Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.

ABSTRACT: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML.

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry.

Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

Molecular MRD status and outcome after transplantation in NPM1-mutated AML.

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Complications associated with surgical treatment of sleep-disordered breathing among hospitalized U.S. adults.

The purpose of this cross-sectional study is to examine the relationship between surgical treatments for sleep-disordered breathing (SDB) and composite measure of surgical complications in a nationally representative sample of hospital discharges among U.S. adults. We performed secondary analyses of 33,679 hospital discharges from the 2002-2012 Nationwide Inpatient Sample that corresponded to U.S. adults (≥18 years) who were free of head-and-neck neoplasms, were diagnosed with SDB and had undergone at least one of seven procedures. Multivariate logistic regression models were constructed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI), controlling for age, sex, race/ethnicity, obstructive sleep apnea (OSA) and obesity diagnoses. Positive associations were found between composite measure of surgical complications and specific procedures: palatal procedure (aOR = 12.69, 95% CI: 11.91,13.53), nasal surgery (aOR = 6.47, 95% CI: 5.99,6.99), transoral robotic assist (aOR = 5.06, 95% CI: 4.34-5.88), tongue base/hypopharynx (aOR = 4.24, 95% CI: 3.88,4.62), maxillomandibular advancement (MMA) (aOR = 3.24, 95% CI: 2.74,3.84), supraglottoplasty (aOR = 2.75, 95% CI: 1.81,4.19). By contrast, a negative association was found between composite measures of surgical complications and tracheostomy (aOR = 0.033, 95% CI: 0.031,0.035). In conclusion, most procedures for SDB, except tracheostomy, were positively associated with complications, whereby palatal procedures exhibited the strongest and supraglottoplasty exhibited the weakest association.

Preliminary investigation of cognitive function in aged multiple sclerosis patients: Challenges in detecting comorbid Alzheimer's disease.

BACKGROUND: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer's disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process. OBJECTIVE: Compare cognition in older MS patients to patients with AD and aMCI. METHODS: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (n = 20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language. RESULTS: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group. CONCLUSION: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology.

Redirection to the bone marrow improves T cell persistence and antitumor functions.

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.

Latent profile analysis of regression-based norms demonstrates relationship of compounding MS symptom burden and negative work events.

OBJECTIVE: We endeavored to clarify how distinct co-occurring symptoms relate to the presence of negative work events in employed multiple sclerosis (MS) patients. Latent profile analysis (LPA) was utilized to elucidate common disability patterns by isolating patient subpopulations. METHOD: Samples of 272 employed MS patients and 209 healthy controls (HC) were administered neuroperformance tests of ambulation, hand dexterity, processing speed, and memory. Regression-based norms were created from the HC sample. LPA identified latent profiles using the regression-based z-scores. Finally, multinomial logistic regression tested for negative work event differences among the latent profiles. RESULTS: Four profiles were identified via LPA: a common profile (55%) characterized by slightly below average performance in all domains, a broadly low-performing profile (18%), a poor motor abilities profile with average cognition (17%), and a generally high-functioning profile (9%). Multinomial regression analysis revealed that the uniformly low-performing profile demonstrated a higher likelihood of reported negative work events. CONCLUSIONS: Employed MS patients with co-occurring motor, memory and processing speed impairments were most likely to report a negative work event, classifying them as uniquely at risk for job loss.

Benchmarks of meaningful impairment on the MSFC and BICAMS.

BACKGROUND: Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research. OBJECTIVE: To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation. METHODS: We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems. RESULTS: All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline. CONCLUSION: We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.

Lateral dissemination and inter-patient transmission of blaKPC-3: role of a conjugative plasmid in spreading carbapenem resistance.

OBJECTIVES: The objective of this study was to describe the nosocomial spread of carbapenemase-producing enterobacteria and characterize a plasmid involved in KPC dissemination. METHODS: Two Klebsiella pneumoniae, one Escherichia coli and one Citrobacter freundii isolated from two patients were studied. Susceptibility profiles were obtained using Etest. Carbapenemase activity was detected using the Carba NP test. ß-Lactamase gene content was screened by PCR and sequencing. K. pneumoniae isolates were genotyped by MLST and PFGE. KPC plasmid sizes were estimated by S1-DNA digestion and PFGE-Southern blot. Plasmids were sequenced using Illumina's technology and Sanger sequencing. RESULTS: Two patients sharing a room on a surgical unit were positive for carbapenemase-producing K. pneumoniae. One patient was also colonized with carbapenemase-producing C. freundii and E. coli. Neither patient had known risk factors for carbapenemase acquisition, although one patient had recent surgery at another Toronto hospital; the other patient's husband had surgery in New York City 3 years prior to her presentation. An extensive investigation was conducted at both hospitals, but no additional cases were identified. blaKPC-3 was detected in all clinical isolates. Variable carbapenem resistance levels were observed. Both K. pneumoniae belonged to the same clone by PFGE and MLST (ST277). pKPC-SMH (∼ 53 kb) was identified in all the clinical isolates, showing identity only with structurally similar IncN plasmids. CONCLUSIONS: We describe intra- and inter-patient dissemination of blaKPC. The involvement of a clone related to the successful K. pneumoniae ST258 and the blaKPC-3 gene detected in an active Tn4401 transposon carried on a conjugative broad-host-range plasmid increased the potential for this horizontal transmission.

