Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study.

AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

Is there a difference in regional read [18F]flutemetamol amyloid patterns between end-of-life subjects and those with amnestic mild cognitive impairment?

PURPOSE: Visual interpretation of PET [18F]flutemetamol images relies on systematic review of five brain regions and is considered positive when an elevated signal is observed in at least one region. Amnestic mild cognitive impairment (aMCI) is an early clinical presentation of Alzheimer's disease (AD); hence it is of interest to determine if the pattern of visually read regional positivity between end-of-life (EoL) patients with and without dementia and aMCI patients is different. METHODS: A total of 180 EoL patients with and without dementia (mean age 81 years, range 59 to 95 years) and 232 aMCI patients (mean age 71 years, range 53 to 91 years) were scanned following intravenous administration of 185-370 MBq [18F]flutemetamol. Images from both studies were read by two groups of five blinded readers who independently classified each of the five regions as either positive or negative. The majority interpretation made by at least three of the five readers was used as the imaging endpoint and compared with a composite standardized uptake value ratio (SUVR) analysis using a predetermined threshold. RESULTS: Amyloid-positive images from 71 of 106 EoL patients coming to autopsy and from 97 aMCI patients were included. In the images from the EoL patients widespread deposition of amyloid was observed, with 76% of the images positive in all five regions and a further 20% positive in four regions. In the images from the aMCI patients, similar results were observed with 87% of the images positive in five regions and a further 5% positive in four regions. The mean SUVR of these positively read images was 2.24 (range 1.48 to 3.14) and 2.08 (range 1.28 to 3.04) in the autopsy and aMCI groups, respectively. There was 95.3% agreement between the visual reading and SUVR quantitation in the aMCI group and 90.4% agreement in the autopsy group. CONCLUSION: Patients with aMCI showed a similar distribution of amyloid deposition determined by both visual reading and SUVR to that observed in patients with and without dementia coming to autopsy. Most of the aMCI patients, who are already within the AD continuum, had widespread amyloid deposition in terms of amount and topographical progression. Attempts to observe potential initial signs of amyloid deposition should focus on populations earlier in the dementia spectrum such as patients with subjective cognitive decline or even at-risk subjects with earlier stages of disease.

Estimation of amyloid distribution by [18F]flutemetamol PET predicts the neuropathological phase of amyloid ß-protein deposition.

The deposition of the amyloid ß-protein (Aß) in senile plaques is one of the histopathological hallmarks of Alzheimer's disease (AD). Aß-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological Aß-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [18F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [18F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [18F]flutemetamol uptake termed PET-Aß phase estimates. When comparing these PET-Aß phase estimates with the neuropathological Aß-phases we found that PET-Aß phase estimate 0 corresponded with Aß-phases 0-2, 1 with Aß-phase 3, 2 with Aß-phase 4, and 3 with Aß-phase 5. Classification using the PET-Aß phase estimates predicted the correct Aß-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of ± 1 phase for a given Aß-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-Aß phase estimates that can be easily translated into neuropathological phases of Aß-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (Aß-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.

Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result.

Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aß and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aß42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aß42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aß42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen ß chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aß42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aß42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aß42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.

Variability in Heart-to-Mediastinum Ratio from Planar 123I-MIBG Images of a Thorax Phantom for 6 Common γ-Camera Models.

A heart-to-mediastinum (H/M) ratio of 1.6 or greater on planar 123I-iobenguane (123I-MIBG) images identifies heart failure patients at low risk of experiencing an adverse cardiac event. This phase-4 study used standardized phantoms to assess the intercamera, intracamera, and interhead variability in H/M ratio determinations from planar cardiac 123I-MIBG imaging using commercially available, dual-head γ-cameras. Methods: A fillable thorax phantom was developed to simulate the typical uptake of 123I-MIBG. The phantom had a nominal H/M ratio of 1.6 on the reference camera. Commercial cameras used in the study were dual-head and capable of 90° configuration for cardiac imaging. The target sample size was 8 units (examples) per camera model. Two imaging technologists independently analyzed planar images of simulated 123I-MIBG uptake from the thorax phantom. H/M was the ratio of the average counts per pixel of the heart and mediastinum regions of interest. The primary endpoint, intercamera variability in H/M ratio from head 1, was determined for each camera model via comparison with the H/M ratio on the reference camera. Only cameras with at least 8 units tested (n ≥ 8) were included in the primary analysis. Intracamera and interhead variability in the H/M ratio were also evaluated. Results: Nine camera models were studied. The mean H/M ratio ranged from 1.342 to 1.677. The primary analysis (6 camera models) using a mixed-model, repeated-measures analysis showed no significant difference in H/M ratio between any camera model and the reference camera. Intracamera variability (head 1) in the H/M ratio among camera models with 8 units or more was high, with SDs ranging from 0.0455 to 0.1193. Interhead variability was low (SDs of the interhead difference, 0.017-0.074). Conclusion: Commonly used γ-cameras produced H/M ratios from simulated 123I-MIBG phantom images that were not significantly different from those on the reference camera. This finding indicates that the results of previous clinical trials of 123I-MIBG, involving many different clinical sites and camera models, are valid. The assessment of the performance of a given camera unit using an 123I planar phantom before H/M results from 123I-MIBG imaging are used for classifying risk in heart failure patients is encouraged.

Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.

INTRODUCTION: Performance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Brain uptake and safety of Flutemetamol F 18 injection in Japanese subjects with probable Alzheimer's disease, subjects with amnestic mild cognitive impairment and healthy volunteers.

OBJECTIVE: This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting ß-amyloid neuritic plaques in Japanese subjects. METHODS: Seventy subjects (25 with probable Alzheimer's disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers' image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test-retest variability in five pAD subjects; and safety. RESULTS: PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ≥3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test-retest variability ranged from 1.14 to 2.27%, and test-retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated. CONCLUSIONS: The detection of brain neuritic plaques in Japanese subjects using [18F]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test-retest variability. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT02813070.

Post-mortem histopathology underlying ß-amyloid PET imaging following flutemetamol F 18 injection.

In vivo imaging of fibrillar ß-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar ß-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of ß-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of ß-amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of ß-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014.

Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology.

Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- ß (Aß) plaques and dementia. Autopsy studies suggest that Aß plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aß plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aß deposits with a visually positive panel consensus decision of a positive [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aß deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aß plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD.

[(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: specific detection of advanced phases of amyloid-ß pathology.

BACKGROUND: Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-ß (Aß) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [(18)F]flutemetamol in relation to Aß pathology at autopsy. METHODS: [(18)F]flutemetamol PET was carried out in a cohort of 68 patients included in a [(18)F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aß plaque pathology was classified into phases of its regional distribution (0-5). RESULTS: [(18)F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aß pathology (Aß phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aß phases 1 and 2, whereas 33.3% of the phase 3 cases were positive. CONCLUSIONS: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aß pathology in preclinical and symptomatic AD cases.