax: ; pchitpha@nmdp.org Brent Logan, PhD, CIBMTR Statistical Center Telephone: ; Fax: ; blogan@mcw.edu Scientific Director: Dennis Confer, MD, National Marrow Donor Program Telephone: ; Fax: ; dconfer@nmdp.org 1. Introduction a. Minutes of February, 2012 meeting (Attachment 1) b. Welcome new Co-Chair Bronwen Shaw, MD, PhD; Anthony Nolan Research Institute, London, UK; bshaw@doctors.org.uk 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. DS09-05a Pulsipher MA, Chitphakdithai P, Logan BR, Shaw BE, Wingard JR, Lazarus HM,Waller EK, Seftel M, Stroncek DF, Lopez AM, Maharaj D, Hematti P, O'Donnell PV, Loren AW, Leitman SF, Anderlini P, Goldstein SC, Levine JE, Navarro WH, Miller JP, and Confer DL. Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program. Blood. 2013; 121(1): b. DS09-05b Pulsipher MA, Chitphakdithai P, Logan BR, Navarro WH, Miller JP, Confer DL. Increased risk of severe adverse events after BM versus PBSC donation: results of a prospective study of 9494 NMDP donors, Presented at the International Donor Registry Conference 2012, Sydney, Australia 4. Studies in progress (Attachment 3) a. DS05-02 RDSafe: A multi-institutional study of HSC donor safety and Open to Accrual quality of life (M Pulsipher) 1

2 Not for publication or presentation b. DS08-01 The identification of cytogenetic abnormalities in donor derived Data Collection hematopoietic cells after unrelated donor stem cell transplantation (N Frey) c. DS09-03 Effects of second donations on marrow and PBSC donors Protocol Development (D Stroncek) d. DS09-04 The effect of race, socioeconomic status, and donor center Data File Preparation size on bone marrow and PBSC donor experiences (M Pulsipher) e. DS09-05b PBSC versus bone marrow donor severe adverse events Data Analysis (M Pulsipher) f. DS10-01 Effect of demographics on peripheral blood CD34+ counts and Protocol Development CD34+ yields in donors undergoing large volume leukapheresis (J Hsu / J Wingard) 5. Future / proposed studies a. PROP Retrospective examination of the role quantity of bone marrow harvests performed by a harvest center has on the overall quality of the harvested product. Assessment of the Potential impacts bone marrow product quality has on utilization of bone marrow as a cell source for transplant (N Prokopishyn) (Attachment 4) 6. Discuss development of new projects/studies a. NMDP has observed a trend towards increased utilization of bone marrow for unrelated donor HCT. Bone marrow collections were up 30% in October-December 2012 versus October-December Should the Committee consider development of projects/studies to improve marrow harvest safety and efficiency? b. Other topics? 7. Other business 2

3 Not for publication or presentation Attachment 1 MINTUES CIBMTR WORKING COMMITTEE FOR DONOR HEALTH AND SAFETY San Diego, CA Thursday, February 2, 2012, 2:45 pm 4:45 pm Co-Chair: Co-Chair: Co-Chair: Statistician: Scientific Director: David Stroncek, MD, National Institutes of Health Telephone: ; Fax: ; dstroncek@dtm.cc.nih.gov Steven Goldstein, MD; University of Michigan Telephone: ; Fax: ; stevengo@med.umich.edu Paul O Donnell, MD; Fred Hutchinson Cancer Research Center Telephone: ; Fax: ; podonnel@fhcrc.org Tanya L. Pedersen, MPH, CIBMTR Minneapolis Telephone: ; Fax: ; tpederse@nmdp.org Brent Logan, PhD, CIBMTR Statistical Center Telephone: ; Fax: ; blogan@mcw.edu Dennis Confer, MD, National Marrow Donor Program Telephone: ; Fax: ; dconfer@nmdp.org 1. Introduction Dave Stroncek called the meeting to order at 2:46 pm. Drs. Stroncek, Goldstein, and O Donnell chaired the meeting. Steve Goldstein reviewed the upcoming forms revisions process and reviewed the form which collects donor demographics, graft manipulation and processing data (Form 2006), which is scheduled to be revised this year. Comments and suggestions for improvement to the form were solicited from the committee and include: adding donor height and weight, pre-donation hematocrit and WBC especially for pediatric donors, anesthesia times, and to make sure that graft/product data were collected at time of infusion. Dennis Confer suggested that the forms include at least the minimum data set recommendations put forth by the Donor Outcome Workshops held in Berne and Leiden, and to use the forms used in the RDSafe study as a guide for revising the Form Tanya Pedersen will gather the minimum data set recommendations and the RDSafe study forms and submit suggestions for revisions to CIBMTR data management staff. Further comments and suggestions from the committee are encouraged. The comment period extends from now until March 2. Please send suggestions for revisions to Emilie Meissner at emeissne@nmdp.org. Dave Stroncek welcomed new Co-Chair Paul O Donnell, MD. 3

4 Not for publication or presentation Attachment 1 2. Accrual summary Dave Stroncek briefly reviewed the accrual summary for the committee. 3. Presentations, published or submitted papers a. DS09-05 Pulsipher MA, Chitphakdithai P, Logan BR, Shaw BE, Wingard JR, Lazarus HM, Waller EK, Seftel M, Stroncek DF, Lopez AM, Maharaj D, Hematti P, O Donnel PV, Loren AW, Leitman SF, Goldstein SC, Levine JE, Navarro WH, Miller JP, Confer DL. Acute toxicities and time to full recovery of unrelated bone marrow versus peripheral blood stem cell donors: results of a prospective trial from the National Marrow Donor Program Submitted. 4. Studies in progress a. DS05-02 RDSafe: A multi-institutional study of HSC donor safety and quality of life (M Pulsipher) Mike Pulsipher updated the committee on this study. Enrollment is 37% complete. 51 centers are currently active and enrolling about 50 donors per month. The study is open to additional centers. Per-donor reimbursement for the study has been doubled to $500. Interested centers should contact the protocol coordinator Amy Hays at: ahays@nmdp.org. b. DS08-01 The identification of cytogenetic abnormalities in donor derived hematopoietic cells after unrelated donor stem cell transplantation (N Frey) The study is currently in data collection. c. DS09-02 Prevalence and clinical significance of monoclonal B cell lymphocytosis (MBL) in unrelated hematopoietic stem cell donors (M Seftel) Donna Wall presented the study. The questions to be answered by this study are should there be screening of potential donors for clonal abnormalities, such as monoclonal B cell lymphocytosis (MBL), that are associated with progression to hematologic malignancy, and whether such donors should be ineligible for donation. Prevalence of MBL increases with age and absolute lymphocyte count, and the risk of progression to CLL or other B cell disorder depends on the B cell count. Risk of progression increases about 1% per year for people with MBL if B cells are 3-5x10 9 /L, and is much lower if B cells are less than 3x10 9 /L. The prevalence of MBL in unrelated donors is not known, and the risk of transmission of MBL to unrelated donor recipients is unknown. The study aims to establish the prevalence of MBL in unrelated donors, describe whether recipients of donors with MBL have an excess risk of second hematologic malignancy, and establish whether donors with MBL later develop CLL or other lymphoid disorder. The study would test samples from the NMDP Sample Repository of donors age 50+ years for MBL, observe recipients of MBL donors for new hematologic malignancies, graft failure, GVHD, relapse, and observe MBL donors for later diagnosis of CLL/NHL. There are 1212 available samples. A power calculation should be made to determine minimum number of samples required. The NMDP sample consent form covers research to assess factors affecting transplantation, but other ethical issues to consider include whether to include a provision to notify the donor of a possible pre-malignant condition. The next step is to assess the human subjects implications of this kind of testing. d. DS09-03 Effects of second donations on marrow and PBSC donors (D Stroncek) Dave Stroncek presented and overview of the study. Suggestions from the committee include adding a covariate of whether the second donation was made for the same recipient and to examine feasibility of inclusion of poor mobilizers in the study population. The protocol will be finalized and routed to the committee for review and comment. e. DS09-04 The Effect of race, socioeconomic status, and donor center size on bone marrow and PBSC donor experiences (M Pulsipher) The study data file is currently being prepared. 4

