Determination of the Standard Visual Criterion for Diagnosing and Treating Presbyopia According to Subjective Patient Symptoms

Presbyopia treatments using various modalities have been developed recently; however, no standard criteria exist for the diagnosis and treatment endpoint. This study assessed the relationship between the near visual acuity (NVA) and the subjective symptoms of phakic presbyopia and determined the numerical NVA threshold to diagnose phakic presbyopia and evaluate the effectiveness of presbyopia treatment. The binocular distance, NVA with habitual correction, and monocular conventional VA were measured. Patients were asked about their awareness of presbyopia and difficulty performing near tasks. This prospective observational study included 70 patients (mean age, 56 years; range, 32–77). Most patients became aware of presbyopia in their late forties, although some had difficulty with vision-related near tasks before becoming aware of presbyopia. Eighty three percent of patients (20/24) experienced difficulty with near vision-related tasks even with excellent NVA at 40 cm with habitual correction of 0.0 logMAR (20/20 in Snellen VA). In conclusion, the current study showed that patients became aware of presbyopia in their late forties, although some had difficulty with near vision-related tasks before becoming aware of presbyopia. Further investigation should include the proposal of appropriate diagnostic criteria for presbyopia and better management for patients with presbyopia.

Comparison of transmural healing and mucosal healing as predictors of positive long-term outcomes in Crohn’s disease

Background: Transmural healing (TH) is being increasingly recognized for reflecting deep remission in Crohn’s disease (CD). The long-term clinical significance of achieving TH is still not fully known. We aimed to evaluate TH as a predictor of long-term positive outcomes using intestinal ultrasonography (US), with comparison with the established endpoint mucosal healing (MH). Methods: CD patients were consecutively recruited from September 2015 to August 2018 at a single tertiary hospital. All patients were evaluated at baseline and followed up at 6 months prospectively with a guideline-based treatment regimen. Achieving TH/MH or not was evaluated by US/colonoscopy at the first follow-up. Long-term outcomes including steroid-free clinical remission (CR), drug escalation, hospitalization, and surgery, were recorded after at least another 12 months. Results: We identified 77 patients with a median age of 30 years (range, 12–73 years). Twenty-five (32%) patients achieved TH, and 31 (40%) patients achieved MH. TH and MH were poorly correlated (Cohen’s κ = 0.387; p < 0.05). Univariate analysis showed that both MH and TH were associated with better long-term outcomes. In multivariate analysis, TH was an independent predictor of steroid-free CR [odds ratio (OR), 52.6; p < 0.001], drug escalation (OR, 0.1; p = 0.002), and hospitalization (OR, 0.05; p = 0.005), while MH was an independent predictor of drug escalation (OR, 0.3; p = 0.05). Smoking habit was the only predictor of surgery (OR, 6.6; p = 0.02). Conclusion: TH is an independent predictor of more favorable long-term outcomes than MH, suggesting that TH could become the potential treatment endpoint in CD. Plain language summary Transmural healing predicts good prognosis in Crohn’s disease The therapeutic endpoints of Crohn’s disease keep evolving. The long-term clinical significance of achieving transmural healing is not fully discovered. Transmural healing is an independent predictor of more favorable long-term outcomes than mucosal healing. Transmural healing could become the potential treatment endpoint in Crohn’s disease.

Risk of Relapse in Patients With Ulcerative Colitis With Persistent Endoscopic Healing: A Durable Treatment Endpoint

Background Deep remission in patients with UC has relied on initial achievement of biochemical, endoscopic, and/or histological remission. We evaluated persistent symptomatic remission and endoscopic healing (EH: Mayo endoscopy score [MES] 0 or 1) on consecutive endoscopic examinations as a durable treatment endpoint. Methods In a retrospective cohort study, we estimated and compared cumulative risk of clinical relapse in patients with persistent EH, with and without persistent histological remission and depth of EH, among adults with active UC treated-to-target of symptomatic remission and EH who achieved and maintained symptomatic remission and EH over two serial endoscopic assessments. We also explored risk of relapse in patients with persistent EH whose therapy was de-escalated. Results Of 270 patients who initially achieved EH with treatment-to-target, 89 maintained symptomatic remission and EH on follow-up endoscopy [interval between EH1 and EH2, 16 months]. On follow-up after EH2 [median, 19 months], 1-year cumulative risk of relapse in patients with persistent EH was 11.5%, and with persistent histological remission was 9.5%. Seventeen patients with persistent EH, who underwent de-escalation of therapy, did not have an increased risk of relapse as compared with patients who continued index therapy [5.3% vs 14%, p = 0.16]. Conclusions Patients with active UC treated-to-target of clinical remission, who achieve and maintain symptomatic remission and EH over consecutive endoscopies, have a low risk of relapse, particularly in a subset of patients who simultaneously achieve histological remission. Persistent EH should be examined as a treatment endpoint suggestive of deep remission.

Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma

Patients with multiple myeloma (MM) carrying high-risk cytogenetic abnormalities (CA) have inferior outcome despite achieving similar complete response (CR) rates when compared to cases with standard-risk CA. This questions the legitimacy of CR as treatment endpoint for high-risk MM, and represents a biological conundrum regarding the nature of tumor reservoirs persisting after therapy in patients with standard- and high-risk CA. Here, we used next-generation flow (NGF) to evaluate measurable residual disease (MRD) in MM patients with standard- (N=300) vs high-risk CA (N=90) enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and to identify mechanisms determining MRD resistance in both patient subgroups (N=40). The 36-month progression-free and overall survival rates were higher than 90% in patients with undetectable MRD, with no significant differences (P≥0.202) between cases having standard- vs high-risk CA. Persistent MRD resulted in median progression-free survival of approximately three and two years in patients with standard- and high-risk CA, respectively (P&lt;0.001). Further use of NGF to isolate MRD followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CA, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying lost or acquired genetic abnormalities driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and ROS-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as treatment endpoint for MM patients with high-risk CA and proposes characterizing MRD clones to understand and overcome MRD resistance.

Precision Medicine Based on the Achievement of Sustained Undetectable Minimal Residual Disease (MRD) By Next-Generation Flow (NGF) and Imaging Leads to Significant Reduction in Risk of Progression of Patients with Multiple Myeloma (MM)

Background: Assessing MRD has become a standard procedure in clinical trials to evaluate treatment efficacy. In accordance with its consistent prognostic value, the International Myeloma Working Group added MRD-negative criteria into response guidelines for its standardized use in clinical trials. That notwithstanding, the expectations for MRD as biomarker are to use it in routine clinical practice to help in treatment decisions, since in most clinical trials the therapeutic approach is defined upfront and does not vary according to patients' depth of response. However, the use of MRD in clinical practice is controversial and it remains unknown if tailoring treatment to achieve MRD-negativity is safe and improves patients' survival. Aim: Compare in clinical practice, outcome and tolerability of a treatment strategy tailored to achieve sustained undetectable MRD by NGF and imaging, as compared to conventional treatment approaches that are not modified according to patients' depth of response. Methods: This study was conducted in a single Hospital and included a total of 66 patients with newly-diagnosed MM from July 2014 to May 2019. All patients younger than 76 were prospectively included, whereas patients with high frailty score, severe senile dementia, other neoplasms, or with significant comorbidities in whom the therapeutic objective was only palliative care were excluded. In accordance to the local ethical committee and the Helsinki Declaration, all patients gave informed consent prior entering the study and were given the choice between the MRD and image driven (MRD-driven) and the conventional treatment (CT) approach. In the former, persistent MRD after the first-line of therapy was considered as treatment failure and patients received subsequent lines until achieving undetectable MRD by NGF and imaging (treatment endpoint). In the CT approach, subsequent lines of therapy were given upon progressive disease. The most commonly used first, second, and third line therapies in the MRD-driven approach were VBMCP/VBAD, VCD, and lenalidomide combinations, whereas in the CT cohort these were VCD for first-line, and lenalidomide combinations in second and third lines. Maintenance therapy (Interferon α2b + Prednisone for a year) was administered in 61% of patients treated according to the MRD-driven approach, and in 12% (bortezomib until progression) in the CT cohort. MRD was assessed in patients achieving complete remission using EuroFlow NGF, with a limit of detection of 2x10-6. Undetectable MRD by imaging was defined by negative PET/CT and by negative MRI of the spine and pelvis. Results: Of the 66 patients enrolled thus far, 49 were treated with the MRD-driven and 17 with the CT approach. There were no significant differences between groups regarding patients' age (median, 62 years), the Revised-ISS (37.5%, 53% and 37.5% with R-ISS-I, -II and -III) or the usage of HDT/ASCT (85% vs 76%; P>.05). Approximately 80% of patients treated with the MRD-driven approach achieved undetectable MRD at 30 months. The median time from start of treatment to undetectable MRD was 24 months, after a average of 2.2 lines of therapy. By contrast, only 1 (6%) patient treated with CT showed undetectable MRD after first line of therapy. With a median follow-up of 29 months, progression-free survival (PFS) rates at 30 months were 92% for patients treated with the MRD-driven vs 28% for the CT approach (hazard ratio 0.10 [0.04-0.30]; p<0.0001). Such impact in PFS was similarly observed in sub analyses of patients treated with or without maintenance. A trend for prolonged overall survival (OS) was observed (92% vs 81% at 30-months, respectively; p=0.12). Of note, PFS and OS rates for patients treated with the MRD-driven strategy and achieving undetectable MRD were of 100% at 30 months. No significant differences were observed regarding the number of patients with adverse events treated with the MRD-driven vs CT (47% vs 59%), the number of adverse events per patient (mean of 1.9 vs 2.4), or in the number of adverse events per year of exposure (annual incidence of 1.2 vs 2.1). Conclusions: We show that as compared to pre-specified therapies that are not modified according to patients' depth of response, an MRD-driven treatment approach reduces by 90% the risk of progression or death without increasing toxicity. These results support the use of undetectable MRD by NGF and imaging as treatment endpoint in routine clinical practice. Disclosures Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau.