Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program.

Limited data are available describing donor adverse events (AEs) associated with filgrastim mobilized peripheral blood stem cell (PBSC) collections in unrelated volunteers. We report results in 2408 unrelated PBSC donors prospectively evaluated by the National Marrow Donor Program (NMDP) between 1999 and 2004. Female donors had higher rates of AEs, requiring central line placement more often (17% vs 4%, P< .001), experiencing more apheresis-related AEs (20% vs 7%, P< .001), more bone pain (odds ratio [OR]=1.49), and higher rates of grades II-IV and III-IV CALGB AEs (OR=2.22 and 2.32). Obese donors experienced more bone pain (obese vs normal, OR=1.73) and heavy donors had higher rates of CALGB toxicities (>95 kg vs <70 kg, OR=1.49). Six percent of donors experienced grade III-IV CALGB toxicities and 0.6% experienced toxicities that were considered serious and unexpected. Complete recovery is universal, however, and no late AEs attributable to donation have been identified. In conclusion, PBSC collection in unrelated donors is generally safe, but nearly all donors will experience bone pain, 1 in 4 will have significant headache, nausea, or citrate toxicity, and a small percentage will experience serious short-term adverse events. In addition, women and larger donors are at higher risk for donation-related AEs.

Methodological and logistical considerations to study design and data collection in racial/ethnic minority populations evaluating outcome disparity in hematopoietic cell transplantation.

Outcome disparity associated with race or ethnicity in the United States has been observed in hematopoietic cell transplantation (HCT). The underlying reasons for such disparity are not known. In the United States, an optimal study of health care disparity by race or ethnicity involves consideration of both biologic and psychosocial determinants, which requires an adequately powered, prospective cohort study design. To better characterize the nature and quantify the magnitude of the many impediments relevant to conducting a successful prospective study involving racial or ethnic minorities in HCT, we conducted a feasibility study to help guide planning of a larger scale outcome and disparity study in HCT. The primary questions to be addressed in the study were: (1) can we establish a racially or ethnically diverse patient sample that will respond to a survey focused on sociodemographic, economic, health insurance, cultural, spiritual, and religious well-being, and social support information? (2) What is the retention rate in the study over time? (3) What is the quality of the data collected from the patients over time? The challenges we faced in conducting this multicenter feasibility study are summarized in this report. Despite the difficulty in conducting disparity studies in racial and ethnic minorities, such studies are essential to ensure that people of all ethnic and racial backgrounds have the best chance possible of benefiting from HCT.

Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide.

We have reported a lower incidence of acute graft-versus-host disease (aGVHD) with a novel conditioning regimen using low-dose rabbit antithymocyte globulin (ATG; Thymoglobulin [TG]) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single-center experience, we performed a retrospective matched-pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). One hundred twenty cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (TRM; 12% versus 34%, P < .001) and grades II-IV aGVHD (15% versus 34%, P < .001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% versus 20%, P < .001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and TRM after HLA-identical sibling HSCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials.

Successful coordination and execution of nontherapeutic studies in a cooperative group setting: lessons learned from Children's Oncology Group studies.

The immense progress made in childhood cancer survival has been due to the systematic and efficient conduct of large multicenter therapeutic trials, using the infrastructure developed by national cooperative groups. These therapeutic trials have been successful, in part due to the high participation rates by the participating member institutions. However, participation in nontherapeutic trials in the cooperative group setting has lagged behind that of therapeutic trials for a variety of reasons, such as lack of institutional resources, leading to low priority given to such activities. The purpose of this report is to share some of the methods developed and successfully implemented by a coordinating center (City of Hope National Medical Center) to maximize institutional participation and patient enrollment and to standardize data collection and quality control, in order to ensure the successful execution of two large, extramurally funded, cooperative group nontherapeutic studies. To date, over 175 institutions have obtained regulatory approval for the protocols showcased here, accrual has been on target, and completeness and quality of the collected data have been excellent. The successful execution of these nontherapeutic studies shows the advantages of diverse study publicity techniques, detailed standardized operating procedures, and effective utilization of technological resources.

Access to hematopoietic stem cell transplantation: effect of race and sex.

BACKGROUND: The purpose of the current study was to determine whether the use of hematopoietic stem cell transplantation (HCT) to treat leukemia, lymphoma, or multiple myeloma (MM) differs by race and sex. METHODS: The annual incidence of leukemia, lymphoma, and MM was estimated in the United States in people aged <70 years by race and sex using the Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1997 and 2002 and US census reports for the year 2000. The annual incidence of autologous, human leukocyte antigen (HLA) identical sibling, and unrelated HCT performed in these groups was estimated using Center for International Blood and Marrow Transplant Research data from 1997 through 2002. Logistic regression analysis was used to calculate the age-adjusted odds ratio (OR) of receiving HCT for Caucasians versus African Americans and for men versus women. RESULTS: The likelihood of undergoing HCT was found to be higher for Caucasians than for African Americans (OR, 1.40; 95% confidence interval [95% CI], 1.34-1.46). This difference existed for each type of HCT: autologous (OR, 1.24; 95% CI, 1.19-1.30), HLA identical sibling (OR, 1.59; 95% CI, 1.46-1.74), and unrelated donor (OR, 2.02; 95% CI, 1.75-2.33). Overall, men were more likely than women to receive HCT (OR, 1.07; 95% CI, 1.05-1.1 [P<.0001]); however, this difference was found to be significant only for autologous HCT (OR, 1.10; 95% CI, 1.07-1.13 [P<.0001]). CONCLUSIONS: HCT is more frequently used to treat leukemia, lymphoma, and MM in Caucasians than in African American individuals. African Americans have lower rates of both autologous and allogeneic HCT, indicating that donor availability cannot fully explain the differences. Women are less likely than men to receive autologous HCT for reasons unexplained by age or disease status.

Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation.

BACKGROUND: Avascular necrosis (AVN) is a debilitating condition reported after chronic steroid use. The purpose of this study was to describe the magnitude of risk in individuals who survived >or=1 years after hematopoietic cell transplantation (HCT), and to investigate the role of immunosuppressive agents such as prednisone, tacrolimus (FK506), mycophenolate mofetil (MMF), and cyclosporine (CSA) in the development of AVN after HCT. METHODS: Using a retrospective study design, the authors followed 1346 eligible patients for the development of AVN. Cumulative incidence was calculated taking into consideration competing risk from death and disease recurrence. Cox proportional regression techniques were used to identify associated risk factors. RESULTS: The median age at HCT was 34 years (range, 7 months-69 years), and median length of follow-up for those surviving was 8.2 years. Seventy-five patients developed AVN of 160 joints. The cumulative incidence of AVN at 10 years was 2.9% after autologous HCT, 5.4% after allogeneic matched related donor HCT, and 15% after unrelated donor HCT (P<.001 compared with autologous HCT recipients). For allogeneic transplant recipients, male sex (relative risk [RR], 2.1; 95% confidence interval [95% CI], 1.1-4.0); presence of chronic graft-versus-host disease (RR, 2.2); and exposure to CSA, FK506, prednisone, and MMF rendered patients at increased risk, especially in patients with a history of exposure to >or=3 drugs (RR, 9.2; 95% CI, 2.42-35.24). CONCLUSIONS: Future studies examining the pathogenetic mechanism underlying AVN should help develop targeted interventions to prevent this chronic debilitating condition.

Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation.

BACKGROUND: The authors investigated the risk of delayed chronic kidney disease (CKD) in 1190 adult hematopoietic cell transplantation (HCT) survivors who underwent HCT for hematologic malignancies or aplastic anemia between 1976 and 1997 and survived for at least 1 year. METHODS: CKD was defined as a sustained elevation of serum creatinine that indicated a glomerular filtration rate of <60 mL per minute per 1.73 m2 for > or =3 months. The median age at HCT was 35 years (range, 18.1-68.6 years), and the median length of follow-up was 7.1 years after HCT (range, 1-24.3 years). RESULTS: Sixty patients with CKD were identified, resulting in a cumulative incidence of 4.4% at 5 years (autologous HCT, 3.8%; matched-sibling HCT, 4.5%; unrelated donor HCT, 10%; P = .09 compared with autologous HCT). Older age at HCT (relative risk [RR] per 5-year increment, 1.33; 95% confidence interval [CI], 1.2-1.5), exposure to cyclosporine without tacrolimus (RR, 1.90; 95% CI, 1.1-3.4) or with tacrolimus (RR, 4.59; 95% CI, 1.8-11.5), and a primary diagnosis of multiple myeloma (RR, 2.51; 95% CI, 1.1-5.6) were associated with an increased risk of delayed CKD. CONCLUSIONS: In this study, the authors identified a subpopulation of patients who underwent HCT and remained at increased risk for CKD. The current findings set the stage for appropriate long-term follow-up of vulnerable patients.

Late congestive heart failure after hematopoietic cell transplantation.

PURPOSE: To examine the independent roles of pre-hematopoietic cell transplantation (HCT) therapeutic exposures, transplantation-related conditioning, and comorbidities (pre- and post-HCT) in the development of late congestive heart failure (CHF) after HCT. METHODS: This was a nested case-control design. Individuals with late CHF (diagnosed >or= 1 year after HCT) were identified from a cohort of 2,938 1+ year survivors who underwent transplantation at City of Hope National Medical Center, Duarte, CA. This cohort formed the sampling frame for selecting controls (without CHF) matched for age and year of HCT, donor source (allogeneic v autologous), and length of follow-up. RESULTS: Sixty patients with late CHF were identified; median age at HCT was 45.3 years (range, 16.6 to 68.6 years); median time to CHF was 3.0 years (range, 1.03 to 18.9 years); 68% received autologous HCT. Median ejection fraction was 36.9% (range, 15% to 53%). Compared with matched controls (n = 166), patients with late CHF received more cycles of pre-HCT chemotherapy (8.6 v 4.9 cycles; P < .01), had greater body mass index at HCT (28.4 v 26.2 kg/m(2); P = .01), greater lifetime anthracycline exposure (285.3 v 175.6 mg/m(2); P < .01), and were more likely to have multiple chronic comorbidities (30.0% v 13.9%; P < .01). Multivariable analysis revealed number of pre-HCT chemotherapy cycles (odds ratio [OR] = 1.2; P < .01), anthracycline dose >/= 250 mg/m(2) (OR = 3.2; P = .05), and two or more chronic comorbidities (OR = 4.3; P = .01) to be independently associated with late CHF. CONCLUSION: Pre-HCT exposure to anthracyclines and presence of comorbidities are primarily responsible for the risk associated with late CHF after HCT. Conditioning-related therapeutic exposure does not contribute significantly to the risk. These results form the basis for identifying high-risk individuals for targeted surveillance, as well as developing preventive strategies in the form of aggressive management of comorbidities.