Remission Time Research Articles

Laryngeal contact granuloma after radiotherapy in patients with nasopharyngeal carcinoma: a case series.

Laryngeal contact granuloma (LCG) is a benign hypertrophic lesion and phonatory injury after abnormal vocal behavior is regarded as its major etiology. Patients receiving radiation for non-laryngeal head and neck tumors are troubled by persistent voice impairment. The occurrence of LCG after radiotherapy for nasopharyngeal carcinoma (NPC) in our practice has implored us to re-exam their underlying etiology. We hypothesize that a proportion of LCG results from voice change caused by non-laryngeal head and neck cancer radiotherapy and firstly describe a distinct LCG population originated after radiotherapy for NPC with respect to the clinical profile, presentation, prognosis and response to treatment of patients. We retrospectively reviewed the laryngoscopic examination and tumor study findings to elucidate the common clinical features of patients who presented with LCG after radiotherapy for NPC. All patients were regularly monitored with telescopic examination until lesions disappeared. Data on age, sex, clinical presentation, telescopic findings, management, latency time of lesion formation, remission time and clinical outcome were reviewed. The medical review identified 27 cases of LCG secondary to radiotherapy for NPC. All lesions had been diagnosed during routine endoscopy following radiation. The interval between radiation onset and endoscopic diagnosis was 3.77 months (range, 0.67-11 months). 20 cases were resolved through simple observation, 4 cases were resolved with the administration of proton pump inhibitors (PPIs), and 3 cases with a poor response to PPI therapy required subsequent surgical resection. The mean remission time in the observation and PPI groups was 4.42 months (range, 0.73-18.9 months) and 5.78 months (range, 2.17-14.63 months), respectively. All patients recovered completely and none experienced recurrence during a mean follow-up of 32.44 months (range, 5.6-71.67 months). Iatrogenic granulomas of vocal process are presenting after radiation for non-laryngeal head and neck cancers. In contrast with spontaneous granulomas, these granulomas can be cured at high remission rates and low recurrence trend without specific intervention. Thus, simple observation may be sufficient for radiation-induced LCG.

Effects of tricyclic antidepressants, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors on the ocular surface.

This study aimed to investigate the effects of tricyclic antidepressants, selective serotonin reuptake inhibitors, and selective serotonin noradrenaline reuptake inhibitors on the ocular surface. The study included 330 eyes of 165 patients using antidepressants and 202 eyes of 101 controls. Tear fluid breakup time, Schirmer I test, and Ocular Surface Disease Index (OSDI) questionnaire were administered. Beck Depression Inventory and Beck Anxiety Inventory were applied to record drug use, dosages, psychiatric disease duration, and remission time. Mean tear fluid breakup time was 14.29 ± 4.81 (4-26) sec, and Schirmer I test value was 16.05 ± 5.89 (2-28) mm in study group. Tear fluid breakup time was 18.16 ± 2.12 (15-24) sec and Schirmer I test value was 16.64 ± 2.31 (15-24) mm in control group (p<0.001 and p=0.005, respectively). In study group, 38.18% (n=63) of patients had dry eye, and 17% (n=18) of patients in control group had dry eye (p<0.001). The mean OSDI score was 82.56 ± 16.21 (66-100) in the tricyclic antidepressants Group, 60.02 ± 29.18 (10-100) in the serotonin reuptake inhibitors Group, and 22.30 ± 20.87 (0-75) in the serotonin-noradrenaline reuptake inhibitors Group (p<0.001). Mean tear fluid breakup time was 14.36 ± 3.35 (10-20) sec in tricyclic antidepressants Group, 13.94 ± 5.81 (4-26) sec in the serotonin reuptake inhibitors Group, and 14.93 ± 4.20 (6-20) sec in serotonin-noradrenaline reuptake inhibitors Group (p=0.730). The mean Schirmer I test value was 9.90 ± 7.22 (2-30) mm in tricyclic antidepressants Group, 15.55 ± 5.15 (2-25) mm in serotonin reuptake inhibitors Group and 17.71 ± 4.21 (10-30) mm in serotonin-noradrenaline reuptake inhibitors Group (p<0.001). There was no statistically significant difference between OSDI score, tear fluid breakup time, and Schirmer I test values in serotonin reuptake inhibitors and serotonin-no-radrenaline reuptake inhibitors subgroups. Dry eye is common in antidepressant users, but considering the ocular surface, serotonin-noradrenaline reuptake inhibitors may be more reliable than other antidepressants. Patients using serotonin-noradrenaline reuptake inhibitors have lower OSDI scores. Serotonin-noradrenaline reuptake inhibitors, which are useful in chronic pain syndromes, may also have a corrective effect on dry eye symptoms.

Clinico-biochemical Profile of Biopsy-proven Minimal Change Disease in Adults from a Tertiary Care Center in South India.