5 Not for publication or presentation Attachment 1 f. DS09-05 Late donor toxicities associated with BM vs. PBSC collection in NMDP donors (M Pulsipher) Mike Pulsipher presented the preliminary results of this study. Previous studies by this committee reported a detailed comparison of the acute toxicities experienced by bone marrow (BM, n=2726) and peripheral blood stem cell (PBSC, n=6768) donors collected at National Marrow Donor Program (NMDP) centers between 2004 and 2009, concluding that although the donation experiences are similar, specific groups of donors (female, obese) were more likely to experience toxicities. Over 1,000 reported events to the NMDP were reviewed by a five physician panel. 103 events met the FDA definition of serious adverse event (SAE). SAEs fell into the following categories: 1) life threatening events, 2) unplanned overnight hospitalization for expected (nausea, fainting, etc.) or unexpected events, 3) persistent or significant disability, or 4) other. Overall rates of SAEs were significantly higher after BM donation (n=65, 2.38%) compared to PBSC donation (n=38, 0.56%; p<0.001). There were more life threatening events, unplanned overnight hospitalizations, and persistent or significant disabilities after BM donation compared to PBSC donation (see table). Female BM donors, but not female PBSC donors, were more likely to experience SAEs compared to males (BM: 3.58 vs. 1.59%, p=0.001; PBSC 0.73 vs. 0.46%, p=0.18). Rates of SAEs did not increase with older age or increasing BMI, but BM donors experienced more SAEs than PBSC donors across all age and BMI categories. This large, prospective trial of hematopoietic cell donors showed that although SAEs are uncommon, they are higher after BM compared with PBSC donation. In addition, women are at higher risk of SAEs with BM donation. The most concerning SAEs were very rare: 1) life-threatening complications (0.26% (n=7) after BM and 0.03% (n=2) after PBSC donation) and 2) persistent or significant disability (0.5% (n=14) after BM and 0.06% (n=4) after PBSC donation). A comparative analysis of rates of cancer and autoimmune illness after BM vs. PBSC donation in this cohort is underway. g. DS10-01 Effect of demographics on peripheral blood CD34+ counts and CD34+ yields in donors undergoing large volume leukapheresis (J Hsu / J Wingard) Jack Hsu presented an overview of the study. The study protocol will be finalized and routed to the committee for review and comment. 5. Future / proposed studies a. PROP Comparison of healthy donor stem cell mobilization practices in the world with respect to CD34+ cell yield and incidence of adverse effects (G Akpek) Gorgun Akpek presented the proposal. The study aims to determine whether a fifth dose of G- CSF is needed. It is important because additional G-CSF may increase HCT cost because of additional drug cost, and the storage of excess cells. As well, a fifth dose may increase toxicity in donors. Previous studies found no difference between higher vs. lower G-CSF doses on mobilization and cells collected. Primary endpoint is to compare CD34+ cell count at first day of collection adjusted by the blood volume processed among donors receiving 4 and 5 doses. Secondary endpoints include frequency of second day apheresis, total number of CD34+ cells collected, incidence of adverse events, and average cost. Because the CIBMTR only collects this level of detailed data on NMDP donors, only an analysis of NMDP donors is possible. The NMDP s peripheral blood protocol calls for 5 days of G-CSF with donation on the fifth day, with a collection on the sixth day if needed. There are 11,703 donors with 5 days of G-CSF, but only 253 donors with 4 days of days of G-CSF. A suggestion was made to check the distribution of the years of collection for these cases as a further check on the feasibility of the study. In voting, the committee gave this proposal a rating of 4.41 on a scale of 1 (high scientific impact) to 9 (low scientific impact). The proposal was not accepted due to lack of related donor data availability. 5

