Hematopoietic Cell Transplantation Procedures Research Articles

Increased clonal hematopoiesis in long-term survivors of pediatric hematopoietic cell transplantation.

In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors and 258 non-transplanted controls. CH was detected in 16% of HCT recipients and 8% of controls, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older hematopoietic age (odds ratio: 1.07, p<0.001) and the HCT procedure (odds ratio: 2.53, p=0.02) independently increased the risk of CH, indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after a cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.

Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit.

Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3vs. 94.1%; p = .57) and bacterial infections (34.6vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39vs. 34; p = .002). Detection rates of resistant organisms were overall low. In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.

Expanding the scope of the infectious diseases pharmacist in HCT: Beyond antimicrobial stewardship.

Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population. This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.

A retrospective case–control study of gastrostomy use in children undergoing hematopoietic cell transplantation

Maintaining a good nutritional status during the hematopoietic cell transplantation (HCT) procedure is challenging in the pediatric population. In a multicentric retrospective study, we compared the outcome of nutritional status and HCT-related parameters in 227 pediatric patients during and after HCT between 2005 and 2015. 112 patients received a gastrostomy before the start of HCT (GS group), and 115 did not receive a gastrostomy (NGS). Data collection was performed at HCT, 3, 6, and 12 months post-HCT. At time point of HCT the Standard Deviation Score (SDS) of weight was 0.17 in the NGS group, and 0.71 in the GS group (p = .01) Patients in the NGS group lost more weight during the first 3 months after HCT than patients in the GS group. At 12 months, patients in the NGS remained at a lower weight, while patients in the GS group slightly increased their weight. There were no differences between the groups in the incidence of acute graft-versus-host-disease (GvHD), overall survival, and non-relapse mortality. However, the number of febrile episodes requiring intravenous treatment with antibiotics, was higher in the GS group as compared to the NGS group, during the first 3 months post-HCT (p < .001). Our results indicate that gastrostomy can be utilized in children undergoing HCT without any negative effects on mortality. Therefore, the use of a gastrostomy appears to be a safe option to maintain a good nutritional status during the HCT procedure.

The soluble VCAM-1 level is a potential biomarker predicting severe acute graft versus host disease after allogeneic hematopoietic cell transplantation

BackgroundSevere graft versus host disease (GVHD) is the main reason for non-relapse mortality following allogeneic hematopoietic cell transplantation (HCT). We investigated the serum protein profiles of patients who had undergone HCT to identify predictive biomarkers of severe acute GVHD (aGVHD).MethodsSerum samples were collected for 30 patients from day − 7 to day + 14 of HCT. The serum levels of plasma beta2-microglobulin (β2-MG), soluble vascular cell adhesion molecule-1 (sVCAM-1), platelet factor 4, and TNFSF-14 were measured by ELISA as potential biomarkers following 310 cytokine profiling array.ResultsThe median age of the study patients was 53.5 years (range, 19–69). All grade and grade 2–4 aGVHD developed in 21 (70.0%) and 17 (56.7%) patients, respectively. Compared with their baseline levels on day − 7, β2-MG and sVCAM-1 were significantly increased on day + 14 of the HCT procedure (P = 0.028 and P < 0.001, respectively). Patients with a grade 2–4 severe aGVHD showed a significantly higher sVCAM-1 level at baseline (day-7) and at day + 14, compared with the other group with a grade 1 aGVHD or no aGVHD (P = 0.028 and P = 0.035, respectively).ConclusionHigher sVCAM- levels at baseline and on day + 14 in HCT patients could be a significant predictive biomarker of severe aGVHD.

Hematopoietic cell transplantation in adults with acute myeloid leukemia: A review of the results from various nationwide registry studies in Japan.

Hematopoietic cell transplantation (HCT) is an integral part of the treatment of acute myeloid leukemia (AML). Although AML is the most common indication for allogeneic HCT, the relatively small number of patients and the highly complex nature of the procedure often render prospective studies on HCT unfeasible. Observational studies using registry data serve as important sources of information under such circumstances. Thus, the Japanese Society of Hematopoietic Cell Transplantation (JSHCT) has been conducting a nationwide survey of HCT since 1993, and this registration program now covers >99% of transplantation centers in Japan. A constant increase in the number of HCT procedures has been noted with recent annual registrations recording more than >1,000 new AML patients undergoing allogeneic or autologous HCT. Since its establishment in 2010, the Adult AML Working Group within the JSHCT has been using this registry data to complete several studies focusing on various aspects of HCT in adults with AML, with particular attention paid to patient-, disease-, and transplantation-related factors. This article comprehensively reviews the results obtained from these studies and discusses the strengths and limitations of these kinds of registry-based studies.