Minimal change disease (MCD) is the most common cause of nephrotic syndrome (NS) in children, and in adults, it contributes to 10%-25% of NS. MCD in adults follows a slightly different course associated with increased incidence of steroid resistance, hematuria, and HTN. This is a prospective-record analysis study aimed to analyze the profile of MCD in adults, response to treatment, and relapse rates. A retrospective observational study was carried out and data were collected retrospectively from all biopsy-proven MCD patients between 2012 and 2018. A total of 86 adults were diagnosed to have biopsy-proven MCD. Of these, 32 were excluded due to insufficient data/lost for follow-up. The IBM SPSS Statistics version 22.0 was used for the statistical analysis. Descriptive analysis includes expression of all the explanatory and outcome variables in terms of frequency and proportions for categorical variables whereas in terms of mean ± standard deviation for continuous variables. Chi-square test was used to compare the age, gender, remission, renal failure and response of different drugs, treatment durations, comorbidity conditions, relapse episodes, and different types of infections based on the degree of proteinuria among study patients. A total of 54 biopsy-proven adult MCD patients were analyzed. The mean age of the patients studied was 36.67 years, with the oldest patient being 76 years. In the study group, 37 (68.5%) patients were male and 14 (31.5%) were female. In the study population, 20 (37%) were hypertensive, 3 (5.6%) were diabetic, and 10 (18.5%) had renal failure at presentation. On treatment, 52 out of 54 patients received steroids, of which 41 (75.9%) were steroid responsive, 6 (11.1%) steroid dependent, and 7 (13%) steroid resistant. The mean time for remission in steroidsensitive patients was 8.8 weeks. Among the steroid-dependent and steroid-resistant patients, 11 patients received calcineurin inhibitors (CNIs), of which 3 were CNI resistant. In the study Group 1 patient received cyclophosphamide and two received rituximab. In the study population, two patients failed to achieve remission and one patient was initiated on hemodialysis and later lost for follow-up. Minimal change NS is a type of NS which is highly responsive to steroids with good prognosis in children. Adult MCD patients require a higher and prolonged course of steroid when compared to children. CNIs and rituximab form a promising second-line drug in patients who are steroid resistant/dependent. However, CNI dependency or relapse after stopping steroids is a concern.

Effect of Medicine and Adverse Drug Reactions of Vonoprazan Fumarate Tablets in Patients with Reflux Esophagitis

To investigate the drug effects of vonoprazan fumarate tablets on reflux esophagitis and their adverse drug reactions is the objective of the study. A total of 102 patients with reflux esophagitis admitted to the Department of Gastroenterology of the Affiliated People’s Hospital of Ningbo University from June 2021 to November 2022 were selected and randomly grouped, with 51 cases in the observation group and 51 cases in the control group. The observation group received vonoprazan fumarate tablets and the control group received rabeprazole for 8 w. The drug effects of the two groups were analyzed, including the duration of symptom relief, changes in esophageal motility, the level of serum gastric hormone, the injury degree of esophageal mucosa and the level of inflammatory factors. Adverse drug reactions were analyzed in the two groups. After medication, the symptom remission time, changes in esophageal motility, serum gastric hormone level, esophageal mucosa injury degree and inflammatory factor level in observation group were better than those in control group (p<0.05). The total incidence of dizziness, rash, diarrhea and other adverse drug reactions in the observation group was 3.92 %, which was significantly lower than that in the control group (9.8 %, p<0.05). In conclusion, vonoprazan fumarate tablets has obvious effect on the treatment of reflux esophagitis with low adverse reactions, which is worthy of clinical promotion.

Comparing the Performance of a Survival Models In a Computerized Dataset

Every patient demonstrates the loss of one year of healthy life. In addition, 7.6% of global DALYs are assigned to the neoplasms. The three leading cancers in both sexes worldwide were lung cancer (13% of the total), breast cancer (11.9%), and colorectal cancer (9.7%); the most common types of cancer in men, respectively, are lung cancer (16.8%), prostate cancer (14.8%) and colorectal cancer (10.1%) while in women they are ordered as breast cancer (25.1%), colorectal cancer (9.2%) and lung cancer (8.8%). The research aimed to compare the performance of Weibull, Log-logistics, and Gompertz survival models on oncological data. The research methodology involved the collection of data cases on oncological study analyzed using descriptive statistics, parametric survival models were also used in the analysis. The result shows the maximum likelihood estimates of dataset 1 with 3 with a different model fit, all the information criteria and log-likelihood of the models indicate that Gompertz model has the smallest value in all the information criteria, indicating that Gompertz model is the best-fitted model to Remission Times of Bladder Cancer patient’s data. The research concludes that a parametric that can best be used to model cancer data known as Gompertz model is the best-used model in the research. The research will enable other researchers such as medical personnel to model or know the best model for cancer-related cases.

Spontaneous remission of vision degrading myodesopsia of posterior vitreous detachment type.