6 Not for publication or presentation Attachment 1 6. Other business a. Update on FACT standards regarding related donor management (P O Donnell) Paul O Donnell presented an update on the effect of the committee s previous study reporting on the potential conflict of interest that exists when the same physician caring for the recipient is also managing, consenting and clearing the related donor. The 4 th Edition of the FACT Standards currently states in section B6.1 that, There shall be written criteria for allogeneic and autologous donor selection, evaluation and management by trained medical personnel. Guidance provided for this section recommends that an independent physician be utilized for evaluating donor suitability to reduce potential bias of the recipient s physician(s). The upcoming 5 th Edition of the FACT Standards (to be released March 2012) now state: B Allogeneic donor suitability should be evaluated by a licensed physician or other licensed health care professional who is not the primary transplant physician or health care professional overseeing care of the recipient. The meeting was adjourned at 4:51 pm. 6

7 Not for publication or presentation Attachment 2 Characteristics of NMDP donors donating between 1987 and December 2011 MARROW PBSC Total Variable N (%) N (%) N (%) Number of donors Donor age, years Median (Range) 36 (18-61) 34 (18-62) 35 (18-62) Donor age at time of transplant 18 to (30) 7975 (37) (34) 30 to (36) 6596 (31) (34) 40 to (27) 4900 (23) (25) ( 7) 1747 ( 8) 3226 ( 8) Unknown 0 N/A 53 N/A 53 N/A Donor race/ethnicity Caucasian (77) (80) (79) Hispanic 1512 ( 7) 1334 ( 6) 2846 ( 7) Black/African American 947 ( 5) 655 ( 3) 1602 ( 4) Asian/Pacific Islander 779 ( 4) 710 ( 3) 1489 ( 4) American Indian/Alaska Native 239 ( 1) 159 ( 1) 398 ( 1) Other/Multiple Race 552 ( 3) 828 ( 4) 1380 ( 3) Decline/Unknown 690 ( 3) 503 ( 2) 1193 ( 3) Number of donations (90) (90) (90) (10) 2085 (10) 4113 (10) ( 1) 80 (<1) 225 ( 1) Donor male sex Male (100) (100) (100) Donor CMV status Indeterminate/Unknown 506 ( 2) 66 (<1) 572 ( 1) Negative (60) (63) (62) Positive 7687 (37) 7747 (36) (37) 7

8 Not for publication or presentation Attachment 2 Continued. MARROW PBSC Total Variable N (%) N (%) N (%) Year of donation (<1) 0 2 (<1) (<1) 0 80 (<1) ( 1) (<1) ( 1) ( 1) ( 2) ( 1) ( 3) ( 1) ( 3) ( 2) ( 4) 5 (<1) 854 ( 2) ( 5) 22 (<1) 1002 ( 2) ( 6) 15 (<1) 1189 ( 3) ( 6) 18 (<1) 1302 ( 3) ( 7) 35 (<1) 1400 ( 3) ( 7) 87 (<1) 1460 ( 3) ( 6) 339 ( 2) 1626 ( 4) ( 5) 507 ( 2) 1617 ( 4) ( 5) 822 ( 4) 1943 ( 5) ( 5) 1162 ( 5) 2108 ( 5) ( 4) 1364 ( 6) 2266 ( 5) ( 4) 1640 ( 8) 2408 ( 6) ( 4) 1849 ( 9) 2682 ( 6) ( 4) 2084 (10) 2904 ( 7) ( 4) 2441 (11) 3301 ( 8) ( 4) 2765 (13) 3640 ( 9) ( 5) 2915 (14) 3865 ( 9) ( 5) 3201 (15) 4197 (10) 8

