Positron Emission Tomography–Based Assessment of Metabolic Tumor Volume Predicts Survival after Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma

Autologous hematopoietic cell transplantation (AHCT) is curative for 60% of patients with relapsed or refractory Hodgkin lymphoma (R/R HL). A more precise assessment of the depth of remission before AHCT may help to identify patients likely to benefit from AHCT. We aimed to determine whether positron emission tomography (PET)-based quantitative parameters of total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and maximal standardized uptake volume (SUV_max) measured before AHCT predict progression-free survival (PFS) after transplant. Pretransplant PET/computed tomography images of 96 consecutive patients with R/R HL were analyzed. Median TMTV, TLG, and SUV_max were 7.97?cm³ (range, 1.3 to 102.1), 23.7 (range, 4.0 to 813.1), and 5.23 (range, 2.7 to 23.2). Two-year PFS in patients with high TMTV (TMTVhigh; more than median; n?=?17) was only 12% (95% CI, 1% to 38%) compared with 53% (95% CI, 28% to 73%; P?=?.05) in patients with TMTVlow (lower or equal to median; n?=?17) and 63% (95% CI, 50% to 74%) in 61 patients with no metabolically active tumor (TMTV0; P?>?.01). In concordance, high TLG (>19) and SUV_max (>4.9) predicted inferior 2-year PFS. In multivariate analysis patients with TMTVhigh had a 3.5-fold higher risk of treatment failure compared with TMTV0/TMTVlow (HR, 3.49; 95% CI, 1.75 to 6.93; P?<?.01). Deauville (D)-scores of 4 to 5 before AHCT predicted worse PFS compared with D-scores of 1 to 3 (HR, 3.7; 95% CI, 1.92 to 7.28; P?<?.01). Yet, TMTV and D-scores were disconcordant in 12 subjects; 9 patients in the D4 group with TMTVlow had 2-year PFS of 44% (95% CI, 14% to 72%), which was 2-fold higher than predicted by D4 score. In conclusion, in patients with R/R HL and PET-positive residual disease, TMTVhigh can identify very poor AHCT responders. Patients with TMTVlow, TLG, and SUV_max before AHCT have similar outcomes to those without metabolically active disease.     

Is Cytomegalovirus Testing of Blood Products Still Needed for Hematopoietic Stem Cell Transplant Recipients in the Era of Universal Leukoreduction?

Hematopoietic stem cell transplantation (HSCT) recipients are a high-risk, immunocompromised group of patients who receive frequent transfusions after transplantation. Transfusion of cytomegalovirus (CMV)-negative blood products has long been the standard of care to prevent transfusion-transmitted CMV in this patient population. Leukoreduction of blood products before transfusion has been shown to significantly reduce the risk of transfusion-transmitted CMV. In the era of universal leukoreduction in Canada, the need for CMV testing of blood products remains unclear. We sought to identify whether there is a difference in transfusion-transmitted CMV viremia in patients receiving only leukoreduced versus CMV-negative and leukoreduced blood products in HSCT recipients. Patients who were CMV negative and received an allogeneic HSCT from a CMV-negative donor between October 1, 1999 and June 30, 2012 were included in the analysis. Transfusion data were collected from The Ottawa Hospital Blood Bank and Canadian Blood Services. CMV viremia was defined as PCR positivity. One hundred sixty-six patients were identified who met the inclusion criteria. Of these, 89 patients received an HSCT before January 2007, during the time when patients received leukoreduced and CMV-negative blood products. Seventy-seven patients received an HSCT after this time, receiving only leukoreduced blood products. The 2 groups did not differ in terms of age, gender, diagnosis, graft type, graft source, conditioning regimen, or ABO compatibility (P > .05). CMV viremia was detected in 3 patients who received CMV-negative leukoreduced blood products (3.37%) and in 1 patient who received only leukoreduced blood products (1.30%, P = .6244). Of the patients who developed CMV viremia, 2 developed suspected CMV disease. Both of these patients were transfused with CMV-negative blood products. Secondary outcomes, including total length of stay in hospital, admission to the intensive care unit, acute and chronic graft versus host disease, and 100-day nonrelapse mortality, did not differ between the groups. In the era of universal leukoreduction of blood products, this study demonstrates that testing for CMV-negative blood products is not needed for HSCT recipients.     