Inter-observer variability in diagnosing radiological features of aneurysmal subarachnoid hemorrhage; a preliminary single centre study comparing observers from different specialties and levels of training.

BACKGROUND: A noncontrast computed tomography (CT) scan remains the initial radiological investigation of choice for a patient with suspected aneurysmal subarachnoid hemorrhage (aSAH). This initial scan may be used to derive key information about the underlying aneurysm which may aid in further management. The interpretation, however, is subject to the skill and experience of the interpreting individual. The authors here evaluate the interpretation of such CT scans by different individuals at different levels of training, and in two different specialties (Radiology and Neurosurgery). METHODS: Initial nonontrast CT scan of 35 patients with aSAH was evaluated independently by four different observers. The observers selected for the study included two from Radiology and two from Neurosurgery at different levels of training; a resident currently in mid training and a resident who had recently graduated from training of each specialty. Measured variables included interpreter's suspicion of presence of subarachnoid blood, side of the subarachnoid hemorrhage, location of the aneurysm, the aneurysm's proximity to vessel bifurcation, number of aneurysm(s), contour of aneurysm(s), presence of intraventricular hemorrhage (IVH), intracerebral hemorrhage (ICH), infarction, hydrocephalus and midline shift. To determine the inter-observer variability (IOV), weighted kappa values were calculated. RESULTS: There was moderate agreement on most of the CT scan findings among all observers. Substantial agreement was found amongst all observers for hydrocephalus, IVH, and ICH. Lowest agreement rates were seen in the location of aneurysm being supra or infra tentorial. There were, however, some noteworthy exceptions. There was substantial to almost perfect agreement between the radiology graduate and radiology resident on most CT findings. The lowest agreement was found between the neurosurgery graduate and the radiology graduate. CONCLUSION: Our study suggests that although agreements were seen in the interpretation of some of the radiological features of aSAH, there is still considerable IOV in the interpretation of most features among physicians belonging to different levels of training and different specialties. Whether these might affect management or outcome is unclear.

Long term follow-up of BEAM-autologous and BEAM-alemtuzumab allogeneic stem cell transplantation in relapsed advanced stage follicular lymphoma.

This is an analysis in 171 patients comparing BEAM-Auto and BEAM-Allo (alemtuzumab)-hematopoietic stem cell transplantation in relapsed follicular lymphoma. BEAM-Allo group had a lower 10 years cumulative incidence of relapse(31.4% vs 55.1%, p=0.042), a trend to a plateau in survival but no statistical differences in OS or DFS, and a TRM of 24%. When transplanted in CR BEAM-Allo patients had better OS and DFS. Incidence of acute and chronic GVHD was 16.6% and 22%. 29% of BEAM-Allo patients received DLI (all but two remain in CR and alive). Our data supports Allo-HSCT as a potential curative treatment for selected patients with FL.

Technology platform development for targeted plasma metabolites in human heart failure.

BACKGROUND: Heart failure is a multifactorial disease associated with staggeringly high morbidity and motility. Recently, alterations of multiple metabolites have been implicated in heart failure; however, the lack of an effective technology platform to assess these metabolites has limited our understanding on how they contribute to this disease phenotype. We have successfully developed a new workflow combining specific sample preparation with tandem mass spectrometry that enables us to extract most of the targeted metabolites. 19 metabolites were chosen ascribing to their biological relevance to heart failure, including extracellular matrix remodeling, inflammation, insulin resistance, renal dysfunction, and cardioprotection against ischemic injury. RESULTS: In this report, we systematically engineered, optimized and refined a protocol applicable to human plasma samples; this study contributes to the methodology development with respect to deproteinization, incubation, reconstitution, and detection with mass spectrometry. The deproteinization step was optimized with 20% methanol/ethanol at a plasma:solvent ratio of 1:3. Subsequently, an incubation step was implemented which remarkably enhanced the metabolite signals and the number of metabolite peaks detected by mass spectrometry in both positive and negative modes. With respect to the step of reconstitution, 0.1% formic acid was designated as the reconstitution solvent vs. 6.5 mM ammonium bicarbonate, based on the comparable number of metabolite peaks detected in both solvents, and yet the signal detected in the former was higher. By adapting this finalized protocol, we were able to retrieve 13 out of 19 targeted metabolites from human plasma. CONCLUSIONS: We have successfully devised a simple albeit effective workflow for the targeted plasma metabolites relevant to human heart failure. This will be employed in tandem with high throughput liquid chromatography mass spectrometry platform to validate and characterize these potential metabolic biomarkers for diagnostic and therapeutic development of heart failure patients.

PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement.

We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement.

Use of audit and feedback with fluorescent targeting to achieve rapid improvements in room cleaning in the intensive care unit and ward settings.

Environmental contamination of high-touch surfaces in patient rooms can lead to the transmission of clinically significant pathogens; thus, such surfaces should be cleaned routinely and thoroughly. Fluorescent targeting can be used to provide feedback to frontline cleaning staff on the thoroughness of room cleaning, which can result in substantial improvements in performance. We demonstrate that auditing with fluorescent targeting can be implemented in both the ward and intensive care unit settings using only modest resources, resulting in rapid improvements in cleaning thoroughness.