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization.

Hematopoietic cell transplantation (HCT) is often a last resort, but potentially curative treatment option for children suffering from hematological malignancies and a variety of non-malignant disorders, such as bone marrow failure, inborn metabolic disease or immune deficiencies. Although efficacy and safety of the HCT procedure has increased significantly over the last decades, the majority of the patients still suffer from severe acute toxicity, viral reactivation, acute or chronic graft-versus-host disease (GvHD) and/or, in case of malignant disease, relapses. Factors influencing HCT outcomes are numerous and versatile. For example, there is variation in the selected graft sources, type of infused cell subsets, cell doses, and the protocols used for conditioning, as well as immune suppression and treatment of adverse events. Moreover, recent pharmacokinetic studies show that medications used in the conditioning regimen (e.g., busulphan, fludarabine, anti-thymocyte globulin) should be dosed patient-specific to achieve optimal exposure in every individual patient. Due to this multitude of variables and site-specific policies/preferences, harmonization between HCT centers is still difficult to achieve. Literature shows that adequate immune recovery post-HCT limits both relapse and non-relapse mortality (death due to viral reactivations and GvHD). Monitoring immune parameters post-HCT may facilitate a timely prediction of outcome. The use of standardized assays to measure immune parameters would facilitate a fast comparison between different strategies tested in different centers or between different clinical trials. We here discuss immune cell markers that may contribute to clinical decision making and may be worth to standardize in multicenter collaborations for future trials.

Incidence of viral and fungal complications after utilization of alternative donor sources in hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) remains the only curable option for adult patients with hematologic malignancies. According to guidelines published by the American Society for Transplantation and Cellular Therapy, allogeneic HCT should be offered to all intermediate- and high-risk patients with acute leukemia. While matched-related donor (MRD) grafts continue to be the preferred stem cell source for allogeneic HCT, studies comparing MRD grafts to matched-unrelated donor (MUD) grafts showed comparable outcomes in patients with acute leukemia. Unfortunately, for those without a suitable matched-related graft, the probability of finding a suitable matched-unrelated donor varies significantly depending on racial and ethnic background. With allogeneic HCT procedures increasing year after year due to the increased availability of suitable donors, each of these alternative donor sources merits special clinical considerations, specifically with regard to infections. Infections remain a significant cause of morbidity and mortality after allogeneic transplant, especially in those receiving alternative donor grafts. Due to the high-risk nature associated with these donor grafts, it is important to understand the true risk of developing infectious complications. While there are a multitude of infections that have been described in patients post-allogeneic HCT, this review seeks to focus on the incidence of cytomegalovirus (CMV) and invasive fungal infections (IFI) in adult patients receiving alternative donor source transplantation for hematologic malignancies.

Epidemiology, Outcome and Risk Factors Analysis of Viral Infections in Children and Adolescents Undergoing Hematopoietic Cell Transplantation: Antiviral Drugs Do Not Prevent Epstein-Barr Virus Reactivation.

ObjectiveThe analysis of epidemiology, risk factors and outcome of viral infections in children and adolescents after hematopoietic cell transplantation (HCT).MethodsIn this multicenter nationwide study a total of 971 HCT procedures (741 allo-HCT; 230 auto-HCT) over a period of 6 years were analyzed.ResultsDuring this period 801 episodes of viral infections were diagnosed in 442 patients. The incidence of viral infections was 57.9% in allo-HCT and 4.8% in auto-HCT patients. The most frequent infections after allo-HCT were caused by cytomegalovirus (CMV), polyoma BK virus (BKV) and Epstein–Barr virus (EBV). The majority of infections occurred within the first 4 months after allo-HCT and over 80% required pharmacotherapy or symptomatic therapy. The median time of treatment of specific viral infection ranged from 7 (for EBV) to 24 (for CMV) days. The highest mortality was observed in case of CMV infection. The risk factors for viral infections were allo-HCT, acute leukemia, acute and chronic graft versus host disease (a/cGVHD), and matched unrelated donor (MUD)/mismatched unrelated donor (MMUD)-HCT. The risk factor for death from viral infection were CMV-IgG seropositivity in acute lymphoblastic leukemia recipient, and MUD/MMUD-HCT. The incidence of EBV infection requiring pre-emptive treatment with rituximab in allo-HCT children was 19.3%. In 30.8% cases of EBV infection, these episodes were preceded by other viral infection and treated with antivirals, which did not prevent development of EBV-DNA-emia with need of rituximab treatment in 81.5% cases. In 47.7% of these cases, GVHD was a factor enabling development of significant EBV-DNA-emia during antiviral therapy of other infection.ConclusionWe have shown that antiviral drugs do not prevent EBV reactivation in allo-HCT pediatric patients.