9 Not for publication or presentation Attachment 3 TO: FROM: RE: Donor Health and Safety Working Committee Members Dennis Confer, MD, Scientific Director for the Donor Health and Safety WC Studies in Progress Summary DS05-02: RDSafe: A multi-institutional study of hematopoietic stem cell transplantation (HCT) donor safety and quality of life (M Pulsipher): The study is a multicenter, observational, prospective study comparing acute stem cell donation toxicities and psychosocial effects in related and unrelated marrow and PBSC donors. The primary endpoint is to compare adverse events in related BM and PBSC donors defined by three age groups (<18, 18 to 60, >60) versus unrelated BM and PBSC donors ages 18 to 60. A smaller quality of life (QOL) cohort of both related and unrelated donors will track psychosocial adverse outcomes. The study is now open to accrual. DS08-01: The identification of cytogenetic abnormalities in donor derived hematopoietic cells after unrelated donor stem cell transplantation (N Frey): The study aims to describe the presentation and natural history of cytogenetic abnormalities and hematopoietic malignancies arising in unrelated donor derived hematopoietic cells after unrelated donor hematopoietic stem cell transplantation (HSCT). The study will also describe the current practice of donor evaluation and management in the event of a donor derived abnormality in the recipient. The study is currently in data collection. DS09-03: Effects of second donations on marrow and PBSC donors (D Stroncek): The study aims to: 1) Compare the second donation experience in terms of baseline counts, hematologic recovery, collection yield and serious, life-threatening or adverse events and long-term pain or disability of NMDP unrelated donors making two PBSC donations or making a BM then PBSC donation with the first donation experience of NMDP unrelated donors making one PBSC donation. 2) Determine first donation results or characteristics which impact the risk of a poor outcome during a second donation. 3) Determine first donation donor characteristics which are predictive of a second donation. The study is currently in protocol development. DS09-04: The effect of race, socioeconomic status, and donor center size on bone marrow and PBSC donor experiences (M Pulsipher): The study aims to compare early donation associated toxicities in donors of BM or PBSC between: donors of different races, donors living in low SEC zip codes vs. middle SEC zip codes vs. high SEC zip codes, and donors collected/harvested at centers with small vs. larger volume. The study is currently in data file preparation. DS09-05: Early and late donor toxicites associated with bone marrow vs. PBSC collection in NMDP donors (M Pulsipher): The study aims to compare peri-donation and post-donation associated toxicities, serious unexpected or life threatening adverse events, and rates of long-term disability and chronic pain in NMDP donors of bone marrow with NMDP donors of peripheral blood stem cells. Results of the first study were presented at the American Society of Hematology Annual Meeting in Orlando, Florida, December The study will result in two papers: one focusing on donation associated toxicities and another focusing on adverse events. The first paper has been submitted, the second paper is in data analysis. 9

10 Not for publication or presentation Attachment 3 DS10-01: Effect of demographics on peripheral blood CD34+ counts and CD34+ cell yields in donors undergoing large volume leukapheresis (J Hsu / J Wingard): To determine the influence of race and ethnicity on CD34+ cell yields in allogeneic peripheral blood donors after G-CSF administration. The study is currently in protocol development. 10

11 Not for publication or presentation Attachment 4 Study Proposal Study Title: Retrospective examination of the role quantity of bone marrow harvests performed by a harvest center has on the overall quality of the harvested product. Assessment of the potential impacts bone marrow product quality has on utilization of bone marrow as a cell source for transplant. PI Information: Nicole Lesley Prokopishyn, Ph.D. Cellular Therapy Lab, Calgary Laboratory Services, Foothills Medical Centre University of Calgary, Department of Laboratory Medicine Specific Aims: 1. Examine the quantity (i.e. number) and relative quality (i.e. volume and total nucleated cell count of product harvested as compared to standard and minimal acceptable amounts) of bone marrow harvests performed by harvest centers from Examine impact of number of harvests performed on achievement of harvest goals. 3. Investigate the impact of harvest success on the utilization of bone marrow products by transplant centers to determine if there is a correlation between use of bone marrow as a cell source, overall quality of product received, number of harvests performed per year, and number of harvests performed by the harvesting centers. Scientific Justification: Bone marrow was the original source of hematopoietic stem/progenitor cells (HSCs) used in allogeneic blood and marrow transplants. With the advent of G-CSF mobilization of HSCs into the peripheral blood and development of efficient apheresis collection methods, the utilization of bone marrow in transplants significantly decreased. Currently in adult transplants, peripheral blood stem cell (PBSC) products are used much more frequently than bone marrow products. In transplant patients over the age of 20 years, the use of bone marrow as a cell source has dropped from ~35% in to ~15% in However, bone marrow is still an essential cell source and often the preferred cell source for specific disease indications in adults (e.g. Aplastic Anemia) and pediatric transplants for a variety of reasons including decreased risk/incidence of graft verse host disease (GVHD) and improved outcome in certain conditions. 2-5 The decreased utilization of bone marrow as a cell source for transplant has a number of potential consequences from a quality assurance perspective. Firstly, the reduced use of bone marrow in the allogeneic transplant setting has resulted in a decreased numbers of harvests performed per year at the majority of centers. For example, requests for unrelated allogeneic bone marrow harvests have decreased at our transplant center over the past 10 years resulting in a range of 0-4 unrelated bone marrow harvests being performed per year over the past 3 years. As such, the ability to ensure ongoing and continued competency of an extremely technical and skilled procedure with staff that are rarely able to practice the skill is becoming increasingly difficult. Additionally, it is problematic for individual collection facilities to properly assess their aptitude with such limited numbers of procedures. 11

