Geriatric assessment predicts nonfatal toxicities and survival for intensively treated older adults with AML.

Given that there are only a few prospective studies with conflicting results, we investigated the prognostic value of multiparameter geriatric assessment (GA) domains on tolerance and outcomes after intensive chemotherapy in older adults with acute myeloid leukemia (AML). In all, 105 newly diagnosed patients with AML who were older than age 60 years and who received intensive chemotherapy consisting of cytarabine and idarubicin were enrolled prospectively. Pretreatment GA included evaluations for social and nutritional support, cognition, depression, distress, and physical function. The median age was 64 years (range, 60-75 years), and 93% had an Eastern Cooperative Oncology Group performance score <2. Between 32.4% and 69.5% of patients met the criteria for impairment for each domain of GA. Physical impairment by the Short Physical Performance Battery (SPPB) and cognitive dysfunction by the Mini-Mental State Examination in the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Assessment Packet (MMSE-KC) were significantly associated with nonfatal toxicities, including grade 3 to 4 infections (SPPB, P = .024; MMSE-KC, P = .044), acute renal failure (SPPB, P = .013), and/or prolonged hospitalization (≥40 days) during induction chemotherapy (MMSE-KC, P = .005). Reduced physical function by SPPB and depressive symptoms by the Korean version of the short form of geriatric depression scales (SGDS-K) were significantly associated with inferior survival (SPPB, P = .027; SGDS-K, P = .048). Gait speed and sit-and-stand speed were the most powerful measurements for predicting survival outcomes. Notably, the addition of SPPB and SGDS-K, gait speed and SGDS-K, or sit-and-stand speed and SGDS-K significantly improved the power of existing survival prediction models. In conclusion, GA improved risk stratification for treatment decisions and may inform interventions to improve outcomes for older adults with AML. This study was registered at the Clinical Research Information Service as #KCT0002172.

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Impact of Lactate Dehydrogenase and Hemoglobin Levels on Clinical Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results From the National Korean PNH Registry.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

Efficacy of ex vivo purging with CD34+ selection to maximize the effects of autologous stem cell transplantation in peripheral T-cell lymphoma patients.

BACKGROUND AIMS: Peripheral T-cell lymphomas (PTCLs) are rare and aggressive tumors with uncertain optimal treatment. This study investigated the clinical outcomes of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) after CD34+ selective purging in PTCL patients. METHODS: Retrospective analysis included 67 PTCL patients who achieved remission and underwent HDT/ASCT. CD34+ selective purging was performed using CliniMACS® (Miltenyi Biotec, Bergisch Gladbach, Germany). Survival outcomes, engraftment, lymphocyte subsets and viral infections were evaluated. RESULTS: CD34+ selective purged autografts were associated with significantly improved overall survival (OS) and disease-free survival (DFS) compared with unpurged autografts (5-year OS, 73.3% versus 37.8%, 5-year DFS, 73.8% versus 33.4%). The cumulative incidence of relapse was also lower in the purged group (31.5% versus 73.3%). Subgroup analysis revealed significant survival benefits in the high-risk group receiving purged autografts. Lymphocyte subset analysis showed increased natural killer (NK) cell counts in the purged group after ASCT. Higher post-ASCT lymphocyte-to-monocyte ratio (LMR) was associated with improved OS and DFS. CONCLUSIONS: CD34+ selective purging in PTCL patients undergoing HDT/ASCT improved survival outcomes and reduced relapse risk. The procedure increased NK cell counts and post-ASCT LMR. CD34+ selective purging may minimize autograft tumor cell contamination and enhance efficacy in T-cell lymphomas.

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case-control study in the International PNH Registry.

The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)-negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20-72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86-92.62]; without recent anticoagulation, 5.33 [0.26-109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54-45.32]; ≥ 50%, 1.97 [0.45-8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2-3 criteria, 3.18 [0.44-23.20]; ≥ 4 criteria, 3.60 [0.38-33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

OBJECTIVES: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. METHODS: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). RESULTS: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). CONCLUSION: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