Hematopoietic Cell Transplantation and Utilization of Fertility Preservation Services.

Conditioning regimens for hematopoietic cell transplantation (HCT) are harmful to reproductive function, but national utilization of fertility preservation (FP) before HCT has not been studied. The primary aim of this descriptive retrospective analysis is to understand FP utilization in the HCT population of patients between ages 18 and 40 years, whereas the secondary aim is to describe temporal trends in FP before HCT. Key dates, procedures codes, and diagnosis codes were extracted from administrative and health services commercial claims data, which were obtained from FAIR Health's national claims database, to construct 29 patient-specific clinical journey timelines detailing the time from diagnosis to FP and to HCT. Patient characteristics studied include sex, age, HCT type (autologous and allogeneic), and census region. Key findings from primary and secondary analyses were that 7% of the HCT cohort had claims for FP services, FP utilization before HCT decreased with increasing age, there were 102 days (median) between FP and HCT procedure date, and 7 of 29 patients who received FP services had a nonmalignant primary indication for HCT. More research is needed to understand the barriers to FP before HCT so that targeted tools can be used to increase utilization and improve quality of life for HCT survivors.

Recommendations from the European Society for Blood and Marrow Transplantation (EBMT) for a curriculum in hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) is increasingly used worldwide. This treatment approach is complex and requires specific knowledge and training. The European Society for Blood and Marrow Transplantation (EBMT) identified the need for a set of international recommendations for the clinical training of physicians to qualify them as being competent in performing HCT procedures as well as novel cellular immune therapies and taking care of such patients. The goal is to implement an EBMT HCT-focused global curriculum (EBMT-GC) that can serve as a tool for the development of the HCT sub-specialty worldwide. Despite the diversity and heterogeneity of health and educational systems around the globe, this set of recommendations can be fairly adopted by any national educational and health authorities and can be adjusted to specific conditions and resources of a given country, if needed. The ultimate goal of the EBMT-GC is to define standards for personal knowledge in allogeneic stem cell transplantation for physicians worldwide in order to ensure that all patients will receive treatment by well-trained physicians.

Current Use of and Trends in Hematopoietic Cell Transplantation in the United States.

Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and nonmalignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Overall, compared with 2017, the number of allogeneic HCTs performed in the United States increased by 1%, and the number of autologous HCTs decreased by 5%. Key findings are fewer autologous HCTs performed for non-Hodgkin lymphoma and increasing numbers of haploidentical HCTs, nearly all of which use post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in HCT in adults age >70 years, particularly for acute myelogenous leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type, and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the United States.

Hospitalizations and Mortality Associated with dsDNA Viral Infections Among Hematopoietic Cell Transplant Recipients

