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The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation
Biology of Blood and Marrow Transplantation 14:2-7 (2008) Q 2008 American Society for Blood and Marrow Transplantation 1083-8791/08/1409-0001$32.00/0 doi:10.1016/j.bbmt.2008.05.017
The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation Karen K. Ballen,1 Roberta J. King,2 Pintip Chitphakdithai,2 Charles D. Bolan, Jr.,3 Edward Agura,4 Robert J. Hartzman,5 Nancy A. Kernan6 1
Massachusetts General Hospital, Boston, Massachusetts; 2 National Marrow Donor Program, Minneapolis, Minnesota; 3 Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Rockville, Maryland; 4 Baylor University Medical Center, Houston, Texas; 5 C.W. Bill Young/Department of Defense Marrow Donor Program, Naval Medical Research Center, Rockville, Maryland; and 6 Memorial Sloan Kettering Cancer Center, New York, New York Correspondence and reprint requests: Karen Ballen, MD, Division of Hematology/Oncology, Massachusetts General Hospital, Zero Emerson, Suite 118, Boston, MA 02114 (e-mail: [email protected]). STATEMENT OF CONFLICT OF INTEREST: See Acknowledgments on page 7. Received May 23, 2008; accepted May 27, 2008
ABSTRACT In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years.
Ó 2008 American Society for Blood and Marrow Transplantation
KEY WORDS National Marrow Donor Program NMDP Unrelated donor Stem cell transplant Transplantation
ESTABLISHMENT OF THE NMDP In 1986, when the National Marrow Donor Program (NMDP) was established, Ronald Reagan was President of the United States, the Big Easy was the most popular movie, and the U.S. Supreme Court ruled that Rotary Clubs must admit women. In science, the first heart and lung transplant was performed, and Prozac and AZT were first approved for use. The NMDP was established in July 1986 when it was awarded a contract with the U.S. Navy to establish the National Bone Marrow Donor Registry. The program had 1 full-time employee and subcontracted the information system to the University of Minnesota. Computer programs were DOS-based programs. The first search requests for donors were processed in September 1987, and the first transplant was facilitated 2
in December 1987. Forty-four donor centers and 7 transplant and collection centers comprised the network. In June 1988, the Board of Directors voted to name the organization the National Marrow Donor Program. Today, the program is supported in part through multiple federal contracts administered by the Health Resources and Services Administration (HRSA). The NMDP employs over 600 people and the program enjoys 160,000 square feet of office space near downtown Minneapolis. The NMDP is comprised of the coordinating center in Minneapolis, 128 U.S. transplant centers, 43 international transplant centers, 66 U.S. donor centers, and 7 international donor centers. A cord blood program was begun in 1998 and now includes 21 U.S. cord blood banks and 3 international cord
3
NMDP Overview
Number of Transplants
1800 1600 1400 1200 1000 800 600
300 200
98 8 19 89 19 90 19 9 19 1 92 19 93 19 94 19 95 19 9 19 6 97 19 98 19 99 20 0 20 0 01 20 0 20 2 0 20 3 0 20 4 05 20 0 20 6 07
Year of Transplant
Figure 2. Number of pediatric transplants facilitated by the NMDP, by year and stem cell source.
acute leukemia from Raleigh, NC. In 2007, 864 pediatric unrelated transplants were performed. PBSC was added as a graft source for primary transplants in 1999; in 2007, 20% percent of NMDP pediatric transplants were PBSC grafts. UCB transplants were added in 2000 for pediatric patients and in 2007 comprised 41% of pediatric unrelated transplants. A significant trend has been an increase in the numbers of transplants in patients over the age of 55 years. This reflects activity in the matched sibling setting, likely because of the introduction of PBSC grafts and RIC regimens [1,2]. This is an important advance, given the median age of 68 years for patients with acute myelogenous leukemia (AML) [3,4]. Figure 3 outlines the number of first NMDP transplants in patients over the age of 55 years. In 2000, 8% (116 of 1543 transplants) of the initial NMDP transplants were in patients 55 years and older. By 2005, 21% (540 of 2522 transplants) of the initial 1100 Percent Number
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Over the past 20 years there have been several major trends in transplant activity. In addition to an increase in the overall number of adult and pediatric transplants, there has been a dramatic increase in transplants for patients over the age of 50 years, in the use of reduced-intensity (RIC) preparative regimens, and in the use of peripheral blood stem cells (PBSC) and, most recently, umbilical cord blood (UCB) as the graft source. There have been modest increases in the use of transplant for nonmalignant diseases. This section will explore these trends, as well as highlight the changing demographics of the NMDP transplant and donor population. Figure 1 outlines the number of adult transplants between 1987 and 2007. In 1988, 54 transplants were performed; in 1997, 879 transplants were performed; and in 2007, 2640 adult transplants were facilitated by the NMDP. PBSC was first used as a graft source for primary transplants in NMDP transplants in 1999, and in 2003, PBSC surpassed bone marrow (BM) as the preferred stem cell source. Presently, PBSC grafts comprise the majority (72%) of adult transplants. In 2000, the NMDP facilitated its first unrelated UCB transplant for an adult patient. The numbers continued to grow, and by 2007 UCB was used as a graft source in 10% of adult transplants. Pediatric transplants have followed some similar trends, as seen in Figure 2. As expected, there are fewer pediatric than adult transplants. In 1987, the first pediatric NMDP transplant was performed in a child with
Umbilical cord blood Peripheral blood stem cells Bone marrow
800
87
TRANSPLANT ACTIVITY
900
19
blood banks. In addition, the NMDP’s extensive network includes 26 Cooperative International Registries located on 6 continents. Approximately 35% of the NMDP-facilitated transplants are performed internationally.
