Avatrombopag for severe refractory thrombocytopenia in a pediatric patient with ALL following allogeneic hematopoietic stem cell transplantation: A case report.

Patients who receive allogeneic hematopoietic stem cell transplantation (alloHSCT) are at risk for developing persistent thrombocytopenia. Here, we describe treatment with avatrombopag, a thrombopoietin receptor agonist, in a pediatric patient with chronic, severe, transfusion-dependent thrombocytopenia (<10 × 103/µL) post-alloHSCT that was persistent despite treatment with romiplostim, another thrombopoietin receptor agonist. Following the granting of a compassionate use investigational new drug authorization, avatrombopag treatment was initiated, and the patient's platelet count increased. To date, the patient has maintained a platelet count >100 × 103/µL. No adverse events or medication toxicities have been reported, and he has resumed his pre-alloHSCT activities.

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders.

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

Incidence and Risk Factors for 30-Day Readmission after Inpatient Chemotherapy among Acute Lymphoblastic Leukemia Patients.

Chemotherapy for acute lymphoblastic leukemia (ALL) patients is complex and intense, resulting in a high readmission rate. We aimed to identify the incidence, causes, and risk factors of readmission following inpatient chemotherapy among ALL patients, using 2016 National Readmission Database. We applied three different definitions of 30-day readmission: (1) nonelective readmission based on readmission type, (2) unplanned readmission defined by CMS, and (3) unintentional readmission, combining (1) and (2). We used unweighted multivariable Poisson regression with robust variance estimates for risk factors analysis, including patient-, hospital-, and admission-related characteristics. Percentage for nonelective, unplanned, and unintentional readmission were 33.3%, 22.4%, and 18.5%, respectively. The top three causes for unplanned readmissions were neutropenia/agranulocytosis (27.8%), septicemia (15.3%), and pancytopenia (11.5%). Risk ratios for unintentional readmission were 1.21 (1.08-1.36) for nonelective vs. elective admission, 1.19 (1.06-1.33) for public vs. private insurance enrollees, 0.96 (0.95-0.98) for each day of hospital stay, 0.77 (0.62-0.95) for large teaching and 0.87 (0.70-1.08) for small teaching vs. nonteaching hospitals. Possible strategies to reduce readmission among ALL patients could be shortening the gap in quality of care among teaching vs. non-teaching hospitals, understanding the difference between privately vs. publicly insured patients, and avoiding aggressive discharge after chemotherapy.

Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study.

Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.

Plasma klotho and cardiovascular disease in adults.

OBJECTIVES: To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease (CVD) in adults. DESIGN: Cross-sectional. SETTING: Population-based sample of adults residing in Tuscany, Italy. PARTICIPANTS: One thousand twenty-three men and women aged 24 to 102 participating in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS: Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, creatinine, C-reactive protein (CRP). Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent CVD. RESULTS: Of 1,023 participants, 259 (25.3%) had CVD. Median (25th, 75th percentile) plasma klotho concentrations were 676 pg/mL (530, 819 pg/mL). Plasma klotho was correlated with age (correlation coefficient (r) = -0.14, P < .001), HDL-C (r = 0.11, P<.001), and CRP (r = -0.10, P < .001) but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means were 626 pg/mL (95% confidence interval (CI) = 601-658 pg/mL) in participants with CVD and 671 pg/mL (95% CI = 652-692 pg/mL) in those without CVD (P = .001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL-C, systolic blood pressure, and diabetes mellitus), log plasma klotho was associated with prevalent CVD (odds ratio per 1 standard deviation increase = 0.85, 95% CI = 0.72-0.99). CONCLUSION: In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having CVD.

Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women.

OBJECTIVE: Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women. DESIGN AND METHODS: A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70-79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication. RESULTS: Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 s.d. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function. CONCLUSION: Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.

