KEY WORDS: Human immunodeficiency virus, Bone marrow transplantation, Malignancy, Allogeneic

Transcription

1 Allogeneic Hematopoietic Cell Transplantation in Human Immunodeficiency Virus Positive Patients with Hematologic Disorders: A Report from the Center for International Blood and Marrow Transplant Research Vikas Gupta, 1 Marcie Tomblyn, 2 Tanya L. Pedersen, 3 Harry L. Atkins, 4 Minoo Battiwalla, 5 Ronald E. Gress, 6 Marilyn S. Pollack, 7 Jan Storek, 8 Jill C. Thompson, 3 Pierre Tiberghien, 9 Jo-Anne H. Young, 2 Patricia Ribaud, 10 Mary M. Horowitz, 11 Armand Keating 1 The role of allogeneic hematopoietic cell transplantation (allohct) in human immunodeficiency virus (HIV)- positive patients is not known. Using the Center for International Blood and Marrow Transplant Research database, we retrospectively evaluated 23 HIV-positive patients undergoing matched sibling donor (n 5 19) or unrelated donor (n 5 4) allohct between 1987 and The median age at allohctwas 32 years. Indications for allohctwere diverse and included malignant (n 5 21) and nonmalignant (n 5 2) hematologic disorders. Nine patients (39%) underwent transplantation after 1996, the approximate year that highly active antiretroviral therapy became standard treatment. The median time to neutrophil engraftment was 16 days (range, 7 to 30 days), and the cumulative incidences of grade II-IV acute graft-versus-host disease (agvhd) at 100 days, chronic GVHD (cgvhd), and survival at 2 years were (95% confidence interval [CI] 5 14% to ), 28% (95% CI 5 12% to 48%), and (95% CI 5 14% to ), respectively. At a median follow-up of 59 months, 6 patients were alive. Survival appears to be better in the patients undergoing allohctafter 1996; 4 of these 9 patients survived, compared with only 2 of 14 those undergoing transplantation before These data suggest that allohct is feasible for selected HIV-positive patients with malignant and nonmalignant disorders. Prospective studies are needed to evaluate the safety and efficacy of this modality in specific diseases in these patients. Biol Blood Marrow Transplant 15: (2009) Ó 2009 American Society for Blood and Marrow Transplantation KEY WORDS: Human immunodeficiency virus, Bone marrow transplantation, Malignancy, Allogeneic INTRODUCTION Both autologous and allogeneic hematopoietic cell transplantation (HCT) are valid treatment options in patients with malignant and nonmalignant hematologic disorders. In persons infected with the human immunodeficiency virus (HIV), the incidence of non- Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is remarkably high [1-4], and the risk of other malignancies, such as acute myelogenous leukemia (AML), also appears to be increased [5]. Cancer is now the most common cause of death in HIV-infected From the 1 Division of Haematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; 2 Division of Hematology, Oncology and Transplantation, University of Minnesota Medical Center, Minneapolis, Minnesota; 3 Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota; 4 Clinical Haematology, Ottawa Hospital, Ottawa, Ontario, Canada; 5 Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York; 6 Experimental Transplantation & Immunology Branch, National Institutes of Health, Bethesda, Maryland; 7 Department of Pathology, University of Texas Health Science Center, San Antonio, Texas; 8 Department ofmedicine,universityofcalgary,calgary,alberta,canada; 9 Inserm U-645, Etablissement Français du Sang, Universite de Franche-Comte, Besançon, France; 10 Service de Greffe de Moelle Osseuse, Hôpital Saint Louis, Universite Paris 7, Paris, France; and 11 Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin. Previously presented at the 2007 BMT Tandem Meeting, Keystone, Colorado Financial disclosure: See Acknowledgments on page 870. Correspondence and reprint requests: Vikas Gupta, MD, MRCP, FRCPath, Blood and Marrow Transplant Program, Princess Margaret Hospital, Suite 5-217, 610 UniversityAvenue, Toronto, ON, Canada M5G 2M9 ( vikas.gupta@uhn.on.ca). Received December 11, 2008; accepted March 28, 2009 Ó 2009 Elsevier Inc. All rights reserved /09/ $36.00/0 doi: /j.bbmt