Year of Transplant
Figure 1. Number of adult transplants facilitated by the NMDP, by year and stem cell source.
Year of Transplant
Figure 3. Initial NMDP transplants in patients 55 years of age and older.
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600
2000 1800
Number of Transplants
Chronic myelogenous leukemia
450
Acute lymphoblastic leukemia
400
Acute myelogenous leukemia
350 300 250 200 150 100 50
87
-1
98 8 19 8 19 9 90 19 91 19 9 19 2 93 19 94 19 95 19 9 19 6 97 19 9 19 8 99 20 00 20 0 20 1 02 20 03 20 04 20 05 20 06 20 07
0
Year of Transplant
Figure 5. Number of pediatric transplants for hematologic malignancies.
transplants facilitated by the NMDP, 530 (7%) were for metabolic disorders, and 595 (8%) were for immune deficiencies. The numbers of these transplants have also increased considerably over time from \20 per year before 1990 to over 300 pediatric transplants annually for non-malignant conditions. This trend is illustrated in Figure 6. For adults, a significant change has been the introduction of unrelated transplant for solid tumors, such as renal cell carcinoma, based on data in the matched sibling setting [6]. The first transplant for a solid tumor was performed in 1994. Seventy-seven transplants have been performed for solid tumors in adults and children at 33 transplant centers. In addition, unrelated transplants are now occasionally performed for autoimmune disease. The number of unrelated transplants for SAA in adults has risen sharply over the last 20 years, with 3 350 Other non-malignant Metabolic disorders Immune deficiencies Severe aplastic anemia
Other leukemia / Plasma cell disorders Lymphoma
300
Myelodysplastic disorders Chronic myelogenous leukemia Acute myelogenous leukemia / Acute lymphoblastic leukemia
1600 1400 1200 1000 800 600 400
Number of Transplants
Number of Transplants
2200
Myelodysplastic disorders
500
2600 2400
Other leukemia / Lymphoma / Plasma cell disorders
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19
NMDP transplants were in recipients over the age of 55 years. Nearly 700 transplants were performed in patients 55 years and older in 2006; over 400 of these were RIC approaches. Less toxic conditioning regimens, the use of PBSC grafts, improvement in supportive care, and optimal patient and donor selection have allowed older patients to receive unrelated transplants with some success. With the introduction of RIC preparative regimens and better supportive care, NMDP transplants are now performed in patients over the age of 65 years, and, rarely, in patients over the age of 70 years. The NMDP has facilitated 461 transplants for patients aged 65 to 69 years, and 86 transplants for patients aged 70 years and over. Eighty-three percent of transplants in the patients 65 years and older were PBSC grafts. The most common diseases for these older patients were AML, myelodysplasia (MDS), and lymphoma. Over the past 20 years, transplants have been performed for a wider variety of diseases. The majority of transplants are for hematologic malignancies (89%) (predominantly leukemia and lymphoma) in both adults and children. There has been a trend to fewer transplants for chronic myelogeneous leukemia (CML), with the introduction of oral tyrosine kinase inhibitors such as imatinib. Recently, there has been more interest in transplant for plasma cell disorders [5]. Figures 4 and 5 demonstrate the breakdown by disease for adults and children over time. Severe aplastic anemia (SAA) is the most common indication for transplantation in children among the nonmalignant diseases. Despite the introduction of immunosuppressive therapy, the number of transplants for SAA has increased in the last 10 years (Figure 6). In children, transplants for other nonmalignant conditions included transplants for immune deficiencies and metabolic disorders. Of the 7724 pediatric
250 200 150 100 50
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98 8 19 89 19 9 19 0 9 19 1 9 19 2 9 19 3 94 19 9 19 5 9 19 6 97 19 98 19 99 20 0 20 0 0 20 1 0 20 2 03 20 04 20 0 20 5 06 20 07
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0
Year of Transplant
Figure 4. Number of adult transplants for hematologic malignancies.
Year of Transplant
Figure 6. Number of pediatric transplants for nonmalignant diseases.