The study aims to observe the spontaneous remission of posterior vitreous detachment (PVD)-type vision degrading myodesopsia (VDM) during long-term follow-up. We retrospectively reviewed VDM patients with PVD type that refused any treatment. The ratio and time of significant spontaneous remission of floater symptoms occurring were described. The associated factors with significant remission of floater symptoms were analyzed in the univariate and multivariate logistic regression analyses. In total, 179 patients with VDM were assessed. The mean age of all patients was 60.56 ± 0.47years old, and the mean duration of follow-up was 23.89 ± 6.63months. Of the patients, 40.78% have significant improvement in their floater symptoms after mean 16.55 ± 10.63-month follow-up. Myopia (OR = 0.280, 95% CI = 0.084-0.932, P = 0.038), the number of floaters > 3 (OR = 0.343, 95% CI = 0.172-0.683, P = 0.002), and floaters with string-like pattern (OR = 0.370, 95% CI = 0.166-0.824, P = 0.015) and blocky pattern (OR = 0.299, 95% CI = 0.090-0.993, P = 0.049) were negatively correlated with the significant spontaneous remission of VDM symptoms in the multiple binary logistic regression analysis. Approximately 40% of VDM patients with PVD may experience significant spontaneous remission during long-term follow-up. Patients that are non-myopic and with fewer floaters are more likely to feel relief from VDM symptoms. Floaters with string-like or blocky patterns are less likely to undergo spontaneous remission.

Predictive Parameters of Steroid Dependency in Minimal Change Disease

The most common type of nephrotic syndrome in children is minimal change disease (MCD), which is usually responsive to steroid therapy. Steroid dependency is one of the handicaps in the management of these children. Thus, the early prediction of the disease course may improve treatment strategy. Demographic characteristics and laboratory parameters of 35 patients at the time of MCD diagnosis were retrospectively obtained from the hospital records. There were 23 (65%) patients with steroid sensitive (SSNS) and 12 (35%) with steroid dependent nephrotic syndrome (SDNS). There was a significant difference between the patients with SSNS and SDNS in terms of age at diagnosis, remission time, and mean values of platelet volume, low density lipoprotein cholesterol, uric acid, urine protein-to-creatinine ratio, total cholesterol and creatinine (p = 0.003, p &lt; 0.001, p = 0.013, p = 0.006, p = 0.036, p = 0.02, p = 0.003, and p = 0.034, respectively). The prediction of early markers of steroid dependency can reduce the side effects of steroids and facilitate the use of appropriate drugs.

Spotlight on a Short-Time Treatment with the IL-4/IL-13 Receptor Blocker in Patients with CRSwNP: microRNAs Modulations and Preliminary Clinical Evidence.

Already used for the treatment of some allergic and inflammatory diseases, such as asthma or atopic dermatitis, dupilumab has also been approved as add-on therapy for patients with CRSwNP, and it could represent the keystone to reducing the remission time as well as to improve healing and quality of life. On the other hand, the role of miRNAs as potential biomarkers of immune modulation is emerging. We analyzed the effects of a short-time treatment with dupilumab in patients with CRSwNP, analyzing the immune response modification as well as miRNAs modulations. First, in this early observation stage, all patients experienced remarkable improvement and were clinically stable. Indeed, we observed a significant decrease in CD4+ T cells and a significant reduction in total IgE (p &lt; 0.05) and serum IL-8 levels (p &lt; 0.01), indicating a reduction in the general inflammatory condition. In addition, we analyzed a panel of about 200 circulating miRNAs. After treatment, we noted a significant downregulation of hsa-mir-25-3p (p-value = 0.02415) and hsa-mir-185-5p (p-value = 0.04547), two miRNAs involved in the proliferation, inflammation, and dug-resistance, in accordance with the clinical status of patients. All these preliminary data aimed to identify new biomarkers of prognosis, identifiable with non-invasive procedures for patients. Further, these patients are still under observation, and others with different levels of responsiveness to treatment need to be enrolled to increase the statistical data.

The Proportional Hazard Generalized Power Weibull Distribution: Properties, Applications and Regression Model

We introduce the proportional hazard generalized power Weibull (PHGPW) model in which hazard rate function can assume increasing, decreasing, unimodal or (upside bathtub) and constant. Some of its mathematical properties are studied including the power series for the quantile function. Monte Carlo simulation was performed to determine the finite sample behaviour of the maximum likelihood estimates of the parameters. The flexibility of the PHGPW distribution compared with some other existing distributions is proved empirically by means of two sets of real data related to remission times of bladder cancer patients and strike duration of manufacturing company. A new regression model was defined based on the PHGPW distribution. The performance of the regression model is proved empirically using real data set.

Low-Grade Hepatic Steatosis Is Associated with Long-term Remission of Type 2 Diabetes Independent of Type of Bariatric-Metabolic Surgery

BackgroundBariatric-metabolic surgery (BS) decreases the grade of steatosis, hepatic inflammation, and fibrosis in patients with severe obesity and non-alcoholic fatty liver disease (NAFLD). Mechanisms include substantial weight loss, but also simultaneous effects on glucose homeostasis. Therefore, we aimed to investigate the association between NAFLD and remission of type 2 diabetes (T2D) up to 8 years following different types of BS.MethodsIn a retrospective cohort study including 107 patients with obesity and T2D at baseline, the association between biopsy-proven NAFLD defined as steatosis in > 5% of hepatocytes at the time of surgery and T2D remission up to 8 years following different surgical procedures was investigated. Univariate regression analysis was used to examine the association between NAFLD and remission of T2D.ResultsLong-term remission of T2D was present in 56% of patients (n = 60). The presence of low-grade liver steatosis (grade 1) was associated with remission of T2D. Patients with a liver steatosis score ≥ 2 showed higher HbA1c levels at baseline. There were no significant differences in preoperative presence of lobular inflammation, hepatocyte ballooning, or fibrosis between patients who achieved T2D remission compared with those with no remission. Type of surgery did not affect remission of T2D.ConclusionOur results suggest that the presence of low-grade liver steatosis is associated with remission of T2D following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Therefore, BS should be considered at an early NAFLD stage in patients with T2D.Graphical