2 Biol Blood Marrow Transplant 15: , 2009 Allogeneic HCT in HIV-Positive Patients 865 persons in regions where highly active antiretroviral treatment (HAART) is widely available [6]. HIV-positive patients often are excluded from consideration for HCT because of concerns about infections and other treatment-related complications. Several recent reports have demonstrated the feasibility and curative potential of autologous transplantation for HIV-associated lymphomas in adults and children, however [7-17]. Although initial reports of allogeneic HCT (allohct) as a primary treatment for HIV infection failed to demonstrate the benefit of this approach, because of either recurrence of HIV infection or treatment-related death [18-20], recent anecdotal reports suggest that allohct may be feasible and beneficial in HIV-positive patients with hematologic malignancies [21-28]. The role of allohct in these patients has not been studied in a - systematic fashion, however. Performing allohct in HIV-positive patients presents several challenges, including significant exposure to opportunistic infections before HCT, a high incidence of concomitant infections (eg, viral hepatitis), complex drug interactions between antiretroviral and transplantation-related medications, and the effects of HIV on T cells, the bone marrow environment, and the cytokine milieu. For these reasons, HIV infection might have an effect on engraftment, regimen-related toxicity, graftversus-host disease (GVHD), infection risk, and survival. We retrospectively evaluated 23 HIV-positive patients who underwent allohct between 1987 and 2003 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The study s primary objective was to determine the clinical outcomes of allohct in HIV-positive patients. Secondary objectives were to evaluate CD4 recovery and viral load (VL) in the posttransplantation period. PATIENTS AND METHODS The study was conducted by the CIBMTR s Infection and Immune Reconstitution Working Committee. Between 1987 and 2003, 50 HIV-positive patients who underwent allohct were reported to the CIBMTR. After eligible patients were identified, the centers were contacted to confirm HIV infection. A total of 31 patients treated at 21 centers were confirmed to be HIVpositive. Of these, 8 patients undergoing transplantation for primary treatment of HIV disease (n 5 5) or from a syngeneic donor (n 5 3) were excluded. The remaining 23 patients, who received a graft from either a matched sibling donor (n 5 19) or an unrelated donor (n 5 4) for a malignant (n 5 21) or nonmalignant (n 5 2) hematologic disorder, were analyzed. Additional information was requested regarding the history of HIV infection, opportunistic infections, antiretroviral therapy, CD4 counts, and VL both pretransplantation and posttransplantation. CIBMTR A formal affiliation of the research division of the National Marrow Donor Program (NMDP) and the International Bone Marrow Transplant Registry at the Medical College of Wisconsin led to the establishment of the CIBMTR in The CIBMTR is a working group comprising more than 500 transplantation centers worldwide that voluntarily contribute data on allogeneic and autologous HCT recipients to a Statistical Center at the Medical College of Wisconsin or the NMDP Coordinating Center in Minneapolis. Participating centers register and provide basic information on all consecutive transplantations, with compliance monitored by onsite audits. Detailed demographic, disease, and transplantation characteristics and outcome data are collected on a sample of registered patients, including all unrelated donor transplantations facilitated by the NMDP in the United States. Patients are followed longitudinally, with yearly follow-up. Computerized error checks, physician review of submitted data, and onsite audits of participating centers ensure data quality. The CIBMTR s observational studies are performed with a waiver of informed consent and in compliance with HIPAA regulations, as determined by the Institutional Review Board and the Privacy Officer of the Medical College of Wisconsin. Definitions and Endpoints Conditioning regimens were defined as myeloablative (MA) and nonmyeloablative (NMA) using the criteria defined by the CIBMTR [29]. At the time of -allohct, performance status (PS) was defined according to the Karnofsky scale for patients age $16 years and according to the Lansky scale for those age \16 years. Primary endpoints were engraftment, acute and chronic GVHD (agvhd, cgvhd), and overall survival (OS). Engraftment was defined as the first of 3 consecutive posttransplantation days on which the neutrophil count exceeded 500/mm 3. agvhd events were any occurrence of grade II, III, or IV skin, gastrointestinal, or liver abnormalities fulfilling the Glucksberg criteria [30]. cgvhd events included symptoms in any organ system fulfilling the criteria for limited or extensive cgvhd [31]. For survival analyses, failure was defined as death from any cause; surviving patients were censored at the time of last follow-up. Statistical Analysis Probabilities of agvhd and cgvhd were calculated using cumulative incidence curves to accommodate competing risks. The competing risk for GVHD was death from any cause. Univariate probabilities of