5
NMDP Overview
90 Severe aplastic anemia
Number of Transplants
80 70 60 50 40 30 20 10
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98 8 19 89 19 9 19 0 9 19 1 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 0 20 3 04 20 05 20 06 20 07
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Figure 7. Number of adult transplants for severe aplastic anemia.
in 1988 and 85 in 2007. Although triple-drug immunosuppressive therapy was introduced as a viable treatment for SAA in 1991, unrelated bone marrow transplantation remains an attractive choice for young patients with SAA, or for those patients who fail immunosuppressive therapy [7-9]. These trends are illustrated in Figure 7. The racial and ethnic composition of the United States has changed in the last 20 years. Census data indicates that in 2000, 69% of Americans we Caucasian. The diversity of both the donor and the recipient pool of the NMDP have changed accordingly [10,11]. Donor issues will be addressed in the chapter on donor activity. In 2007, 552 transplants (16%) were performed in non-Caucasians. These transplants include 172 (5%) in African Americans, 238 (7%) in Hispanics, 92 (3%) in Asian/Pacific Islanders, and 11 (0.3%) in Native Americans (Figure 8). Although numerous advances in donor recruitment and patient access have
Transplant Recipients 1993–1997 API 3% Hispanic 6%
Native 0.3%
Mult/Oth 1% Dec/Unk 1%
Black 4%
been made, the number of African American unrelated transplant recipients in the United States is underrepresented compared to the population as a whole (12% in census 2000 data, 5% of transplant recipients from 2003 to 2007). Ethnically diverse donor recruitment and patient access to transplantation remain challenges that the NMDP is actively addressing, in the following section. As stated above, a major advance over the last 20 years is the ability to transplant older patients successfully. This advance is because of, in large part, the introduction of non-myeloablative or RIC preparative regimens. First pioneered in the related donor setting, these regimens are immunosuppressive, not myeloablative, and better tolerated by patients in terms of organ function, mucositis, and risk of infection [12-14]. Starting in 1999, these RIC transplants have had exponential growth. In 1997, 8% of transplants were reduced-intensity. Presently, reduced-intensity approaches are utilized in approximately half of NMDP-facilitated transplants. Definitions of a nonablative or RIC transplant differ widely; current Center for International Blood and Marrow Transplant Research (CIBMTR) guidelines define regimens with .800 cGy total body radiation (TBI) and .150 mg/ m2 melphalan as myeloablative [15]. Results of the first 285 RIC transplants facilitated by the NMDP were recently reported by Giralt et al. [15]. Patients who received RIC unrelated transplants were older (median 55 years versus 33 years) and had more advanced disease (81% versus 51%) than recipients of myeloablative transplants. The 5-year survival rate was 23%. As expected, patients who were young, with a good performance status, earlier disease stage, and a fully matched donor did best. Further outcome data on RIC transplants will be presented in this issue of the Journal.
Transplant Recipients 2003–2007
Native 0.3% API 3%
Mult/Oth 1%
Dec/Unk 12%
Black 5%
API 4%
Native 0.7%
Mult/Oth 8%
Hispanic 6%
Hispanic 7% Caucasian 85%
U.S. Population Census 2000
Caucasian 72%
Black 12%
Caucasian 69%
Figure 8. Comparison between transplant recipient population and U.S. population. Black 5 Black/African American; API 5 Asian/Pacific Islander; Native 5 American Indian/Alaska Native; Mult/Oth 5 multiple race/other race; Dec/Unk 5 declined/unknown.
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CONTRIBUTIONS OF THE NMDP The contributions of the NMDP in the last 20 years transcend the transplant numbers illustrated above. The program has had extensive influence on the transplant community in areas such as education on unrelated hematopoietic cell transplantation (HSCT), donor and patient safety; information systems, including sophisticated matching algorithms; access to transplantation; patient and donor advocacy; and clinical research activity, most notably with elucidating the level of histocompatibility required between patient and donor for successful outcome. Since 1987, the NMDP has brought its network of centers together at the annual Council Meeting, a dynamic educational event where attendees gain essential training and education on advances in unrelated hematopoietic cell transplantation. Today, the Council Meeting attracts nearly 1000 attendees from over 35 countries. In addition to the annual Council Meeting, the NMDP provides extensive training to new network staff and ongoing training for existing staff through inperson training sessions and Web-based training events. Donor and patient safety is of paramount importance to the NMDP. The NMDP has established standards that govern criteria for participating centers, recruitment of adult and cord blood donors, medical evaluation of donors, and the collection, transportation, processing, and labeling of hematopoietic cells. These standards specify, for example, required donor testing for infectious diseases, the maximum harvest volumes for BM donors and post-donation follow-up for BM and PBSC donors. In addition, the NMDP has developed guidelines that contribute to donor safety. These include calcium replacement guidelines for PBSC donors and guidelines on the number of times a donor may be requested for subsequent donations for the same recipient. Many institutions have adapted these safety parameters for their related donors as well. The NMDP Donor and Patient Safety Monitoring Committee meets 4 times a year to address donor and patient safety concerns. The NMDP is a leader in developing information systems to support its extensive network of centers, patients, and the public. In 1992, the NMDP introduced its proprietary Search Tracking and Registry (STARÔ) computer system that was designed to expedite the process of matching potential donors with patients and improving communication between the NMDP Coordinating Center and its network of centers. The STAR system has evolved over the past 15 years to include sophisticated software applications that support the work performed at transplant centers, donor centers, CB banks, and the NMDP repositories. HapLogicSM, an enhancement to the search algorithm, was implemented in 2006. HapLogic utilizes