Introduction: Hematopoietic cell transplant (HCT) recipients who experience reactivation or primary infections with double-stranded DNA (dsDNA) viruses such as cytomegalovirus (CMV), varicella zoster (VZV), Epstein-Barr virus (EBV) and BK virus (BKV) suffer substantial morbidity and mortality. The objective of this study was to examine the frequency of dsDNA viral infections during the index hospitalization for HCT. In addition, hospital length of stay (LOS) and the frequency of hospital readmission and mortality were assessed among HCT recipients who had dsDNA viral infections during hospitalization for HCT in comparison those who did not.Methods: Patients who underwent HCT between January 2009 and September 2013 were identified from the hospital discharge records of the Premier Hospital database based on ICD-9-CM diagnosis codes. The hospitalization with the HCT procedure was defined as the index hospitalization. HCT recipients were grouped into two study cohorts: patients with a dsDNA viral infection during the index hospitalization and those without. Demographics, clinical characteristics, and hospital LOS during the index hospitalization were evaluated. Mortality during the index hospitalization was evaluated, as well as readmission mortality and hospital readmission frequency during a 12-month period following the index HCT hospitalization.Results: Among the overall study population of HCT recipients (n=4,495; mean age: 50.4 years), 58% were male and 91% were ≥18 years of age. Of the overall study population, 2,798 patients received autologous HCT (62%) and 1,697 patients received allogeneic HCT (38%). Most patients received HCT in urban (94%), large (≥600 beds: 66%), teaching hospitals (88%). As identified by ICD-9-CM coding, 7.4% (n=332; mean age: 41 years) of the study population had a dsDNA viral infection during their index hospitalization and 92.6% (n=4,163; mean age: 51 years) did not. Among patients with a dsDNA viral infection, the most frequent virus infections were CMV (41%), herpes simplex virus (HSV, 28%), VZV (15%), BKV (11%), and human herpes virus (7%). LOS during the index HCT hospitalization was significantly greater for patients with a dsDNA viral infection vs. those without (43 vs. 23 days, p<0.001). A significantly higher proportion of patients died among those who had a dsDNA viral infection during the index hospitalization (12.1%, n=40) compared with 2.8% (n=117, p<0.001) of patients who did not have a clinically recorded dsDNA viral infection. Among the patients who survived the index hospitalization, mortality was also significantly higher over the subsequent 12 months among patients who had a dsDNA viral infection reported during the index hospitalization vs. those who did not have a reported viral infection (15% vs. 9%, p=0.002). In addition, a greater proportion of patients who had a dsDNA viral infection during the index hospitalization were readmitted over the next 12 months for a dsDNA viral infection (18% with vs. 9% without a dsDNA infection during the index hospitalization, p<0.001); specific infections cited among the two patient groups were CMV (11% vs. 6%, p<0.001) and BKV (4% vs. 1%, p<0.001).Conclusions: Patients who had a dsDNA viral infection during their initial HCT hospitalization had significantly higher rates of hospital readmission and mortality in comparison to patients who did not have a dsDNA viral infection during their HCT hospitalization. Therapeutic strategies that can decrease the risk of reactivation or primary dsDNA viral infections have the potential to significantly impact mortality and morbidity, as well as healthcare resource use associated with hospital readmissions. DisclosuresMozaffari:Chimerix Inc.: Employment, Equity Ownership. Lin:Novosys Health: Employment; Chimerix, Inc.: Consultancy; Daiichi Sankyo, Inc: Consultancy; Bristol-Myers Squibb: Consultancy. Lingohr-Smith:Daiichi Sankyo, Inc: Consultancy; Bristol-Myers Squibb: Consultancy; Chimerix, Inc.: Consultancy; Novosys Health: Employment.

Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen

Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens are increasingly used for the hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases. Early experience suggests that these regimens are associated with good survival but a high incidence of mixed chimerism, which we have previously shown to be influenced by the alemtuzumab schedule. We hypothesized that the underlying diagnosis and donor graft source would also affect the development of mixed chimerism and that the majority of patients would survive RIC HCT without graft loss. To examine this, we conducted a retrospective study of 206 patients with metabolic diseases, non-Fanconi anemia marrow failure disorders, and primary immune deficiencies who underwent 210 consecutive RIC HCT procedures at Cincinnati Children's Hospital. Ninety-seven percent of the patients engrafted. Mixed donor and recipient chimerism developed in 46% of patients. Patients with marrow failure had a low risk of mixed chimerism (hazard ratio [HR], .208; 95% confidence interval [CI], .061 to .709; P = .012). The risk of mixed chimerism was high in patients who received a cord blood graft (HR, 3.122; 95% CI, 1.236 to 7.888; P = .016). As expected, patients who received a proximal or higher dose per kilogram of alemtuzumab schedule also experienced higher rates of mixed chimerism (all HR > 2, all P < .05). At the time of last follow-up (median, 654 days; range, 13 to 3337), over 75% of patients had greater than 90% whole blood donor chimerism. A second transplantation was performed in 5% of patients. Three-year survival without retransplantation was 84% (95% CI, 71% to 98%) for patients who underwent transplantation with an HLA-matched sibling donor. Survival without retransplantation was negatively affected by lack of a matched related donor, increasing age, and development of grades III and IV acute graft-versus-host disease. We conclude that alemtuzumab, fludarabine, and melphalan RIC HCT offers good results for many patients and that the risk of developing mixed chimerism is influenced by underlying diagnosis, graft source, and alemtuzumab dosing.