3 866 V. Gupta et al. Biol Blood Marrow Transplant 15: , 2009 Table 1. Patient, Disease, and Transplantation-Related Characteristics Characteristic n Evaluated n Number of patients Number of centers 17 Median age at allohct, years (range) (9-43) Age at allohct, years 23 # 20 3 (13%) (74%) > 40 3 (13%) Male sex (78%) PS score at allohct 23 # 80 7 () > () Patients with detailed HIV data (57%) Coinfection with hepatitis virus at allohct 10 Hepatitis B surface antigen positive 1 () Hepatitis C virus antibody positive 1 () Timing of diagnosis of HIV infection 13 Before diagnosis of disorder for allohct 4 (31%) At the time of diagnosis of disorder for allohct 3 (23%) After diagnosis of disorder of allohct 2 (15%) Incidental detection during allohct workup 4 (31%) Opportunistic infections before allohct 13 Pneumocystis carinii pneumonia 2 (15%) CMV 4 (31%) Invasive fungal 1 (8%) Mycobacteria 1 (8%) Others 1 (8%) Antiretroviral therapy before allohct 13 Patients undergoing transplantation before None 2 (33%) Monotherapy 3 () Double therapy 1 (17%) Patients undergoing transplantation after None 0 Monotherapy or double therapy 1 (14%) Triple therapy 6 (86%) Indication for allohct 23 Malignant NHL 10 (43%) Low-grade 1 Intermediate 4 High-grade 5 Acute leukemias 7 () Myelodysplastic syndrome/aml 5 Acute lymphoblastic leukemia 1 Biphenotypic acute leukemia 1 CML 4 (17%) Nonmalignant 2 (9%) Aplastic anemia 1 Inherited erythrocyte disorder 1 Median interval from diagnosis of blood (4-172) disorder to allohct, months (range) Year of allohct (61%) (39%) Graft type 23 Bone marrow 18 (78%) Peripheral blood 5 (22%) Donor type 23 HLA-identical sibling 19 (83%) Matched unrelated 4 (17%) Recipient/donor CMV status 23 +/+, +/-, or -/+ 19 (83%) -/- 2 (9%) Unknown 2 (9%) Conditioning regimen 23 Myeloablative CY + TBI ± others 9 (39%) TBI ± others 3 (13%) Bu + CY ± others 6 (26%) (Continued ) Table 1. (Continued) OS were calculated using the Kaplan-Meier estimator. Estimates of standard error for the survival function were calculated using Greenwood s formula, and 95% confidence intervals (CIs) were constructed using log-transformed intervals. Assessment of infections used infection density, defined as the number of infectious episodes per patient days at risk, to account for multiple infections in single patients. Analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC). Data were updated as of July RESULTS Characteristic n Evaluated n Cy ± others 2 (9%) Nonmyeloablative 3 (13%) GVHD prophylaxis 23 CsA/FK-506 ± MTX 16 () MTX ± others 3 (13%) T cell depletion 1 (4%) Others 3 (13%) Bu indicates, busulfan; CsA, cyclosporine; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; CMV, cytomegalovirus; NHL, non-hodgkin leukemia; Cy, high-dose cyclophosphamide; FK- 506, tacrolimus; MTX, methotrexate. Patient and Donor Characteristics Patient, HIV disease, hematologic disorder, and transplantation-related characteristics are summarized in Table 1. The median age of recipients at allohct was 32 years (range, 9 to 43 years). Indications for allografting were diverse and included NHL in 10 patients, AML/myelodysplastic syndrome (MDS) in 5 patients, acute lymphoblastic leukemia (ALL) in 1 patient, biphenotypic acute leukemia (AA) in 1 patient, chronic myelogenous leukemia (CML) in 4 patients, aplastic anemia in 1 patient, and inherited abnormality of erythrocyte differentiation/function in 1 patient. The donors were 19 HLA-identical siblings (83%) and 4 matched unrelated donors (17%). The conditioning regimen was MA in 20 patients (87%) and NMA in 3 patients (13%). Cyclophosphamide (Cy) in combination with either total body irradiation (TBI; n 5 9) or busulfan (Bu; n 5 6) were the most commonly used MA conditioning regimens (Table 1). Most patients (16/23; ) received cyclosporine (CsA)-based GVHD prophylaxis with or without methotrexate (MTX). Nine patients (39%) underwent transplantation after 1996, the approximate time when HAART and VL testing became standard practice. In this subset of patients, the median age was 37 years (range, 30 to 43 years), and disease indications for allohct included CML in 4 patients, NHL in 4 patients, and AML in 1 patient. The donors were 6 HLA-identical siblings (67%) and 3 matched unrelated donors