K. K. Ballen et al.
mathematic formulas developed by Mori et al. [16] to predict a donor’s or cord blood unit’s (CBU) highresolution match with a patient, thus contributing to a reduction in the number of donors or CBUs requested for testing and to faster identification of a donor or CBU for transplantation. The NMDP maintains a public Web site (www.marrow.org) to provide information to donors, patients and their families, referring physicians, and other interested persons from the public and medical community. Access to transplant for the diverse American population has been a major focus of the NMDP. Donor recruitment campaigns targeted to specific racial and ethnic groups have contributed to the racial and ethnic diversity of the NMDP Registry, whereas educational programs for referring physicians and third party payors have increased access to transplant for patients who otherwise may not have had this treatment option available to them. The Marrow Foundation, the official charitable organization of the NMDP, was established in 1991. Funds raised by The Marrow Foundation provide financial support to help patients through their transplant journey, add fully HLA typed donors to the registry, and fund research. In 2007, The Marrow Foundation provided more than 4 million dollars to help more than 1000 patients manage the cost of transplant. The NMDP established the Office of Patient Advocacy (OPA) in 1991 to assist patients and their families through the process of searching for a donor and transplantation. Today, professional case managers help patients learn about transplantation, review transplant statistics, prepare financial plans, and understand insurance coverage. In 2007, OPA provided service to over 11,500 patients. In 2001, the NMDP formally established a Donor Advocacy Program. This program is designed to provide donors with information about potential complications and help if complications do occur, find answers to donor insurance and financial questions, and overcome barriers to donation. The founders of the NMDP had the foresight to require transplant centers to submit baseline and outcomes data on all NMDP-facilitated transplants, thus establishing a research database from which retrospective outcome analyses could be performed. In addition to recipient outcomes, the NMDP also collected data on donor outcomes. In 1992, the NMDP established a research sample repository that stores blood samples from recipients and their donors. The repository now includes over 16,000 donor/recipient paired samples and is the cornerstone of the immunogenetics research program. In 2004, the NMDP expanded its research focus from unrelated transplantation to include allogeneic related and unrelated transplantation and autologous
NMDP Overview
transplantation when it formed an affiliation with the International Bone Marrow Transplant Registry to create the Center for International Blood and Marrow Transplant Research (CIBMTR). This research organization, with its 17 working committees, is responsible for the design and implementation of retrospective recipient and donor outcomes studies, immunogenetics research, health services research, and prospective clinical trials. In addition to its own prospective clinical trials program, the CIBMTR, together with the NMDP and EMMES Corporation, serves as the data coordinating center for the National Institutes of Health funded Blood and Marrow Transplant Clinical Trials Network (BMT CTN). In 2007, the CIBMTR and NMDP published 59 articles in peer-reviewed journals. The NMDP has grown into a large international organization providing patients with access to over 7 million donors in the NMDP Registry and 10 million donors worldwide. The NMDP continues to face challenges in terms of funding, minority recruitment, and expansion. Nonetheless, the basic principles of donor safety, concern for the patient, and advancement of the field remain paramount. Over 30,000 patients have benefited from this remarkable organization. The articles that follow outline the organization’s achievements in pediatric and adult transplant outcomes, advances in HLA typing, and donor activity and outcomes. ACKNOWLEDGEMENTS Financial Disclosure: Drs. King and Chitphakdithai are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Drs. Ballen, Bolan, Agura, Hartzman, and Kernan have nothing to disclose. REFERENCES 1. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoeitic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390-3400. 2. Daly A, McAfee S, Dey B, et al. Nonmyeloablative bone marrow transplantation: infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant. 2003;9:373-382. 3. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-3485. 4. Section 13. Leukemia. In: Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK, editors. SEER [Surveillance Epidemiology and End Results] Cancer Statistics Review, 1975-2001. Bethesda, MD: National Cancer Institute; 2004.
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5. Ballen KK, King R, Carston M, et al. Outcome of unrelated transplants in patients with multiple myeloma. Bone Marrow Transplant. 2005;35:675-681. 6. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral blood stem-cell transplantation. N Engl J Med. 2000; 343:750-758. 7. Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med. 1991;324:1297-1304. 8. Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colonystimulating factor for severe aplastic anemia: update of the GITMO/EBMT study on 100 patients. Blood. 2000;95: 1931-1934. 9. Deeg HJ, Seidel K, Casper J, et al. Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy. Biol Blood Marrow Transplant. 1999;5:243-252. 10. Baker KS, Hassebroek A, Ballen K, et al. Impact of ethnicity and socioeconomic status on outcome of unrelated donor (URD) hematopoietic stem cell transplantation (HcT). Blood (ASH Annual Meeting Abstracts). 2007;110:3064. 11. Schipper RF, D’Amaro J, Bakker JT, Bakker J, van Rood JJ, Oudshoorn M. HLA gene and haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol. 1997;52: 54-71. 12. Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematologic diseases. Blood. 2003;101: 1620-1629. 13. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756-763. 14. Dey BR, McAfee S, Sackstein R, et al. Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation. Biol Blood Marrow Transplant. 2001;7:604-612. 15. Giralt S, Logan B, Rizzo D, et al. Reduced-intensity conditioning for unrelated donor progenitor cell transplantation: longterm follow-up of the first 285 reported to the National Marrow Donor Program. Biol Blood Marrow Transplant. 2007;13: 844-852. 16. Mori M, Graves M, Milford EL, Beatty PG. Computer program to predict likelihood of finding an HLA-matched donor: methodology, validation, and application. Biol Blood Marrow Transplant. 1996;2:134-144.