12 Not for publication or presentation Attachment 4 Similarly, the reduced use of bone marrow as a cell source for transplant makes it difficult for an individual transplant center to assess the quality of the products used due to lack of sufficient data. It requires several years to assess the overall quality of the bone marrow products received and uncover any trends related to those products. For example, our transplant center only opted for bone marrow as a cell source in 1 out of 30 unrelated allogeneic adult transplants in 2011 and did not use bone marrow for any adult transplants in This is in stark contrast to 2000 and 2001 in which bone marrow was used in 20 and 14 allogeneic adult transplants, respectively (Figure 1, blue line). Review of our bone marrow products utilized in transplants over the past 11 years uncovered a very concerning finding regarding a downward trend in total nucleated cells received in products for transplant. This examination revealed a correlation between decreased utilization, year transplant was performed, and relative quality/quantity of bone marrow products received (Figure 1). Relative quality of the bone marrow products was assessed by examining the total nucleated cell count (NC) received divided by the total NC requested for transplant. This value is depicted as a percent (%) in Figure 1. As can be seen in Figure 1, the relative quality of the bone marrow product decreases over the time periods specified with a significant drop in % NC received verses NC requested between the periods of and Additionally, it can be observed that this decreased relative quality matches the decreased utilization of bone marrow in the transplant program. With the data at our center alone, it is apparent that there is a downward trend in the quantity of nucleated cells obtained during bone marrow harvest even when the requested nucleated cell count has not changed significantly (Figure 2). NC Received/NC Requested (%) Year Performed Number of Transplants Figure 1: Total number of Nucleated Cells received in bone marrow products decrease correlates with decreased utilization of bone marrow as a cell source in transplants at our centre. Total nucleated cell count (NC) received as compared to nucleated cell count requested (NC Received/NC Requested (%)) correlates with decreased number of bone marrow products utilized in transplant over the past 11 years. These data raise a number of critical questions regarding the continued use of bone marrow products for transplant. Firstly, is the phenomenon observed at our center an isolated incident or a universal trend across harvest and transplant centers? Secondly, if this trend to reduce quality in bone marrow products received continues, will these products be sufficient for engraftment of transplant patients? 12

13 Not for publication or presentation Attachment 4 Thirdly, if this trend is a universal issue among centers, what are the contributing factors to reduced quality in bone marrow harvests? Access to data from a wide range of harvest and transplant centers will allow for a more comprehensive examination of the data and enable a better assessment of the universal state of harvests in the transplant field. Furthermore, information gained from these analyses will provide avenues to address important issues regarding competency and training in bone marrow harvest to ensure this essential resource is available for future transplants. 300 Total Nucleated Cells (NC) x Year of Transplant Figure 2: Total nucleated cells (NC) x 10 8 received in bone marrow products has decreased where as total NC requested in product remains constant over time. Study Population: All adult patient populations are available for inclusion in this study. Due to the significant difference in pediatric patient weights, as compared to the adult population, it is not feasible to include bone marrow harvests planned for pediatric patients in this study. Data Requirements: This retrospective study requires the examination of CIBMTR collected data related to bone marrow harvests for use in transplant from