Neutropenic Diet – Good Practice or Myth?

Hematopoietic cell transplant (HCT) is one of the most complex procedures in medicine. Since its inception several decades ago, it has been continuously refined and is now a standard procedure for many hematologic malignancies and some nonmalignant diseases. However, despite these advances, relapse of the underlying disease, graft-versus-host disease (GVHD), organ toxicities, and infectious complications continue to be major obstacles to success. Inherent to the HCT procedure is a profound posttransplantation immunodeficiency, which increases the risk of serious and often fatal infectious complications. Infections can originate from exogenous acquisition of pathogens or reactivation from latency. Once infected, the patient may develop progressive and often fatal disease. Infections have also been implicated in the development of GVHD. To minimize exposure from food-borne pathogens, most cancer centers recommend a restricted diet. This diet, also referred to as the ‘‘neutropenic diet’’, is usually recommended throughout the period of immunosuppression with the goal to minimize invasive infections originating from food-derived pathogens and, in the allogeneic transplantation setting, also to potentially minimize GVHD. The practice to recommend this diet is endorsed by evidence-based guidelines; however, the quality of the evidence is generally weak mostly category III (ie, based on expert opinion) [1,2]. In fact, although there are theoretical arguments as well as preclinical nonhuman studies and clinical results from the early days of HCT [3] to support the concept, the strategy as a whole has never been evaluated and proven to be

Acute leukemia in adults: novel allogeneic transplant strategies

Acute myeloid leukemia (AML) is the most common indication for hematopoietic cell transplantation (HCT). Significant improvements in histocompatibility testing have resulted in identifying better alternative donors to provide grafts; coupled with expanding use of reduced-intensity conditioning (RIC) regimens, patient outcomes have improved. Most AML patients in complete remission now can undergo allogeneic HCT procedures with an anticipated result that approaches that obtained with sibling donors and myeloablative conditioning (MAC). Treatment-related mortality (TRM), relapse, GVHD and, for umbilical cord blood (UCB) grafts, slow engraftment/engraftment failures, however, continue to plague HCT. Newer strategies include the use of double unit UCB HCT and ex vivo expansion of UCB units using: multipotent mesenchymal stromal cells (MSCs); polyamine copper chelator tetraethylenepentamine (TEPA); and Notch ligand. Haploidentical bone marrow and blood HCT are increasing in numbers given the improved outcome with post-HCT cyclophosphamide therapy. Novel chemotherapeutic preparative regimens incorporating agents such as clofarabine and treosulfan, and novel radiation preparative regimens utilizing selective radiation approaches (helical tomotherapy) and targeted myeloablative radioimmunotherapy appear to enhance the anti-AML effect. Immunological approaches with chimeric antigen receptor-redirected T lymphocytes have been added to the armamentarium. Other novel maneuvers include more sophisticated T-cell depletion of the donor graft and post-transplant immunotherapy with regulatory T cell (Treg) therapy and MSCs for GVHD prevention. These and other strategies are improving the outlook of AML HCT recipients.

Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies

Conventional myeloablative conditioning regimens prior to hematopoietic cell transplantation (HCT) are associated with significant transplant-related morbidity and mortality in children affected by primary immunodeficiency disorders. Reduced-intensity conditioning regimens have been extensively used without severe acute toxicity in patients with pre-HCT comorbidities, with the additional advantage of reducing or avoiding long-term sequelae such as infertility and growth retardation. Compared with myeloablative HCT, reduced-intensity conditioning regimens are associated with an increased incidence of mixed donor chimerism and graft rejection. While mixed donor engraftment is likely to correct the phenotypic expression of most children with primary immunodeficiency disorders, the use of donor lymphocyte infusion to increase donor chimerism or second HCT procedures may be required in some cases. Here we discuss the most recent data on the use of different reduced-intensity conditioning protocols in children with primary immunodeficiency disorders, highlighting significant clinical lessons and areas that need additional study.