The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation Karen K. Ballen,1 Roberta J. King,2 Pintip Chitphakdithai,2 Charles D. Bolan, Jr.,3 Edward Agura,4 Robert J. Hartzman,5 Nancy A. Kernan6 1
Massachusetts General Hospital, Boston, Massachusetts; 2 National Marrow Donor Program, Minneapolis, Minnesota; 3 Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Rockville, Maryland; 4 Baylor University Medical Center, Houston, Texas; 5 C.W. Bill Young/Department of Defense Marrow Donor Program, Naval Medical Research Center, Rockville, Maryland; and 6 Memorial Sloan Kettering Cancer Center, New York, New York Correspondence and reprint requests: Karen Ballen, MD, Division of Hematology/Oncology, Massachusetts General Hospital, Zero Emerson, Suite 118, Boston, MA 02114 (e-mail: [email protected]). STATEMENT OF CONFLICT OF INTEREST: See Acknowledgments on page 7. Received May 23, 2008; accepted May 27, 2008
ABSTRACT In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years.
Ó 2008 American Society for Blood and Marrow Transplantation
KEY WORDS National Marrow Donor Program NMDP Unrelated donor Stem cell transplant Transplantation
ESTABLISHMENT OF THE NMDP In 1986, when the National Marrow Donor Program (NMDP) was established, Ronald Reagan was President of the United States, the Big Easy was the most popular movie, and the U.S. Supreme Court ruled that Rotary Clubs must admit women. In science, the first heart and lung transplant was performed, and Prozac and AZT were first approved for use. The NMDP was established in July 1986 when it was awarded a contract with the U.S. Navy to establish the National Bone Marrow Donor Registry. The program had 1 full-time employee and subcontracted the information system to the University of Minnesota. Computer programs were DOS-based programs. The first search requests for donors were processed in September 1987, and the first transplant was facilitated 2
in December 1987. Forty-four donor centers and 7 transplant and collection centers comprised the network. In June 1988, the Board of Directors voted to name the organization the National Marrow Donor Program. Today, the program is supported in part through multiple federal contracts administered by the Health Resources and Services Administration (HRSA). The NMDP employs over 600 people and the program enjoys 160,000 square feet of office space near downtown Minneapolis. The NMDP is comprised of the coordinating center in Minneapolis, 128 U.S. transplant centers, 43 international transplant centers, 66 U.S. donor centers, and 7 international donor centers. A cord blood program was begun in 1998 and now includes 21 U.S. cord blood banks and 3 international cord
3
NMDP Overview
Number of Transplants
1800 1600 1400 1200 1000 800 600
300 200
98 8 19 89 19 90 19 9 19 1 92 19 93 19 94 19 95 19 9 19 6 97 19 98 19 99 20 0 20 0 01 20 0 20 2 0 20 3 0 20 4 05 20 0 20 6 07
Year of Transplant
Figure 2. Number of pediatric transplants facilitated by the NMDP, by year and stem cell source.
acute leukemia from Raleigh, NC. In 2007, 864 pediatric unrelated transplants were performed. PBSC was added as a graft source for primary transplants in 1999; in 2007, 20% percent of NMDP pediatric transplants were PBSC grafts. UCB transplants were added in 2000 for pediatric patients and in 2007 comprised 41% of pediatric unrelated transplants. A significant trend has been an increase in the numbers of transplants in patients over the age of 55 years. This reflects activity in the matched sibling setting, likely because of the introduction of PBSC grafts and RIC regimens [1,2]. This is an important advance, given the median age of 68 years for patients with acute myelogenous leukemia (AML) [3,4]. Figure 3 outlines the number of first NMDP transplants in patients over the age of 55 years. In 2000, 8% (116 of 1543 transplants) of the initial NMDP transplants were in patients 55 years and older. By 2005, 21% (540 of 2522 transplants) of the initial 1100 Percent Number
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Umbilical cord blood Peripheral blood stem cells Bone marrow
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Over the past 20 years there have been several major trends in transplant activity. In addition to an increase in the overall number of adult and pediatric transplants, there has been a dramatic increase in transplants for patients over the age of 50 years, in the use of reduced-intensity (RIC) preparative regimens, and in the use of peripheral blood stem cells (PBSC) and, most recently, umbilical cord blood (UCB) as the graft source. There have been modest increases in the use of transplant for nonmalignant diseases. This section will explore these trends, as well as highlight the changing demographics of the NMDP transplant and donor population. Figure 1 outlines the number of adult transplants between 1987 and 2007. In 1988, 54 transplants were performed; in 1997, 879 transplants were performed; and in 2007, 2640 adult transplants were facilitated by the NMDP. PBSC was first used as a graft source for primary transplants in NMDP transplants in 1999, and in 2003, PBSC surpassed bone marrow (BM) as the preferred stem cell source. Presently, PBSC grafts comprise the majority (72%) of adult transplants. In 2000, the NMDP facilitated its first unrelated UCB transplant for an adult patient. The numbers continued to grow, and by 2007 UCB was used as a graft source in 10% of adult transplants. Pediatric transplants have followed some similar trends, as seen in Figure 2. As expected, there are fewer pediatric than adult transplants. In 1987, the first pediatric NMDP transplant was performed in a child with
Umbilical cord blood Peripheral blood stem cells Bone marrow
800
87
TRANSPLANT ACTIVITY
900
19
blood banks. In addition, the NMDP’s extensive network includes 26 Cooperative International Registries located on 6 continents. Approximately 35% of the NMDP-facilitated transplants are performed internationally.