Efficacy and tolerability of a 12-week combination chemotherapy followed by lomustine consolidation treatment in canine B- and T-cell lymphoma

BackgroundHigh-grade lymphoma in dogs is a chemotherapy-responsive neoplasia with remission rates exceeding 80% under combination chemotherapy protocols. Usually these protocols are intensive and 24 + weeks. The objective of the present study was to investigate if a shorter protocol combined with an oral lomustine maintenance treatment (3 × in 8 weeks) would present an acceptable result, both for B- and T-cell lymphomas, and for the different types of lymphomas normally encountered in private veterinary practice.Results144 dogs entered the study. Lymphoma types included multicentric (n = 123), alimentary (n = 13), miscellaneous (n = 7), and mediastinal lymphoma (n = 1). Overall response rate was 83.3% (B-cell: 86.6%, T-cell: 79.4%). Complete remission (CR) was achieved in 72.2% (B-cell: 77.3%, T-cell: 67.6%) and partial remission (PR) in 11.1% (B-cell: 9.3%, T-cell: 11.8%) of the dogs. Median duration of first CR amounted to 242 days (B-cell: 263 d, T-cell: 161 d). Median survival in dogs with CR was 374 days (B-cell: 436 d, T-cell: 252 d), and median overall survival time was 291 days (B-cell: 357d, T-cell: 210d). Immunophenotype demonstrated an independent significant influence on duration of remission and survival in the whole group. Findings of splenic and hepatic cytology were not significant associated with patient outcome. Treatment was well tolerated; the majority of adverse events were classified as grade 1 or 2.ConclusionsShort-term chemotherapy followed by lomustine consolidation leads to compara-ble remission and survival times compared to conventional protocols with cyclophosphamide, doxorubicin, vincristine and prednisolone with acceptable toxicosis in dogs with both B-cell and T-cell lymphoma.

CO148 Time in Remission as an Alternative Outcome Measure for Ankylosing Spondylitis: A 4-Year Prospective Study of 1900 Users of Anti-TNF

We have recently validated time in remission (TIR; https://www.medevio.cz/tir-calculator/) as novel outcome measure for rheumatoid arthritis patients. This study aimed to introduce TIR in ankylosing spondylitis (AS).

Patient Preferences for Rescue Medications in the Treatment of Breakthrough Cancer Pain.

The discrete choice experiment (DCE) is conducted in this study to discuss Chinese cancer patients' risk-benefit preferences for rescue medications (RD) and their willingness to pay (WTP) in the treatment of breakthrough cancer pain (BTcP). Through literature reviews, specialist consultation, and patient surveys, this work finally included five attributes in the DCE questionnaire, i.e., the remission time of breakthrough pain, adverse reactions of the digestive system, adverse reactions of the neuropsychiatric system, administration routes, and drug costs (estimating patients' WTP). The alternative-specific conditional logit model is used to analyze patients' preferences and WTP for each attribute and its level and to assess the sociodemographic impact and clinical characteristics. A total of 134 effective questionnaires were collected from January, 1 to April, 5 in 2022. Results show that the five attributes all have a significant impact on cancer patients' choice of "rescue medications" (P<0.05). Among these attributes, the remission time after drug administration (10.0; 95%CI 8.5-11.5) is the most important concern for patients, followed by adverse reactions of the digestive system (8.5; 95%CI 7.0-10.0), adverse reactions of the neuropsychiatric system (2.9; 95%CI 1.4-4.3), and administration routes (0.9; 95%CI 0-1.8). The respondents are willing to spend 1182 yuan (95%CI 605-1720 yuan) per month for "rescue medications" to take effect within 15 minutes and spend 1002 yuan (95%CI 605-1760 yuan) per month on reducing the incidence of drug-induced adverse reactions in the digestive system to 5%. For Chinese cancer patients, especially those with moderate/severe cancer pain, the priority is to relieve the BTcP more rapidly and reduce adverse drug reactions more effectively. This study indicates these patients' expectations for the quick control of breakthrough pain and their emphasis on the reduction of adverse reactions. These findings are useful for doctors, who are encouraged to communicate with cancer patients about how to better alleviate the BTcP.

Randomized controlled trial demonstrates nutritional management is superior to metronidazole for treatment of acute colitis in dogs.