Risk Factors Affecting Cardiac Left Ventricular Systolic and Diastolic Function and Hypertrophy in the Chronic Phase Post-Allogeneic Hematopietic Cell Transplantation

Abstract 2000The long-term survival rate after allogeneic hematopoietic cell transplantation (HCT) has been significantly improved over recent decades due to improvements in the HCT procedure. However, chronic complications such as cardiovascular disease have become increasingly evident and constitute a serious problem among long-term survivors after HCT.It is well-known that high-dose cyclophosphamide (CY) used for conditioning is one of the major causes of acute cardiotoxicity after HCT; however, it is still unclear which factors contribute to chronic cardiotoxicity. Although there is a possibility that chronic GVHD (cGVHD) causes cardiac tissue damage via cytokines such as IL-2, or TNF-alpha, it is unclear whether or not cGVHD influences cardiac function.In the present retrospective cohort study, we investigated which factors affected cardiac function and left ventricular hypertrophy (LVH) in the chronic phase after HCT. We examined left ventricular systolic and diastolic functions and LVH in patients who received HCT between April 2000 and March 2011 and survived for more than one year post-HCT. Only the patients who had undergone an echocardiographic examination before HCT were eligible for the study. We assessed left ventricular ejection fraction (LVEF) as a surrogate marker of LV systolic function and the early peak flow velocity/atrial peak flow velocity (E/A) as a surrogate marker of LV diastolic function using echocardiography. LVH after HCT was identified when the interventricular septal wall (IVS) and/or the posterior wall (PW) became more than 12 mm thick after HCT. We examined the factors that could have had some influence on cardiac function after HCT including age, sex, cumulative dose of anthracycline, use of high-dose CY in the conditioning, total body irradiation (TBI), intensity of conditioning regimen (myeloablative vs. reduced intensity conditioning), a history of hypertension, hemoglobin and serum ferritin levels.A total of 58 patients (25 males and 33 females) were eligible for participation in the study. The median age of enrolled patients was 46 years (range: 21–73). The median cumulative dose of anthracycline was 90 mg/m2 (0–431mg/m2). Forty-nine patients received myeloablative conditioning and 20 of these patients received myeloabative conditioning with TBI 12 Gy. Twenty-four patients were treated for cGVHD and 7 had a history of hypertension and 2 had an LVEF of less than 55% before HCT. Six had an LVEF of less than 55% at more than 1 year after HCT. In the multiple regression analysis that assessed the relationship between LVEF or E/A and the factors, myeloablative conditioning with TBI 12Gy was significantly associated with a decrease in LVEF after HCT (coefficient= −7.57, P=.001). However, in a comparison of Ara-C/CY/TBI and CY/TBI conditioning, the degree of change in the LVEF before and after HCT was similar between the two groups (repeated measures of ANOVA analysis. P=.0972). Patients who had received myeloablative conditioning had a significant decrease in E/A after HCT(coefficient= -.31, P=.02). Furthermore, a history of hypertension was also slightly associated with a decrease in E/A after HCT(coefficient= -.30, P=.05). In addition, only age was identified as a significant risk factor of left ventricular hypertrophy after HCT in the multivariate logistic analysis. However, in the present study, we could not identify a significant impact of cGVHD on cardiac function and LVH post HCT.We concluded, based on our results, that the presence of cGVHD did not significantly contribute to a decrease in cardiac function in the chronic phase after HCT. Our results also suggest that the intensity of conditioning for HCT had a significant effect on chronic cardiac function after HCT. Disclosures:No relevant conflicts of interest to declare.

Chronic Granulomatous Disease: Lessons from a Rare Disorder

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs).

Transplant Utilization, Procedure Patterns And Patient Characteristics In North American Transplant Centers From 1994-2005

Autologous (Auto) and allogeneic (Allo) hematopoietic cell transplantation (HCT) have been used to cure malignant and non-malignant conditions for >40 years. Recent advances in HCT techniques and supportive care, new HCT indications, and improvements in survival outcomes may have increased access to and utilization of HCT. We describe the HCT population, utilization and procedure patterns in North American (US and Canada) HCT centers reporting to the CIBMTR from 1994-2005. We divided the population into six 2-year cohorts (Table).