Reduced retinal neovascularization, vascular permeability, and apoptosis in ischemic retinopathy in the absence of prolyl hydroxylase-1 due to the prevention of hyperoxia-induced vascular obliteration.

PURPOSE: Prolyl hydroxylases (PHDs) are oxygen sensors that stabilize hypoxia-inducible factors (HIFs) to induce proinflammatory, vasopermeability, and proapoptotic factors. These may be potential targets to reduce the complications of ischemic retinopathies. METHODS: Oxygen-induced ischemic retinopathy (OIR) was generated as a model for retinopathy of prematurity (ROP) by placing 7-day-old mice in 75% oxygen for 5 days and returning them to the relative hypoxia of room air for 5 days. Neovascularization (NV) and avascular areas were assessed on retinal flat-mounts by image analysis. Blood-retinal barrier breakdown was assessed using ³H-mannitol as a tracer. Apoptosis was detected with TUNEL staining. HIF-1α and VEGF were quantified using Western blot analysis and ELISA. RESULTS: PHD1-deficient mice demonstrated reduced hyperoxia-associated vascular obliteration during oxygen-induced ischemic retinopathy. This was associated with subsequent reduced avascularity, vascular leakage, and pathologic NV during the hypoxic phase, which could be accounted for by a reduced expression of HIF-1α and VEGF. Apoptosis in the retina was also reduced in PHD1-depleted mice after 2 days in hyperoxia. CONCLUSIONS: PHD1 deficiency is associated with a reduction of ischemia-induced retinal NV. The regulatory mechanism in this model appears to be: PHD1 depletion prevents HIF-1α degradation in hyperoxia, which induces VEGF, thus preventing hyperoxia-related vessel loss. Without a vessel deficiency, there would not be relative hypoxia when the mice are returned to room air and there would be no need to initiate angiogenesis signaling. Blocking PHD1 may be beneficial for ischemic retinopathies and inflammatory and neurodegenerative disorders.

Endogenous secretory receptor for advanced glycation end products is associated with low serum interleukin-1 receptor antagonist and elevated IL-6 in older community-dwelling adults.

BACKGROUND: Advanced glycation end products (AGEs) are thought to cause inflammation through interaction with the receptor for AGEs (RAGE), therefore contributing to adverse aging-related processes. The relationship between AGEs, RAGE, and inflammation has not been well characterized. METHODS: We examined the relationship of plasma endogenous secretory RAGE (esRAGE); carboxymethyl-lysine (CML), a circulating AGE; and inflammatory mediators in 1,298 adults, 20-97 years, who participated in the InCHIANTI study in Tuscany, Italy. Blood levels of esRAGE, CML, interleukin-1 receptor antagonist (IL-1RA), IL-1ß, tumor necrosis factor-α (TNF-α), IL-6, IL-6 receptor (IL-6R), IL-18, C-reactive protein (CRP), transforming growth factor-ß (TGF-ß), and fibrinogen were measured. RESULTS: Log plasma esRAGE was associated with log IL-1RA (ß = -0.069, SE = 0.036, p = .05) and log IL-6 (ß = 0.077, SE = 0.035, p = .03), respectively, in separate multivariable linear regression models, adjusting for potential confounders. Log plasma esRAGE was also negatively associated with log TGF-ß but did not reach statistical significance (ß = -0.091, SE = 0.053, p = .09). Log plasma esRAGE was not significantly associated with log IL-1ß, log TNF-α, IL-6R, log IL-18, or CRP. Log plasma CML was not associated with any of the inflammatory mediators except for IL-6R (ß = -14.10, SE = 5.94, p = .02) and fibrinogen (ß = 13.95, SE = 7.21, p = .05) in separate multivariable models, adjusting for potential confounders. CONCLUSIONS: Plasma esRAGE is correlated with higher IL-6 and lower IL-1RA. These findings suggest that plasma esRAGE plays a role in modulating inflammation, although the exact mechanisms remain to be elucidated.