To describe the outcome of dietary management of canine noninfectious acute colitis with or without concurrent oral administration of metronidazole using a randomized controlled clinical trial. 59 client-owned dogs with noninfectious acute colitis. Dogs with acute noninfectious colitis were enrolled in a 30-day diet trial after exclusion of parasitic infectious etiologies (fecal centrifugation floatation, Giardia/Cryptosporidium antigen testing) and systemic disease (CBC, biochemistry, urinalysis). Dogs were randomized into 3 placebo-controlled groups: group 1, easily digestible diet + placebo tablet; group 2, easily digestible diet + metronidazole tablet; and group 3, psyllium-enhanced easily digestible diet + placebo tablet. Dogs were evaluated serially using fecal scoring for time to remission, average fecal score, relapse after remission, and dysbiosis index. Median remission time was significantly different among the 3 groups (P < .01) with median times of 5 days (range, 4 to 10) for group 1, 8.5 days (range, 7 to 12) for group 2, and 5 days (range, 3 to 6) for group 3. Metronidazole addition affected the fecal dysbiosis index negatively at days 7 to 10. No adverse effects or complications were noted throughout the study. For canine noninfectious acute colitis, dietary management with an easily digestible diet with or without psyllium enhancement proved a superior management strategy compared to metronidazole. The omission of metronidazole reduced the adverse impact significantly on intestinal microbiota. Longitudinal clinical trials are necessary to compare the long-term response, stability, and complications associated with dietary management alone versus combined dietary and antimicrobial therapy for canine acute colitis.

Cell-Free DNA (cfDNA)-Based Measurable Residual Disease (MRD) Detection As a Predictor of Relapse Post-Allogeneic Blood or Marrow Transplant (alloBMT) in Patients with Myeloid Malignancies

Background: AlloBMT is the only curative therapy for many patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). With the significant improvement in non-relapse mortality, disease relapse remains the main cause of therapeutic failure. The presence of leukemia-specific somatic mutations provides an attractive strategy for molecular assessment of measurable residual disease (MRD). The level of MRD at the time of complete remission (CR) has been an important predictor of relapse in patients undergoing alloBMT. Widely utilized molecular MRD assays require invasive bone marrow (BM) aspiration to ensure an adequate amount of residual leukemia cells. Circulating tumor DNA (ctDNA) released from malignant cells can be reliably detected in patients' plasma and has been widely used in diagnosis, early detection, and disease burden monitoring in solid tumors. This assay is not widely used in myeloid malignancies as the proper assessment of its technical and clinical utility as an MRD monitoring strategy has not been performed. In the current study, we aimed to determine the differential sensitivity between bone marrow and ctDNA-based MRD and its utility as a minimally invasive diagnostic and disease monitoring tool. Additionally, we evaluated the clinical utility of dynamic ctDNA-based MRD monitoring and its effect on post-alloBMT relapse by using plasma samples from 2 large prospective clinical trials (BMT CTN 0201 and 0402). Methods: The technical validation cohort included 20 consecutive patients with myeloid malignancies undergoing alloBMT at Johns Hopkins. A minimum of 10mL of plasma and bone marrow DNA was collected at the time of remission and at multiple time points after alloBMT. The clinical validation cohort included 90 patients participating in two prospective alloBMT trials (BMT CTN-0201 and 0402). The eligibility criteria included the diagnosis of myeloid malignancy (72 AML, 18 MDS) and the minimum of 2mL of plasma available from day 0 and/or day 90 after alloBMT. Ultra-deep error-corrected targeted sequencing was performed on plasma and bone marrow-derived DNA. The variant allele frequency (VAF) per patient was represented by the maximum VAF of all detected mutations. Results: To measure the exact contribution of hematopoietic tissue to plasma cell-free DNA (cfDNA) we analyzed cfDNA in alloBMT recipients. Using donor and recipient-specific polymorphisms we demonstrated that after full donor hematopoietic reconstitution by standard chimerism assays (day +180), 94.6% (range 93.9-95.3%) of cfDNA was of hematopoietic origin. To determine the differential sensitivity of the cfDNA vs. BM-based MRD we focused only on leukemia-specific mutations found in the diagnostic specimens. The minimum level of detection was 0.03%. Forty leukemia-specific mutations were detected in the technical validation cohort. Out of 31 mutations seen in the BM, only 3 were not detected in cfDNA (3/31, 9.7%). On the contrary, out of 37 mutations in cfDNA, 9 were not seen in BM (9/37, 25%). While we observed a strong positive correlation (rho = 0.8, p<0.0001) at any level of MRD between BM and cfDNA, cfDNA was superior at the lower MRD level (VAF cut-off < 0.26%). The clinical utility of cfDNA MRD was utilized in a separate validation cohort of 90 patients enrolled on 2 BMT CTN trials. The median (Q1, Q3) follow-up was 26 months (25 - 27 months). cfDNA-MRD positivity (VAF cutoff >0.25%) at day +90 was associated with significantly worse relapse-free survival (RFS) (46.2% vs 84.0%, p<0.001) and overall survival (OS) at two years (53.8% vs 87.2%, p=0.0013) after alloBMT. Conclusions: cfDNA-based MRD assessment appears to be a promising, minimally invasive test that provides important prognostic information in patients with myeloid malignancies undergoing alloBMT. The presence of cfDNA MRD at day 90 post alloBMT was associated with significantly worse RFS and OS in patients with myeloid malignancies. The dynamic assessment of MRD by cfDNA may not only provide important prognostic information but may also guide the therapeutic decision-making and timely implementation of post-alloBMT maintenance therapies to improve outcomes of patients with myeloid malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Whole Genome Sequencing Comparison of Acute Myeloid Leukemia at Presentation and Remission Predicts Patient Outcome

Background: Acute myeloid leukemia (AML) is the most common leukemia in adults with more than 20,000 new cases in the U.S. each year. While about two-thirds of patients who receive standard induction chemotherapy reach complete remission, about half of those will relapse within two years. There are several known risk factors for relapse including age, cytogenetics, and a few specific mutations; however, there is still a need for better prognostic information to guide therapy and improve patient outcome. Measurement of residual disease has proven helpful in predicting patient outcome. Current approaches for measuring minimal residual disease (MRD) include multiparameter flow cytometry, which can detect abnormal myeloid blast populations based on the expression of cell-surface markers, and targeted molecular assays measuring variant frequency of common mutations. Molecular approaches have higher sensitivity than flow cytometry; however, many targeted assays follow only a single mutation, which does not capture the within patient genomic heterogeneity of AML. In this study, we applied whole genome sequencing (WGS) to study MRD at the time of complete remission in AML, revealing the full spectrum of genomic response to treatment and its correlation with patient outcome. Methods: Bone marrow biopsy or peripheral blood specimens were collected at the time of presentation and remission from 18 patients with AML. All patients were treated with standard-of-care induction chemotherapy. Among the 18 patients, 8 relapsed and 10 did not relapse. Corresponding clinical and outcome data (median follow-up of 26 months) were collected as well as matched flow cytometry data at remission on 11 of 18 cases. Deep whole genome sequencing (104x median depth) was performed on DNA from paired presentation and remission specimens. Single nucleotide variants were called from both samples, with a mutation caller capable of identifying low frequency variants. Quality filters and population frequency filters were applied to the variant set. Remaining variants were then classified into five classes based on their variant frequency pattern. Results: Figure 1A shows variant frequencies for two representative patients. Variants can be broadly classified into five classes: (A) likely germline variants, clustered at the expected variant frequency of 0.5 (grey); (B) leukemia-specific variants which are dramatically reduced in frequency upon treatment (dark red); (C) leukemia-enriched variants which are incompletely reduced at remission (bright red); (D) remission-specific variants that were not detectable at presentation but are prevalent at remission (dark blue); and (E) remission-enriched variants which have increased in frequency at remission (light blue). The proportion of variants belonging to classes B, C, D, and E correlates with both MRD status and patient outcome, as shown in Figure 1B. Patients with a higher ratio of leukemia-specific to leukemia-enriched variants are more likely to be alive at one year. Patients who relapsed tend to have a higher number of leukemia-enriched variants, which may represent variants in pre-leukemic cells or leukemic stem cell populations. Patients with a poor outcome also tend to have a higher number of new and increasing remission-specific and remission-enriched variants. This suggests that their remission state has not returned to normal, but is re-populated with clonal populations of cells containing a significant number of somatic variants. The few discrepancies between WGS and MRD flow cytometry suggest that the WGS data could be more predictive of patient outcome. For example, there are two MRD positive cases in which the WGS profiles suggest a good outcome, consistent with the actual patient outcome. In two other cases, neither flow cytometry nor WGS profiles predicted the patients’ relapses. We find that DNMT3A, TET2, ASXL1 mutations have high frequencies at both time points and cluster outside of the labeled classes of variants, whereas other driver gene mutations such as NPM1, NRAS, and IDH1 cluster with the leukemia-specific variants. Conclusion: Our study shows promising evidence for the utility of WGS to predict patient outcome in AML in the setting of intensive chemotherapy. Combining WGS with targeted deep sequencing approaches may further increase the predictive power of genomic approaches. Collection and analysis of a larger case series is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The CAR-Hematotox Score Identifies Patients at High Risk for Hematological Toxicity, Infections and Poor Clinical Outcomes Following Brexucabtagene Autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Background: Hematological toxicity and infectious complications drive the toxicity burden of CD19 CAR-T. We recently developed the CAR-HEMATOTOX (HT) score - a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes in LBCL patients (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters associated with pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of prognostic utility in relapsed/refractory mantle cell lymphoma (R/R MCL) remains unstudied. Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and survival in 78 patients receiving standard-of-care brexucabtagene autoleucel (brexu-cel) across seven international sites. Patterns of hematopoietic recovery were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). The duration of severe neutropenia was assessed as the total cumulative days with an ANC<500/µl between days 0-60. Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (Grade ≥3) infections were defined as requiring intravenous anti-infectives and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Results: The study cohort comprised a representative cohort of R/R MCL patients treated in a real-world setting: median age was 68 (range 49-89), median ECOG PS was 1, median LDH was 217 U/L (interquartile range 171-289 U/L), and patients had received a median of 3 prior treatment lines (IQR 2-4). Of note, 28% of patients had received a prior autologous stem cell transplant (ASCT) and >90% were BTKi exposed. The rate of severe (grade ≥3) CRS and ICANS was 2.6% and 27%, respectively. Tocilizumab was applied in 82% of patients, while glucocorticoids were used in 64% of all cases. Across all patients, the median duration of severe neutropenia was 8 days (IQR 5-15). The distribution of neutrophil recovery phenotypes was: 30% quick, 46% intermittent, and 24% aplastic. The cumulative 90-day incidence of any-grade and severe infections was 37% and 17%, respectively. The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 42 HTlow (Score 0-1) and 36 HThigh (Score ≥2) patients. When comparing risk groups, we noted higher serum LDH levels in HThigh patients(median 261 vs. 209 U/L, p=0.07).In terms of toxicity, the incidence of severe CRS and ICANS was comparable between both groups. However, the duration of neutropenia was significantly increased in HThigh patients compared to their HTlow counterparts (15 vs. 7 days, p<0.001). Moreover, the proportion of patients displaying an aplastic phenotype of neutrophil recovery, defined by continuous severe neutropenia ≥14 days, was markedly increased in the HThigh group (53 vs. 0%, p<0.0001, Fig. 1A). This translated into a higher rate of severe infectious complications in the HThighgroup (28% vs. 7%, p=0.03), including 3 life-threatening (all bacterial), and 2 fatal infections (1 bacterial, 1 fungal).Notably, a high HT score was associated with markedly inferior PFS (median 7.5 months vs. not-reached, p=0.0006, Fig. 1B) and OS (median 15.3 months vs. not-reached, p=0.0004). Comparing the HThigh vs. HTlow groups, we observed 1-year PFS of 73% vs. 38% and 1-year OS of 88% vs. 51%. Conclusions: Taken together, these findings underline the importance of pre-CAR-T bone marrow reserve and systemic inflammation in driving immunotoxicity after CD19 CAR-T therapy. Importantly, they validate the utility of the HT score to risk-stratify patients for hematotoxicity, severe infections and poor survival outcomes prior to brexu-cel infusion. The score can be used to aid clinical decision-making concerning anti-infective prophylaxis and early or prophylactic G-CSF use. Considering that ASCT represents a mainstay of frontline MCL therapy, the HT score may also guide the use of stem cell rescue (obtained at time of remission) for the patients developing severe CAR-T-related aplasia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multiparameter Flow Cytometry-Based Residual Disease Analysis Identifies Intermediate-Risk AML Patients Who May Benefit from Allogeneic Hematopoietic Stem Cell Transplantation