14 Not for publication or presentation Attachment 4 Data fields required for study are as follows for each bone marrow product used in a BM Transplant: From Harvest Center: HPC, Marrow product harvested Harvest Centre Code (de-identified) Date of harvest Donor weight & ABO/Rh HPC, Marrow product harvested information including total nucleated cell count and volume From Transplant Center: Transplant Centre Code (de-identified) Date of transplant Disease diagnosis of patient being transplanted Recipient weight & ABO/Rh Post collection processing performed on HPC, Marrow Engraftment information (i.e. engrafted, delayed engraftment, failed engraftment) Standard values of 3 x 108 TNC/kg requested and 2 x 108/kg minimum acceptable for transplant will be used as requested dose unless otherwise noted. Sample Requirements: This proposal does not require biologic samples. Study Design: The proposed study will involve utilizing the above data in the following manner to realize our specific aims for this project as outlined above. 1. Determination of bone marrow harvest quality. Individual bone marrow harvests performed from will be examined to determine the success of each harvest performed. The bone marrow harvest information for each product will be compared to the standard values of 3 x 108 TNC/kg (standard amount requested) and 2 x 108/kg (typical minimum accepted for transplant). Specifically, bone marrow products will be reviewed for total nucleated cell count (NC) received and the percent (%) NC received to NC standard and minimum acceptable dose will be calculated to allow for a direct comparison of harvested products. Information regarding volume (ml) harvested will also be examined at this time. It is anticipated that Total Nucleated Cell Count will be the most significant value when accessing the harvest quality. 2. Assessing the role bone marrow harvest quantities has on bone marrow harvest quality. The above generated quality score (i.e. % NC Received/NC standard and minimum request) will be used to assess the influence of harvest quantities (i.e. the number of harvest performed within a given time period) on harvest proficiency for a given harvest center. The data will be used to determine if the number of harvests performed within a given year significantly influences the quality of the product. Furthermore, these analysis will map the proficiency of harvesting centers over a given time period. 3. The above collected data will be expanded to examine the role harvest proficiency plays in utilization of bone marrow as a cell source for specific transplant centers. As such, the quality score will be analyzed in conjunction with the total number of transplants performed by the center at specific times and for specific disease diagnoses to determine if other centers have experiences similar to those described above by our center. Lately, these data will be used to examine the impact bone marrow quality has on engraftment and other clinical events. 14

15 Not for publication or presentation Attachment 4 References: 1. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, Available at: 2. Couban S, Barnett M. The source of cells for allografting. Biol Blood Marrow Transplant. 2003; 9(11): Eapen M, Logan BR, Confer DL, et al. Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant. 2007; 13(12): Flowers MED, Parker PM, Johnston LJ, 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. 2002; 100(2): Remberger M, Beelen DW, Fauser A, et al. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood. 2005; 105(2):

16 Not for publication or presentation Attachment 4 Characteristics of NMDP donors donating between 1987 and December 2011 (Marrow only) Variable N (%) Number of donors Donor age, years Median (Range) 36 (18-61) Donor age at time of transplant 18 to (30) 30 to (36) 40 to (27) ( 7) Donor race/ethnicity Caucasian (77) Hispanic 1512 ( 7) Black/African American 947 ( 5) Asian/Pacific Islander 779 ( 4) American Indian/Alaska Native 239 ( 1) Other/Multiple Race 552 ( 3) Decline/Unknown 690 ( 3) Number of donations (90) (10) ( 1) Donor male sex Male (>99) Donor CMV status Indeterminate/Unknown 506 ( 2) Negative (60) Positive 7687 (37) 16

17 Not for publication or presentation Attachment 4 Continued. Variable N (%) Year of donation (<1) (<1) ( 1) ( 1) ( 2) ( 3) ( 3) ( 4) ( 5) ( 6) ( 6) ( 7) ( 7) ( 6) ( 5) ( 5) ( 5) ( 4) ( 4) ( 4) ( 4) ( 4) ( 4) ( 5) ( 5) 17