National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction

Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile

Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation to Treat Patients with Poor-Risk, Relapsed, or Refractory Multiple Myeloma

AbstractThe purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m2) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value = .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival

TNF-Receptor Inhibitor Therapy for the Treatment of Children with Idiopathic Pneumonia Syndrome. A Joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521)

AbstractIdiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS

Outcome of transplantation for acute lymphoblastic leukemia in children with down syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106900/1/pbc24918.pd

allogeneic hematopoietic cell transplantation hct in the eighth decade of life how much does age matter

n/

Outcome of Transplantation for Acute Myelogenous Leukemia in Children with Down Syndrome

AbstractData on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors

BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, −3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute–National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.

Health-Related Quality of Life among Older Related Hematopoietic Stem Cell Donors (>60 Years) Is Equivalent to That of Younger Related Donors (18 to 60 Years): A Related Donor Safety Study

The increasing number of older adults with blood-related disorders and the introduction of reduced intensity conditioning regimens has led to increases in hematopoietic stem cell (HSC) transplantation among older adults and a corresponding increase in the age of siblings who donate HSCs to these patients. Data regarding the donation-related experiences of older donors is lacking. The Related Donor Safety Study (RDSafe) aimed to examine/compare health-related quality of life (HRQoL) of older versus younger HSC donors. 60 peripheral blood stem cell (PBSC) donors ages 18–60 and 104 PBSC donors age >60 completed validated questionnaires at pre-donation, 4 weeks and 1 year post-donation. Prior to donation, older donors had poorer general physical health (t=−3.27; p=.001) but better mental health (t=2.11; p<.05). There were no age differences in multiple other donation-related factors. At 4 weeks post-donation, there were no group differences in general physical/mental health, but older donors were less likely to report donation-related pain (t=−2.26; p<.05) and concerns (t=−3.38; p=.001). At both 4 weeks and 1 year post-donation, there were no significant differences in the percentage of each age group feeling physically back to normal or in the number of days it took donors to feel completely well. There was no evidence that increasing age within the older donor group was associated with poorer donation-related HRQoL. Taken together, these data support the current practice of HSC donation by sibling donors above age 60, providing no evidence of worsening HRQoL up to one year after donation in individuals up to age 76