Year of Transplant
Figure 1. Number of adult transplants facilitated by the NMDP, by year and stem cell source.
Year of Transplant
Figure 3. Initial NMDP transplants in patients 55 years of age and older.
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600
2000 1800
Number of Transplants
Chronic myelogenous leukemia
450
Acute lymphoblastic leukemia
400
Acute myelogenous leukemia
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87
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98 8 19 8 19 9 90 19 91 19 9 19 2 93 19 94 19 95 19 9 19 6 97 19 9 19 8 99 20 00 20 0 20 1 02 20 03 20 04 20 05 20 06 20 07
0
Year of Transplant
Figure 5. Number of pediatric transplants for hematologic malignancies.
transplants facilitated by the NMDP, 530 (7%) were for metabolic disorders, and 595 (8%) were for immune deficiencies. The numbers of these transplants have also increased considerably over time from \20 per year before 1990 to over 300 pediatric transplants annually for non-malignant conditions. This trend is illustrated in Figure 6. For adults, a significant change has been the introduction of unrelated transplant for solid tumors, such as renal cell carcinoma, based on data in the matched sibling setting [6]. The first transplant for a solid tumor was performed in 1994. Seventy-seven transplants have been performed for solid tumors in adults and children at 33 transplant centers. In addition, unrelated transplants are now occasionally performed for autoimmune disease. The number of unrelated transplants for SAA in adults has risen sharply over the last 20 years, with 3 350 Other non-malignant Metabolic disorders Immune deficiencies Severe aplastic anemia
Other leukemia / Plasma cell disorders Lymphoma
300
Myelodysplastic disorders Chronic myelogenous leukemia Acute myelogenous leukemia / Acute lymphoblastic leukemia
1600 1400 1200 1000 800 600 400
Number of Transplants
Number of Transplants
2200
Myelodysplastic disorders
500
2600 2400
Other leukemia / Lymphoma / Plasma cell disorders
550
19
NMDP transplants were in recipients over the age of 55 years. Nearly 700 transplants were performed in patients 55 years and older in 2006; over 400 of these were RIC approaches. Less toxic conditioning regimens, the use of PBSC grafts, improvement in supportive care, and optimal patient and donor selection have allowed older patients to receive unrelated transplants with some success. With the introduction of RIC preparative regimens and better supportive care, NMDP transplants are now performed in patients over the age of 65 years, and, rarely, in patients over the age of 70 years. The NMDP has facilitated 461 transplants for patients aged 65 to 69 years, and 86 transplants for patients aged 70 years and over. Eighty-three percent of transplants in the patients 65 years and older were PBSC grafts. The most common diseases for these older patients were AML, myelodysplasia (MDS), and lymphoma. Over the past 20 years, transplants have been performed for a wider variety of diseases. The majority of transplants are for hematologic malignancies (89%) (predominantly leukemia and lymphoma) in both adults and children. There has been a trend to fewer transplants for chronic myelogeneous leukemia (CML), with the introduction of oral tyrosine kinase inhibitors such as imatinib. Recently, there has been more interest in transplant for plasma cell disorders [5]. Figures 4 and 5 demonstrate the breakdown by disease for adults and children over time. Severe aplastic anemia (SAA) is the most common indication for transplantation in children among the nonmalignant diseases. Despite the introduction of immunosuppressive therapy, the number of transplants for SAA has increased in the last 10 years (Figure 6). In children, transplants for other nonmalignant conditions included transplants for immune deficiencies and metabolic disorders. Of the 7724 pediatric
250 200 150 100 50
200 0 -1 9 19
19 87
87
-1
98 8 19 89 19 9 19 0 9 19 1 9 19 2 9 19 3 94 19 9 19 5 9 19 6 97 19 98 19 99 20 0 20 0 0 20 1 0 20 2 03 20 04 20 0 20 5 06 20 07
88 19 8 19 9 9 19 0 91 19 92 19 9 19 3 9 19 4 95 19 96 19 97 19 9 19 8 99 20 00 20 01 20 02 20 0 20 3 04 20 05 20 0 20 6 07
0
Year of Transplant
Figure 4. Number of adult transplants for hematologic malignancies.
Year of Transplant
Figure 6. Number of pediatric transplants for nonmalignant diseases.