Background Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative therapeutic modality in acute myeloid leukemia (AML). While numerous studies have confirmed the benefit of alloSCT - improved overall survival (OS) and reduced cumulative incidence of relapse (CIR) - restricted mainly to the intermediate and high-risk groups, indications for alloSCT are becoming more restricted over time. Residual disease (RD) monitoring has been proven to be highly predictive of long-term AML outcomes and is now used commonly to guide ongoing therapy decisions. RD-based guidelines in AML propose the use of multiparameter flow cytometry-based RD (FRD) analyses in patients whose disease cannot be followed by molecular means (e.g. CBF AML, APL, NPM1-mutated AML). Methods We performed a retrospective review to evaluate the potential therapeutic benefit of alloSCT in AML patients who achieved first complete remission (CR1) and to further define this benefit based on the FRD status at remission. We performed a time-dependent analysis using the covariate of time-to-alloSCT as the primary endpoint of the study. The Mantel-Byar method was applied to compare time to event between the alloSCT and non-transplant groups, addressing time bias concerns that occur with alloSCT studies, according to the FRD status at the time of remission. Results The FRD assay has been part of our standard of care since 2015 with a sensitivity of 0.1%. The cohort analyzed included 435 patients treated between 2015 and 2018, of which 336 patients had FRD assessment at CR1. The patients were risk classified using the European Leukemia Network (ELN) 2017 classification which integrates cytogenetic and mutational analyses. The proportion of patients with positive FRD (RDpos) at the post-induction time-point was 35.1% (n=118). Negative residual disease (RDneg) status after induction occurred more frequently in de novo, favorable risk, and NPM1-mutated AMLs, than in the adverse risk or secondary AML groups. Overall, across all ELN 2017 groups, the impact of alloSCT was neutral for both OS and relapse free survival (RFS). A potential impact of alloSCT could be discerned, however, when patients were grouped by FRD status at CR assessment. Overall, in the RDpos group, alloSCT improved OS and RFS, while not benefitting the RDneg group. The impact of alloSCT was defined further by considering ELN 2017 risk groups, with an OS/RFS benefit observed in adverse risk patients (n=186; HR for OS 0.55 [0.31-0.99]; p=0.05); HR for RFS 0.57 [0.31-1.05], p=0.07), while an increased risk of death or of an RFS event was seen in favorable risk patients (n=151; HR for OS 4.3 [1.65-11.2], p=0.003; HR for RFS 2.29 [1.07-4.93], p=0.03). In the ELN 2017 intermediate risk patients (n=98), a survival benefit of alloSCT was not seen (HR for OS 1.05 [0.45-2.46], p=0.92; HR for RFS 0.86 [0.42-1.78], p=0.69), although alloSCT was associated with a lower CIR (HR 0.43 [0.20-0.90], p=0.03). However, when only RDpos patients were considered (n=27), trends towards benefit from alloSCT in OS (HR 0.52 [0.11-2.52], p=0.42), RFS (HR 0.38 [0.09-1.62], p=0.19), and CIR (HR 0.44 [0.07-2.72], p=0.38) were observed. In RDneg patients (n=53), alloSCT was associated only with a lower CIR (HR 0.18 [0.05-0.66], p=0.01). We then re-analyzed the data using the older UK-MRC risk classification of AML based exclusively on cytogenetics at diagnosis. This approach increased the patients in the intermediate group from 98 (ELN 2017) to 298 (UK-MRC). When using UK-MRC, an RFS benefit from alloSCT was observed for intermediate risk RDpos patients (n=211; HR 0.44 [0.20-0.96], p=0.04). Trends for benefit in OS (HR 0.45 [0.19-1.03], p=0.06) and CIR (HR 0.45 [0.20-1.04], p=0.06) were observed as well. In RDneg patients, however, an RFS/CIR benefit of alloSCT was not observed, while inferior OS was seen in the alloSCT group from increased non-relapse mortality. Conclusion Our data underscore the established benefit of alloSCT in adverse risk AML and suggest a potential benefit of this treatment modality in RDpos intermediate risk patients, thus confirming the utility of ongoing RD assessment in AML. Our results also indicate that ongoing sophistication in AML risk assignment, based on mutational profile at diagnosis, influences the potential benefit of alloSCT. Further studies are needed to better define the subgroup of RDpos intermediate risk patients who may benefit from alloSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Novel Germline PAX5 Single Exon Deletion in a Paediatric Patient with B-Cell Leukaemia