Cytogenetic and molecular characteristics and outcomes of adult patients with early T-cell precursor acute lymphoblastic leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently identified high-risk subgroup of T-cell ALL in children. However, there have been conflicting reports and limited data have been reported in adult patients. We retrospectively analyzed the cytogenetic and molecular characteristics and long-term survival outcomes of adult patients with ETP-ALL versus non-ETP-ALL. We analyzed 58 patients (median age, 35 years [range, 18-76 years]) with newly diagnosed T-cell ALL who received a uniform remission induction and consolidation chemotherapy with suitable samples for genetic analyses. If a donor was available, all patients were recommended allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Out of 58 patients, 21 (36.2%) had ETP-ALL. Patients with ETP-ALL were older and had a higher proportion of complex karyotype than non-ETP-ALL. Additionally, more DNMT3A mutations were detected in ETP-ALL, whereas FBXW7 mutations and CDKN2A/CDKN2B deletions were found nearly exclusively in non-ETP-ALL. The overall complete remission (CR) rates were not different between ETP-ALL (95.2%) and non-ETP-ALL (81.1%) and subsequent allo-HCT proceeding rates in CR1 were 61.9% for ETP-ALL and 43.2% for non-ETP-ALL, respectively. The overall prognosis of patients with T-ALL was poor that estimated 5-year overall survival (OS) was 33.3% for ETP-ALL and 29.5% for non-ETP-ALL. In a subgroup analysis of patients treated with allo-HCT in CR1 (n = 29), 5-year OS was 53.8% for ETP-ALL and 55.4% for non-ETP-ALL. Our data showed molecular characteristics of ETP-ALL and non-ETP-ALL and revealed that intensive chemotherapy followed by allo-HCT for post-remission therapy can contribute to preserved survival outcome of adult patients with ETP-ALL.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

3.6 mW Active-Electrode ECG/ETI Sensor System Using Wideband Low-Noise Instrumentation Amplifier and High Impedance Balanced Current Driver.

An active electrode (AE) and back-end (BE) integrated system for enhanced electrocardiogram (ECG)/electrode-tissue impedance (ETI) measurement is proposed. The AE consists of a balanced current driver and a preamplifier. To increase the output impedance, the current driver uses a matched current source and sink, which operates under negative feedback. To increase the linear input range, a new source degeneration method is proposed. The preamplifier is realized using a capacitively-coupled instrumentation amplifier (CCIA) with a ripple-reduction loop (RRL). Compared to the traditional Miller compensation, active frequency feedback compensation (AFFC) achieves bandwidth extension using the reduced size of the compensation capacitor. The BE performs three types of signal sensing: ECG, band power (BP), and impedance (IMP) data. The BP channel is used to detect the Q-, R-, and S-wave (QRS) complex in the ECG signal. The IMP channel measures the resistance and reactance of the electrode-tissue. The integrated circuits for the ECG/ETI system are realized in the 180 nm CMOS process and occupy a 1.26 mm2 area. The measured results show that the current driver supplies a relatively high current (>600 µApp) and achieves a high output impedance (1 MΩ at 500 kHz). The ETI system can detect resistance and capacitance in the ranges of 10 mΩ-3 kΩ and 100 nF-100 µF, respectively. The ECG/ETI system consumes 3.6 mW using a single 1.8 V supply.

A Compact and Efficient Boost Converter in a 28 nm CMOS with 90 mV Self-Startup and Maximum Output Voltage Tracking ZCS for Thermoelectric Energy Harvesting.

There are increasing demands for the Internet of Things (IoT), wearable electronics, and medical implants. Wearable devices provide various important daily applications by monitoring real-life human activities. They demand low-cost autonomous operation in a miniaturized form factor, which is challenging to realize using a rechargeable battery. One promising energy source is thermoelectric generators (TEGs), considered the only way to generate a small amount of electric power for the autonomous operation of wearable devices. In this work, we propose a compact and efficient converter system for energy harvesting from TEGs. The system consists of an 83.7% efficient boost converter and a 90 mV self-startup, sharing a single inductor. Innovated techniques are applied to adaptive maximum power point tracking (A-MPPT) and indirect zero current switching (I-ZCS) controllers for efficient operation. The startup circuit is realized using a gain-boosted tri-state buffer, which achieves 69.8% improved gain at the input VIN = 200 mV compared to the conventional approach. To extract the maximum power, we use an A-MPPT controller based on a simple capacitive divider, achieving 95.2% tracking efficiency. To address the challenge of realizing accurate voltage or current sensors, we propose an I-ZCS controller based on a new concept of maximum output voltage tracking (MOVT). The integrated circuit (IC) is fabricated using a 28 nm CMOS in a compact chip area of 0.03 mm2. The compact size, which has not been obtained with previous designs, is suitable for wearable device applications. Measured results show successful startup operation at an ultralow input, VIN = 90 mV. A peak conversion efficiency of 85.9% is achieved for the output of 1.07 mW.

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.

Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria.

This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.

Effect of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria with or without high disease activity: Real-world findings from the International Paroxysmal Nocturnal Hemoglobinuria Registry.

BACKGROUND: The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high-disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major adverse vascular events (MAVEs; including thrombotic events [TEs]); anemia; and/or physician-reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated. METHODS: Registry patients were stratified by baseline HDA and eculizumab-treatment status. Longitudinal changes in laboratory and clinical PNH-related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates). RESULTS: As of May 1, 2017, 3009 patients (HDA/eculizumab-treated, n = 913; HDA/never-treated, n = 651; no-HDA/eculizumab-treated, n = 173; no-HDA/never-treated, n = 1272) were analyzed. Higher proportions of eculizumab-treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean [SD]: -5.3 [4.0] and -2.3 [3.8]); (2) incidence rate ratio (IRR) for MAVEs (-80% and -70%); (3) IRR for TEs (-80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5 units). CONCLUSIONS: Eculizumab treatment in a real-world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.

Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies.

OBJECTIVES: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years. METHODS: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed. RESULTS: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%). CONCLUSIONS: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.

Splenectomy Outcomes in Relapsed or Refractory Immune Thrombocytopenia according to First-Line Intravenous Immunoglobulin Response.

OBJECTIVES: Although splenectomy has long been second-line option for immune thrombocytopenia (ITP) patients, an indicator that reliably predicts the efficacy of splenectomy is still being explored. We investigated the treatment outcomes of splenectomy as a second-line therapy for relapsed/refractory ITP according to first-line intravenous immunoglobulin (IVIG) responses. METHODS: Fifty-two adult patients treated with splenectomy as second-line therapy for ITP between 2009 and 2019 were included, and they were classified according to first-line IVIG responses (no response to IVIG: nonresponders; only transient IVIG response shorter than 4 weeks: poor responders; IVIG response for a longer period; stable responders). The efficacy of splenectomy was analyzed in the three subgroups. RESULTS: Of the 52 patients, 10 were IVIG nonresponders, 34 were poor responders, and the remaining 8 were stable responders. Response to splenectomy was observed in 50.0% of IVIG nonresponders, 94.1% of poor responders, and 100% of stable responders (p = 0.0030). Among the 45 patients who responded to splenectomy, 51.1% relapsed subsequently, and a significantly lower relapse rate was noted in the stable IVIG responders (12.5%, p = 0.0220) than in nonresponders (60.0%) and poor responders (59.4%). CONCLUSIONS: First-line IVIG response is indicated as a useful predictive factor for response to splenectomy.

An 11.8-fJ/Conversion-Step Noise Shaping SAR ADC with Embedded Passive Gain for Energy-Efficient IoT Sensors.

Herein, we present a noise shaping successive-approximation-register (SAR) analog-to-digital converter (ADC) with an embedded passive gain multiplication technique. The noise shaping moves the in-band quantization noise from the signal band to out-of-band for improved signal-to-noise ratio (SNR). The proposed approach tackles the drawback of the previous active noise shaping (increased power and extra noise) and passive noise shaping (limited noise suppression and signal loss). Both noise shaping and gain multiplication are realized on-chip in an energy-efficient manner without an opamp. This approach uses only capacitors and switches in the finite impulse response (FIR) and infinite impulse response (IIR) filters. A comparator suppressing kickback noise is presented to handle the tradeoff between noise suppression and the filter capacitor size. The energy-efficient merged-capacitor switching (MCS) technique is effectively combined with rail-to-rail swing comparator and thermometer-coded capacitor array, which reduces the settling error in the digital to analog converter (DAC). The process-induced mismatch effect in the capacitive DAC is investigated using a behavioral model of the ADC. Additionally, we propose dynamic element matching (DEM) for the thermometer-coded capacitor array. The ADC is fabricated using a 0.18 µm CMOS process in an area of 0.26 mm2. Consuming 4.1 µW, the ADC achieves a signal-to-noise and distortion ratio (SNDR) of 66.5 dB and a spurious-free dynamic range (SFDR) of 79.1 dB. The figure-of-merit (FoM) of the ADC is 11.8 fJ/conversion-step.

A 12-b Subranging SAR ADC Using Detect-and-Skip Switching and Mismatch Calibration for Biopotential Sensing Applications.

This paper presents a 12-b successive approximation register (SAR) analog-to-digital converter (ADC) for biopotential sensing applications. To reduce the digital-to-analog converter (DAC) switching energy of the high-resolution ADC, we combine merged-capacitor-switching (MCS) and detect-and-skip (DAS) methods, successfully embedded in the subranging structure. The proposed method saves 96.7% of switching energy compared to the conventional method. Without an extra burden on the realization of the calibration circuit, we achieve mismatch calibration by reusing the on-chip DAC. The mismatch data are processed in the digital domain to compensate for the nonlinearity caused by the DAC mismatch. The ADC is realized using a 0.18 µm CMOS process with a core area of 0.7 mm2. At the sampling rate fS = 9 kS/s, the ADC achieves a signal-to-noise ratio and distortion (SINAD) of 67.4 dB. The proposed calibration technique improves the spurious-free dynamic range (SFDR) by 7.2 dB, resulting in 73.5 dB. At an increased fS = 200 kS/s, the ADC achieves a SINAD of 65.9 dB and an SFDR of 68.8 dB with a figure-of-merit (FoM) of 13.2 fJ/conversion-step.

Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.