5
NMDP Overview
90 Severe aplastic anemia
Number of Transplants
80 70 60 50 40 30 20 10
19
87
-1
98 8 19 89 19 9 19 0 9 19 1 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 0 20 3 04 20 05 20 06 20 07
0
Year of Transplant
Figure 7. Number of adult transplants for severe aplastic anemia.
in 1988 and 85 in 2007. Although triple-drug immunosuppressive therapy was introduced as a viable treatment for SAA in 1991, unrelated bone marrow transplantation remains an attractive choice for young patients with SAA, or for those patients who fail immunosuppressive therapy [7-9]. These trends are illustrated in Figure 7. The racial and ethnic composition of the United States has changed in the last 20 years. Census data indicates that in 2000, 69% of Americans we Caucasian. The diversity of both the donor and the recipient pool of the NMDP have changed accordingly [10,11]. Donor issues will be addressed in the chapter on donor activity. In 2007, 552 transplants (16%) were performed in non-Caucasians. These transplants include 172 (5%) in African Americans, 238 (7%) in Hispanics, 92 (3%) in Asian/Pacific Islanders, and 11 (0.3%) in Native Americans (Figure 8). Although numerous advances in donor recruitment and patient access have
Transplant Recipients 1993–1997 API 3% Hispanic 6%
Native 0.3%
Mult/Oth 1% Dec/Unk 1%
Black 4%
been made, the number of African American unrelated transplant recipients in the United States is underrepresented compared to the population as a whole (12% in census 2000 data, 5% of transplant recipients from 2003 to 2007). Ethnically diverse donor recruitment and patient access to transplantation remain challenges that the NMDP is actively addressing, in the following section. As stated above, a major advance over the last 20 years is the ability to transplant older patients successfully. This advance is because of, in large part, the introduction of non-myeloablative or RIC preparative regimens. First pioneered in the related donor setting, these regimens are immunosuppressive, not myeloablative, and better tolerated by patients in terms of organ function, mucositis, and risk of infection [12-14]. Starting in 1999, these RIC transplants have had exponential growth. In 1997, 8% of transplants were reduced-intensity. Presently, reduced-intensity approaches are utilized in approximately half of NMDP-facilitated transplants. Definitions of a nonablative or RIC transplant differ widely; current Center for International Blood and Marrow Transplant Research (CIBMTR) guidelines define regimens with .800 cGy total body radiation (TBI) and .150 mg/ m2 melphalan as myeloablative [15]. Results of the first 285 RIC transplants facilitated by the NMDP were recently reported by Giralt et al. [15]. Patients who received RIC unrelated transplants were older (median 55 years versus 33 years) and had more advanced disease (81% versus 51%) than recipients of myeloablative transplants. The 5-year survival rate was 23%. As expected, patients who were young, with a good performance status, earlier disease stage, and a fully matched donor did best. Further outcome data on RIC transplants will be presented in this issue of the Journal.
Transplant Recipients 2003–2007
Native 0.3% API 3%
Mult/Oth 1%
Dec/Unk 12%
Black 5%
API 4%
Native 0.7%
Mult/Oth 8%
Hispanic 6%
Hispanic 7% Caucasian 85%
U.S. Population Census 2000
Caucasian 72%
Black 12%
Caucasian 69%
Figure 8. Comparison between transplant recipient population and U.S. population. Black 5 Black/African American; API 5 Asian/Pacific Islander; Native 5 American Indian/Alaska Native; Mult/Oth 5 multiple race/other race; Dec/Unk 5 declined/unknown.
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CONTRIBUTIONS OF THE NMDP The contributions of the NMDP in the last 20 years transcend the transplant numbers illustrated above. The program has had extensive influence on the transplant community in areas such as education on unrelated hematopoietic cell transplantation (HSCT), donor and patient safety; information systems, including sophisticated matching algorithms; access to transplantation; patient and donor advocacy; and clinical research activity, most notably with elucidating the level of histocompatibility required between patient and donor for successful outcome. Since 1987, the NMDP has brought its network of centers together at the annual Council Meeting, a dynamic educational event where attendees gain essential training and education on advances in unrelated hematopoietic cell transplantation. Today, the Council Meeting attracts nearly 1000 attendees from over 35 countries. In addition to the annual Council Meeting, the NMDP provides extensive training to new network staff and ongoing training for existing staff through inperson training sessions and Web-based training events. Donor and patient safety is of paramount importance to the NMDP. The NMDP has established standards that govern criteria for participating centers, recruitment of adult and cord blood donors, medical evaluation of donors, and the collection, transportation, processing, and labeling of hematopoietic cells. These standards specify, for example, required donor testing for infectious diseases, the maximum harvest volumes for BM donors and post-donation follow-up for BM and PBSC donors. In addition, the NMDP has developed guidelines that contribute to donor safety. These include calcium replacement guidelines for PBSC donors and guidelines on the number of times a donor may be requested for subsequent donations for the same recipient. Many institutions have adapted these safety parameters for their related donors as well. The NMDP Donor and Patient Safety Monitoring Committee meets 4 times a year to address donor and patient safety concerns. The NMDP is a leader in developing information systems to support its extensive network of centers, patients, and the public. In 1992, the NMDP introduced its proprietary Search Tracking and Registry (STARÔ) computer system that was designed to expedite the process of matching potential donors with patients and improving communication between the NMDP Coordinating Center and its network of centers. The STAR system has evolved over the past 15 years to include sophisticated software applications that support the work performed at transplant centers, donor centers, CB banks, and the NMDP repositories. HapLogicSM, an enhancement to the search algorithm, was implemented in 2006. HapLogic utilizes