4 Biol Blood Marrow Transplant 15: , 2009 Allogeneic HCT in HIV-Positive Patients 867 (33%). As expected, the 3 patients who received NMA conditioning underwent transplantation after Diagnosis and History of HIV Infection Details regarding the diagnosis and treatment history of HIV infection and infectious complications before transplantation were provided for 13 patients (57%). The diagnosis of HIV infection was made in 4 of these 13 patients (31%) before the diagnosis of the hematologic disorder for which transplantation was performed. Five patients were diagnosed with HIV either at the time of diagnosis (n 5 3; 23%) or after the diagnosis (n 5 2; 15%) of the hematologic disorder, and 4 patients (31%) were found to be HIV-positive during the allohct workup. Eight of the 9 patients undergoing transplantation after 1996 had detailed HIV information available. Three of these 8 patients were diagnosed with HIV before the onset of the disease for which the transplantation was indicated; the remaining 5 patients were diagnosed with HIV concomitantly with the malignancy (n 5 3), between the onset of malignancy and performance of allohct (n 5 1), or at the time of the allohct workup (n 5 1). Table 1 provides information on opportunistic infections before allohct in all 13 patients. Antiretroviral Therapy Information on antiretroviral therapy before allohct was available for 13 patients. Of the 14 patients who underwent transplantation before 1996, 2 were not on antiretroviral therapy before or during transplantation, and 4 received either monotherapy with zidovudine (n 5 1) or didanosine (n 5 2) or double therapy with didanosine and stavudine (n 5 1). Data were not available on the remaining 8 patients who underwent transplantation before Of the 9 patients undergoing transplantation after 1996, 7 had available data on antiretroviral therapy. All but 1 patient was on triple therapy. Information was provided that 2 patients had planned cessation of their antiretroviral therapy peritransplantation and the therapy was restarted within 1 month posttransplantation. Outcomes of AlloHCT in HIV-Positive Patients Table 2 summarizes the outcomes of HIV-positive patients who underwent allohct. Engraftment Eighteen of the 23 patients achieved neutrophil engraftment, at a median of 16 days (range, 7 to 30 days). Three of the 5 patients who did not achieve engraftment died very early (on days 2, 6, and 10) because of regimen-related toxicity. One patient treated with NMA conditioning and HLA-matched unrelated donor bone marrow transplantation experienced secondary graft failure. Table 2. Outcomes in HIV-Positive Patients Undergoing AlloHCT for Malignant and Nonmalignant Hematologic Disorders Outcome n Evaluated n Median days to neutrophil engraftment (range) (7-30) Cumulative incidence of grade II-IV acute 23% (14%-) GVHD, probability (95% CI) at 100 days Cumulative incidence of chronic GVHD, 23% probability (95% CI) At 1 year 28% (12%-48%) At 2 years 28% (12%-48%) Episodes of infection posttransplantation # 100 days Culture-positive bacterial 10 Invasive fungal 1 Pnemocystis carinii pneumonia 0 CMV reactivation 3 Mycobacteria 0 Hepatitis B or C 1 Others 5 >100 days Culture-positive bacterial 4 Invasive fungal 1 Pnemocystis carinii pneumonia 0 CMV reactivation 0 Mycobacteria 0 Hepatitis B or C 1 Others 2 Median follow-up of survivors, months (range) 6 Before 1996 (n 5 2) 75 (59-90) After 1996 (n 5 4) 51 (23-74) Overall survival, probability (95% CI) 23% At 1 year (14%-) At 2 years (14%-) Primary cause of death 17% Disease relapse 1 (6%) Nonrelapse mortality Regimen-related toxicities Pulmonary toxicity 6 (35%) Other organ toxicities 3 (19%) Graft failure 1 (6%) Infections 4 (24%) GVHD 1 (6%) Others 1 (6%) CMV indicates cytomegalovirus; GVHD, graft-versus-host disease.. GVHD Eight of the 23 patients developed grade II-IV agvhd (5 with grade II, 2 with grade III, and 1 with grade IV). The cumulative incidence of acute GVHD grade II-IV was (95% CI 5 14% to ) at 100 days (Figure 1A). The median time of onset of agvhd was 16 days after allohct (range, 5 to 47 days). The cumulative incidence of cgvhd at 2 years was 28% (95% CI 5 12% to 48%) (Figure 1B). Survival In the 6 surviving patients, the median follow-up was 59 months (range, 23 to 90 months). Kaplan- Meie probabilities of survival were at 57% (95% CI 5 36% to 76%) at 100 days, (95% CI 5 14% to ) at 1 year, and (95% CI 5 14% to ) at 2 years (Figure 2). Four of the 9 patients who underwent transplantation after 1996 survived, compared with only 2 of the 14 patients who underwent transplantation before Primary causes of