Pretransplantation Fluorine-18-Deoxyglucose–Positron Emission Tomography Scan Lacks Prognostic Value in Chemosensitive B Cell Non-Hodgkin Lymphoma Patients Undergoing Nonmyeloablative Allogeneic Stem Cell Transplantation

Whether chemosensitivity, as determined by positron emission tomography using fluorine-18-deoxyglucose (FDG-PET), is a requirement for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) has yet to be established. We analyzed 88 patients with B cell non-Hodgkin lymphoma (B-NHL) for event-free (EFS) and overall survival (OS) according to computed tomography (CT) and FDG-PET criteria before uniform nonmyeloablative (NMA) allo-SCT. Patients who were chemosensitive, according to CT criteria, experienced significantly greater EFS (P < .001) and OS (P < .03) compared with those who were chemorefractory at the time of allo-SCT. Of 58 patients within this cohort who were chemosensitive by CT criteria, there was no difference in EFS (P = .85) or OS (P = .96) between FDG-PET–positive (Deauville 4 to 5, n = 24) and FDG-PET–negative (Deauville 1 to 3, n = 34) patients. There was no difference in survival according to age < or ≥ 60 years, prior autologous-stem cell transplantation, allograft characteristics, or histology. FDG-PET adds no prognostic value in chemosensitive B-NHL before NMA-allo-SCT.     

β-d-Glucan Screening for Detection of Invasive Fungal Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

While the assessment of β-d-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and Candida sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness.     

Comparative Analysis of Flow Cytometry and RQ-PCR for the Detection of Minimal Residual Disease in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia after Hematopoietic Stem Cell Transplantation

The aim of this study was to examine the value of minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR) at the early stage after hematopoietic stem cell transplantation for predicting relapse and leukemia-free survival (LFS) in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+-ALL). Patients who maintained complete molecular remission (BCR-ABL <.01%) status at 1 and 3 months were associated with a lower relapse rate (P?=?.02 and <.001) and better LFS (P?=?.014 and .013) than were those without a complete molecular remission. Negative MFC at 1, 2, and 3 months was associated with a lower relapse rate (P?=?.01, .004, and .04, respectively) and better LFS (P?=?.044, <.0001, and .013, respectively). Multivariate analysis showed that MRD positivity identified by MFC or RQ-PCR at 3 months was an independent risk factor for relapse (hazard ratio [HR], 6.042 (95% confidence interval [CI], 2.283 to 15.988), P?<?.001), LFS (HR, 3.614 (95% CI, 1.610 to 8.111), P = .002), and overall survival (HR, 2.547, 95% CI, 1.008 to 6.443), P = .048). In summary, MRD detection by MFC and RQ-PCR detection of BCR-ABL at the early stage were important predictors of outcome in patients with Ph+-ALL, and these tests played complementary roles in predicting prognosis.     

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children: a retrospective study of the Italian Hematology-Oncology Association–Hematopoietic Stem Cell Transplantation Group

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P?=?.0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.     

Occurrence and Severity of Donor Lymphocyte Infusion–Associated Chronic Graft-versus-Host Disease Influence the Clinical Outcomes in Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

The aim of this study was to investigate the occurrence and severity of chemotherapy plus donor lymphocyte infusion (Chemo-DLI)-associated chronic graft-versus-host disease (cGVHD) in a consecutive cohort of patients with acute leukemia who experienced relapse after allogeneic hematopoietic stem cell transplantation (n = 104). The 5-year cumulative incidence of complete remission after Chemo-DLI was 81.0% (95% CI, 73.3% to 88.7%) and 84.6% (95% CI, 74.5% to 94.7%) in the moderate and severe cGVHD groups, respectively, which was significantly higher than that of the mild cGVHD group at 40.9% (95% CI, 29.3% to 52.5%) and non-cGVHD group at 29.2% (95% CI 23.1% to 35.3%). The cumulative incidence of nonrelapse mortality was comparable between patients with and without cGVHD. The 5-year probabilities of progression-free survival after Chemo-DLI were 42.9% (95% CI, 26.2% to 70.2%) and 34.6% (95% CI, 15.3% to 78.2%) in the moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD group at 9.1% (95% CI, 2.4% to 34.1%) and non-cGVHD group at 8.3% (95% CI 3.3% to 21.3%). The 5-year probabilities of overall survival after Chemo-DLI were 56.7% (95% CI, 38.9% to 82.7%) and 43.1% (95% CI, 22.1% to 84.0%) in the moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD group at 9.1% (95% CI 1.8% to 47.1%) and non-cGVHD group at 14.9% (95% CI, 7.3% to 30.2%). Our observations highlight the close relationship between cGVHD and immune-mediated graft-versus-leukemia (GVL) effect in patients with relapse receiving Chemo-DLI; however, mild cGVHD may not be associated with a sufficiently strong GVL effect to induce remission and improve survival.     