K. K. Ballen et al.
mathematic formulas developed by Mori et al. [16] to predict a donor’s or cord blood unit’s (CBU) highresolution match with a patient, thus contributing to a reduction in the number of donors or CBUs requested for testing and to faster identification of a donor or CBU for transplantation. The NMDP maintains a public Web site (www.marrow.org) to provide information to donors, patients and their families, referring physicians, and other interested persons from the public and medical community. Access to transplant for the diverse American population has been a major focus of the NMDP. Donor recruitment campaigns targeted to specific racial and ethnic groups have contributed to the racial and ethnic diversity of the NMDP Registry, whereas educational programs for referring physicians and third party payors have increased access to transplant for patients who otherwise may not have had this treatment option available to them. The Marrow Foundation, the official charitable organization of the NMDP, was established in 1991. Funds raised by The Marrow Foundation provide financial support to help patients through their transplant journey, add fully HLA typed donors to the registry, and fund research. In 2007, The Marrow Foundation provided more than 4 million dollars to help more than 1000 patients manage the cost of transplant. The NMDP established the Office of Patient Advocacy (OPA) in 1991 to assist patients and their families through the process of searching for a donor and transplantation. Today, professional case managers help patients learn about transplantation, review transplant statistics, prepare financial plans, and understand insurance coverage. In 2007, OPA provided service to over 11,500 patients. In 2001, the NMDP formally established a Donor Advocacy Program. This program is designed to provide donors with information about potential complications and help if complications do occur, find answers to donor insurance and financial questions, and overcome barriers to donation. The founders of the NMDP had the foresight to require transplant centers to submit baseline and outcomes data on all NMDP-facilitated transplants, thus establishing a research database from which retrospective outcome analyses could be performed. In addition to recipient outcomes, the NMDP also collected data on donor outcomes. In 1992, the NMDP established a research sample repository that stores blood samples from recipients and their donors. The repository now includes over 16,000 donor/recipient paired samples and is the cornerstone of the immunogenetics research program. In 2004, the NMDP expanded its research focus from unrelated transplantation to include allogeneic related and unrelated transplantation and autologous
NMDP Overview
transplantation when it formed an affiliation with the International Bone Marrow Transplant Registry to create the Center for International Blood and Marrow Transplant Research (CIBMTR). This research organization, with its 17 working committees, is responsible for the design and implementation of retrospective recipient and donor outcomes studies, immunogenetics research, health services research, and prospective clinical trials. In addition to its own prospective clinical trials program, the CIBMTR, together with the NMDP and EMMES Corporation, serves as the data coordinating center for the National Institutes of Health funded Blood and Marrow Transplant Clinical Trials Network (BMT CTN). In 2007, the CIBMTR and NMDP published 59 articles in peer-reviewed journals. The NMDP has grown into a large international organization providing patients with access to over 7 million donors in the NMDP Registry and 10 million donors worldwide. The NMDP continues to face challenges in terms of funding, minority recruitment, and expansion. Nonetheless, the basic principles of donor safety, concern for the patient, and advancement of the field remain paramount. Over 30,000 patients have benefited from this remarkable organization. The articles that follow outline the organization’s achievements in pediatric and adult transplant outcomes, advances in HLA typing, and donor activity and outcomes. ACKNOWLEDGEMENTS Financial Disclosure: Drs. King and Chitphakdithai are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Drs. Ballen, Bolan, Agura, Hartzman, and Kernan have nothing to disclose. REFERENCES 1. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoeitic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390-3400. 2. Daly A, McAfee S, Dey B, et al. Nonmyeloablative bone marrow transplantation: infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant. 2003;9:373-382. 3. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-3485. 4. Section 13. Leukemia. In: Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK, editors. SEER [Surveillance Epidemiology and End Results] Cancer Statistics Review, 1975-2001. Bethesda, MD: National Cancer Institute; 2004.
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5. Ballen KK, King R, Carston M, et al. Outcome of unrelated transplants in patients with multiple myeloma. Bone Marrow Transplant. 2005;35:675-681. 6. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral blood stem-cell transplantation. N Engl J Med. 2000; 343:750-758. 7. Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med. 1991;324:1297-1304. 8. Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colonystimulating factor for severe aplastic anemia: update of the GITMO/EBMT study on 100 patients. Blood. 2000;95: 1931-1934. 9. Deeg HJ, Seidel K, Casper J, et al. Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy. Biol Blood Marrow Transplant. 1999;5:243-252. 10. Baker KS, Hassebroek A, Ballen K, et al. Impact of ethnicity and socioeconomic status on outcome of unrelated donor (URD) hematopoietic stem cell transplantation (HcT). Blood (ASH Annual Meeting Abstracts). 2007;110:3064. 11. Schipper RF, D’Amaro J, Bakker JT, Bakker J, van Rood JJ, Oudshoorn M. HLA gene and haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol. 1997;52: 54-71. 12. Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematologic diseases. Blood. 2003;101: 1620-1629. 13. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756-763. 14. Dey BR, McAfee S, Sackstein R, et al. Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation. Biol Blood Marrow Transplant. 2001;7:604-612. 15. Giralt S, Logan B, Rizzo D, et al. Reduced-intensity conditioning for unrelated donor progenitor cell transplantation: longterm follow-up of the first 285 reported to the National Marrow Donor Program. Biol Blood Marrow Transplant. 2007;13: 844-852. 16. Mori M, Graves M, Milford EL, Beatty PG. Computer program to predict likelihood of finding an HLA-matched donor: methodology, validation, and application. Biol Blood Marrow Transplant. 1996;2:134-144.