5 868 V. Gupta et al. Biol Blood Marrow Transplant 15: , 2009 A Probability B Days After Transplant Probability Months After Transplant Figure 1. Cumulative incidence of acute GVHD (A) and chronic GVHD (B) in 23 patients with HIV undergoing allohct. death are summarized in Table 2. Of particular note, 6 of the 12 patients receiving high-dose TBI-containing conditioning regimens died from pulmonary toxicity. Posttransplantation Infections Detailed data on infections in the posttransplantation period were available for 19 patients and are summarized in Table 2. Culture-positive bacterial Probability Months After Transplant Figure 2. Overall survival of 23 HIV-positive patients undergoing allohct for a hematologic disorder.

6 Biol Blood Marrow Transplant 15: , 2009 Allogeneic HCT in HIV-Positive Patients 869 infections and cytomegalovirus (CMV) reactivation were the 2 most common infection-related events. The infection density for the entire cohort was 1.16 infections per patient during the first 100 days. When analyzed by transplantation period, the infection density in the first 100 days was 0.95 per patient in those who underwent transplantation before 1996 and 1.43 per patient in those who underwent transplantation after CD4 Counts and VL Information on CD4 counts was available for 9 patients, and 7 had data available on both pretransplantation and posttransplantation counts. Among 8 patients with available pretransplantation CD4 counts, the median CD4 count was 173/mL (range, 0 to 1200/mL) at a median of 24 days (range, 11 to 65 days) before transplantation. At 1 month posttransplantation, the median CD4 count was 38/mL (range, 0 to 370/mL). At 1 year posttransplantation, the CD4 counts in the 3 patients assessed were 640, 302, and 503/mL. VL data were submitted for 6 patients, although both pretransplantation and posttransplantation values were available for only 4 patients. Pretransplantation, 4 patients had no detectable virus; the remaining patient had 3.6 log copies. In the 5 patients with available data, the median VL was 1.7 log copies (range, undetectable to 4.4 log copies) at a median of 58 days posttransplantation (range, 28 to 104 days). At 1 year posttransplantation, the VLs in the 3 patients assessed were 1.7, 3.0, and 4.4 log copies. DISCUSSION This is the largest series assessing the outcome of allohct in HIV-positive patients. Primary engraftment was achieved in most of the evaluable patients; 1 patient who underwent NMA transplantation experienced secondary graft failure. This engraftment pattern seems comparable to that seen in HIV-negative patients. The cumulative incidences of agvhd and cgvhd do not differ significantly from those expected in HIV-negative patients. Survival was low in this series, particularly in those patients who underwent transplantation before Major causes of death were regimen-related toxicities and infections. Among the regimen-related toxicities, pulmonary toxicity was common, particularly in those patients receiving high-dose TBI. A high incidence of pulmonary toxicity may be related to opportunistic infections pretransplantation. Data on pretransplantation opportunistic infections were available in 57% of our patients. Because of the limited sample size, the impact of opportunistic infections on posttransplantation outcomes could not be assessed. Modern supportive care strategies and conditioning regimens with lower toxicity may reduce regimen-related toxicities. The risk of posttransplantation infections may be greater in HIV-positive patients compared with HIV-negative patients, although this increased risk was not evident in our cohort, in which the infection density was just slightly greater than 1 infection per patient in the first 100 days posttransplantation. CD4 count and VL data during the posttransplantation period were available for only 3 patients. These 3 patients exhibited a decrease in CD4 count between pretransplantation and 1 month posttransplantation and subsequent slow recovery to. 300/mL at 1 year posttransplantation. The recovery did not appear to be slower in the HIV-positive patients than in the HIV-negative patients; in HIV-negative marrow recipients, CD4 counts typically recover to. 200/mL by 1 year [32]. Our study is limited by small number of