Impact of an Additional Chromosome on the Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome–Positive Acute Myeloid Leukemia in Adults

The incidence of Philadelphia chromosome positivity (Ph⁺) in adults with acute myeloid leukemia (AML) is very low. Ph⁺ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph⁺ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3?+?7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400?mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph⁺ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P?=?.083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P?=?.214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low-dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph⁺ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph⁺ AML, including therapy-related AML.     

Fluoroquinolone Prophylaxis Is Highly Effective for the Prevention of Central Line–Associated Bloodstream Infections in Autologous Stem Cell Transplant Patients

Patients undergoing stem cell transplant (SCT) for the treatment of hematologic malignancy are at increased risk for central line–associated bloodstream infections (CLABSIs). The use of prophylactic antibiotics to prevent CLABSIs in the setting of autologous SCT is of unclear benefit. We aimed to evaluate the impact of levofloxacin prophylaxis on reducing CLABSIs in this high-risk population. Patients undergoing autologous SCT at a tertiary care hospital received levofloxacin prophylaxis from January 13, 2016 to January 12, 2017. Levofloxacin was administered from autologous SCT (day 0) until day 13, absolute neutrophil count > 500/mm³, or neutropenic fever, whichever occurred first. Clinical outcomes were compared with a baseline group who underwent autologous SCT but did not receive antibacterial prophylaxis during the previous year. The primary endpoint was incidence of CLABSIs assessed using Cox proportional hazards regression. A total of 324 patients underwent autologous SCT during the entire study period, with 150 receiving levofloxacin prophylaxis during the intervention period. The rate of CLABSIs was reduced from 18.4% during the baseline period to 6.0% during the intervention period. On multivariable analysis levofloxacin prophylaxis significantly reduced CLABSI incidence (hazard ratio, .33; 95% confidence interval [CI], .16 to .69; P = .003). There was also a reduction in the risk of neutropenic fever (odds ratio [OR], .23; 95% CI, .14 to .39; P < .001) and a trend toward a reduction in intensive care unit transfer for sepsis (OR, .33; 95% CI, .09 to 1.24; P = .10) in patients receiving levofloxacin prophylaxis. Notably, there was no increase in Clostridium difficile infection in the levofloxacin group (OR, .66; 95% CI, .29 to 1.49; P = .32). Levofloxacin prophylaxis was effective in reducing CLABSIs and neutropenic fever in patients undergoing autologous SCT. Further studies are needed to identify specific patient groups who will benefit most from antibiotic prophylaxis.     

T Cell–Depleted Stem Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia: Long-Term Survival for Patients in First Complete Remission with a Decreased Risk of Graft-versus-Host Disease

Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell–depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation–based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those who did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.     

Do Bone Density,Bone Microarchitecture,and Body Composition Differ in Recipients of Allogeneic Hematopoietic Stem Cell Transplant? A Cross-Sectional Study from Southern India

The significant advancements made in the field of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have ensured increased longevity in transplant recipients. However, they do have late effects that may adversely affect the endocrine system, bone health, and body composition. This study was undertaken to evaluate bone mineral density (BMD), trabecular bone score, and body composition in recipients of allo-HSCT and compare them with age, sex, and body mass index (BMI) matched controls. This was a cross-sectional study done in 63 cases and 65 matched controls. The mean femoral neck BMD was found to be lower in cases than in controls (0.777 [0.119] versus 0.846 [0.122] g/cm², P =  .002). Among cases, the mean BMD at the neck of femur was lower in patients who had received myeloablative conditioning compared with those who had received the nonmyeloablative regimen (0.731 [0.090] versus 0.802 [0.126] g/cm², P = .014]. The mean (SD) bone density at the lumbar spine was significantly lower in the group that had received total body irradiation compared with the group that did not (0.930 [0.111] versus 0.993 [0.127], P = .044). Trabecular bone score did not differ between cases and controls (1.383 [0.877] versus 1.389 [0.750], P = .670). The lean mass was significantly lower (15.9 [2.4] versus 18.6 [4.8] kg/m², P < .001) and the prevalence of sarcopenia (42% versus 11%, P < .001) significantly higher in cases than in controls. Normal-weight obesity was also noted to be higher among those with sarcopenia than in those without (12/26 versus 5/36; P = .009). The procedure of allo-HSCT may thus cause an impairment of bone health and alterations in body composition well after the cure of the primary disease.     

Outcomes of Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency: A Report from the Australian and New Zealand Children’s Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry

We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Children’s Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation.     

Outcome of Donor Lymphocyte Infusion after T Cell–depleted Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndromes

Relapse occurs in 30%-50% of recipients of T cell–depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.     

Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans,Non-Human Primates,Canines, and Alzheimer Disease–Like Transgenic Mouse Models

Amyloid-β (Aβ) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aβ), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aβ peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aβ deposition in humans and animal models. PyroGlu-3 Aβ immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Aβ IR. PyroGlu-3 Aβ is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Aβ deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Aβ deposition preceding pyroGlu-3 Aβ deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Aβ is a major species of β-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Aβ peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.Alzheimer disease (AD) is the most common form of dementia, predicted to affect approximately 42 million people worldwide in the year 2020.¹ The two prominent histopathological hallmarks of AD are extracellular neuritic plaques composed of aggregated amyloid-β protein (Aβ) and intracellular neurofibrillary tangles comprising hyperphosphorylated tau.^2,3 Aβ is formed via the amyloidogenic pathway in which the amyloid precursor protein (APP) is liberated by two sequential endopeptidase cleavages (β- and γ-secretase).⁴ Besides a marked C-terminal heterogeneity of Aβ peptides represented by the isoforms Aβ40 and Aβ42, N-terminal variants are also frequently found, eg, pyroGlu-3 Aβ and pyroGlu-11 Aβ.⁵N-terminally truncated and modified Aβ species have been shown to be a major component of Aβ deposited in plaques and vessels of AD and Down syndrome (DS) patients.^6–9 Current hypotheses suggest that pyroGlu-3 Aβ may play an early and seminal role in the oligomerization and seeding of Aβ in familial AD (FAD) and sporadic AD.^10–12 PyroGlu-3 Aβ is formed by cyclization of glutamate residues 3 or 11 by glutaminyl cyclase (QC).¹³ An N-terminal truncation of Aβ precedes formation of pyroglutamic acid. Such post-translationally modified species have been shown to be highly toxic to neuronal and glial cultures.¹⁴ When compared to unmodified Aβ, pyroGlu-3 Aβ has a higher aggregation propensity and stability, and exhibits increased potential to interfere with hippocampal LTP.^15–17 Inhibition of QC has been shown to prevent pyroGlu-3 Aβ formation in vitro¹⁸ and in vivo.^19,20 Accordingly, QC inhibitors are currently in development as a novel pharmacological approach to treat and/or prevent AD.²⁰With the advent of numerous preclinical models, it is now possible to mimic at least some of the pathological hallmarks of AD for characterization and testing of potential treatments. With regard to the established role of pyroGlu-3 Aβ in AD pathology represented by neuron loss and cognitive decline,^12,21,22 a detailed characterization of pyroGlu-3 Aβ distribution of available transgenic (tg) and nontransgenic models and their comparison to human pathology is urgently needed. In this regard, recent research has focused only on select models.^23–26Here, we completed detailed IHC analyses in human AD, nondemented aged controls (AC), and DS brains, as well as in the Caribbean vervet,²⁷ aged beagle canines,²⁸ and 12 AD-like tg mouse strains. Our results support the early deposition of pyroGlu-3 Aβ along with general Aβ in humans, nonhuman primates, and canines, in contrast to later deposition in AD-like tg mouse models, underlining differences in plaque pathology between nontransgenic/nonrodent and transgenic murine model systems.     

Synergistic Effect of Major Histocompatibility Complex Class I–Related Chain A and Human Leukocyte Antigen–DPB1 Mismatches in Association with Acute Graft-versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation

The clinical relevance of mismatches at the MHC class I–related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes after unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II to IV acute graft-versus-host disease (GVHD) was greater for patients with MICA mismatch (hazard ratio [HR], 1.73; P = .02) than for those with HLA-DPB1 mismatch (HR, 1.62; P = .07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR, 2.51; P < .01) and those mismatched at only 1 locus had somewhat greater risk (HR, 1.53; P = .12) than patients matched at both loci; this remained significant in multivariable analysis. The 100-day incidence was 66%, 45%, and 31%, respectively (P = .03). Results were similar for grade III and IV acute GVHD, with 100-day incidence 34%, 16%, and 8% (P = .01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GVHD.     

Allogeneic Hematopoietic Stem Cell Transplantation,Especially Haploidentical,May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.