patients treated in the post-haart era and incomplete CD4 count and VL data. Nevertheless, survival appears to be better in the patients treated after 1996 than in those treated before This is presumably because of the effect of better supportive care strategies and the routine use of HAART, which became standard at around this time. This study demonstrates that some patients treated for various malignant and nonmalignant hematologic disorders achieved long-term disease control. Because of our heterogeneous study population, drawing conclusions about the efficacy of this treatment modality for a particular disease is difficult. The availability of HAART apparently has led to a trend toward increasing use of autologous transplantation in HIV-positive patients with lymphoma, although these patients still rarely undergo allohct. This may be related to the hesitancy of physicians to use this modality because of concerns about high treatment-related mortality (TRM) and lack of published data. Accumulating data on solid organ transplantation indicate that transplantation outcomes in HIV-positive patients are not inferior to those in HIV-negative patients [33,34]. A recent study using kidney transplantation data from the United Network for Organ Sharing found comparable graft and patient survival in 38 HIV-positive patients and HIV-negative patients [34]. Thus, there is increasing debate regarding the ethical justifications of excluding HIV-positive patients from transplantation and cancer clinical trials [35]. Many researchers believe that the situation of a well-controlled HIV infection is no different from medical comorbidities requiring regular treatment. In summary, our data demonstrate that despite early toxicity because of conditioning regimens and the risk of opportunistic infections, several patients achieved prolonged survival. Given the improvements in supportive care, the availability of conditioning regimens with lower toxicity, and the ability to suppress HIV VL with currently available medical care, allohct should not be dismissed as a treatment

7 870 V. Gupta et al. Biol Blood Marrow Transplant 15: , 2009 option in HIV-positive patients with hematologic disorders for which allohct is considered the therapy of choice. Prospective studies are needed in HIV-positive patients to evaluate the efficacy of this modality in specific diseases and identify optimal transplantation and antiretroviral strategies. ACKNOWLEDGMENTS Financial disclosure: This project was supported by funding from the National Marrow Donor Program and the Health Resources and Services Administration (Contracts and , to the National Marrow Donor Program). The views expressed in this article do not reflect the official policy or position of the Health Resources and Services Administration or the National Marrow Donor Program. The authors thank the data managers at the participating transplantation centers, whose diligence in obtaining and reporting the data made this study possible. The CIBMTR is supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; the Office of Naval Research; the Health Resources and Services Administration; and grants from AABB, Aetna, American International Group, American Society for Blood and Marrow Transplantation, Amgen, an anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Baxter International, Bayer HealthCare Pharmaceuticals, BioOne, Blood Center of Wisconsin, Blue Cross and Blue Shield Association, Bone Marrow Foundation, Bristol-Myers Squibb, Cangene, Celgene, CellGenix, Cerus, Cubist Pharmaceuticals, Cylex, CytoTherm, DOR BioPharma, Dynal Biotech, EKR Therapeutics, Enzon Pharmaceuticals, Gambro BCT, Gamida Cell, Genzyme, Gift of Life Bone Marrow Foundation, GlaxoSmithKline, Histogenetics, HKS Medical Information Systems, Hospira, Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co, Merck & Company, Medical College of Wisconsin, MGI Pharma, Millennium Pharmaceuticals, Miller Pharmacal Group, Milliman USA, Miltenyi Biotec, MultiPlan, National Marrow Donor Program, Nature Publishing Group, Oncology Nursing Society, Osiris Therapeutics, Pall Life Sciences, PDL BioPharma, Pfizer, Pharmion, Roche Laboratories, Schering Plough, Society for Healthcare Epidemiology of America, StemCyte, StemSoft Software, SuperGen, Sysmex, Teva Pharmaceutical Industries, The Marrow Foundation, THERAKOS, University of Colorado Cord Blood Bank, ViaCell, Vidacare, ViraCor Laboratories, ViroPharma, and Wellpoint. 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