Germline predisposition underlies leukaemia development in children in 5-10% of the cases. Over the past years, several somatic drivers for leukaemia, including IKZF1, RUNX1, ETV6 and PAX5, have also been identified as leukaemia predisposing genes. For example, two germline PAX5 missense variants (p.Arg38His and p.Gly183Ser) have been identified in five families with a high incidence of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). The susceptibility to BCP-ALL in these patients is inherited in an autosomal dominant pattern with an incomplete but relatively high penetrance. The leukemic cells in the patients showed loss of the wild-type allele or a somatic mutation, suggesting a second hit is required for leukaemia development in this context. We present a boy who developed BCP-ALL at 5-years-old, with a father who was diagnosed with acute undifferentiated leukaemia at infancy. Because of his family history, germline testing of the patient and his parents was performed using SNP-based copy number analysis and whole exome sequencing (WES). This revealed a PAX5 exon 6 deletion in the child, which was absent in both parents. The PAX5 deletion causes a frameshift with premature stop in exon 7, resulting in a truncated protein with loss of the C-terminal transactivating and inhibitory domains. In contrast to what has been observed in patients with germline PAX5 missense variants, a second somatic hit in PAX5 was not observed. Genotype analysis, using heterozygous SNPs around the PAX5 deletion, revealed that the PAX5 deletion had occurred on the paternal allele. To test whether this deletion was present in (low) mosaic state in the father, we developed a sensitive breakpoint spanning PCR. Also with this method, the PAX5 deletion was not detected in DNA derived from blood and buccal cells of the father. Since we expected a causative germline variant to be inherited from the father, we re-analysed all sequence and copy number variants in the patient-parents' trio datasets for any other aberrations, but no plausible alternative candidates were identified. Since routine diagnostic analysis of PAX5 deletions is usually performed only in leukaemia samples, germline deletions could potentially be missed, particularly in isolated cases. To investigate the incidence of germline PAX5 deletions, we used a multiplex-ligated probe amplification (MLPA) dataset from 2041 ALL patients, from which we selected 303 cases with single-exon or partial (multiple exon) PAX5 deletion. Subsequently, we performed MLPA on 261 DNA samples from bone marrow or peripheral blood at time of remission. No additional case was found, suggesting that germline PAX5 deletions, if recurrent, are very rare. In conclusion, we present a boy with ALL carrying a de novo germline PAX5 exon 6 deletion leading to a truncated protein. Germline PAX5 deletions have not yet been described in ALL patients but since somatic PAX5 aberrations are common in ALL and germline PAX5 variants have been associated with ALL, we consider that this focal germline PAX5 deletion did contribute to leukaemia development in the boy.

Impact of Trial Eligibility Criteria on Outcomes of 1,245 Patients with Follicular Lymphoma Treated in the Real-World Setting: A Danish Population-Based Study

Background For most patients, follicular lymphoma (FL) is an incurable, chronic disease and time in remission gradually becomes shorter with each new treatment intervention. Survival after 1st line immunochemotherapy is excellent overall, but outcomes for the minority with progression of disease within 24 months of first line treatment (POD24) are dismal. The 10-year overall survival (OS) rate in clinical trials of 1st line immunochemotherapy is around 80%, making further survival improvements difficult to achieve. However, the unmet medical needs could be more substantial for the group of patients which are excluded from trial participation due to violation of inclusion/exclusion criteria. Aim To investigate the impact of commonly used in/exclusion criteria in clinical trials on the OS of real-world patients with FL. Methods This study is based on a nationwide population-based lymphoma registry (LYFO). Patients ≥18 years with grade 1-3 FL (including 3B as grade 3 is not subcategorized in LYFO) and diagnosed between 2000-2018 were included if they had received 1st line treatment with R-CVP, R-CHOP or R-Bendamustin within 90 days of date of diagnosis. The eligibility criteria from following trials were applied to the patient population: GALLIUM, RELEVANCE, BRIGHT, and StiL NHL1. First, patients were selected to match the age group and disease stages relevant for the trials. The impact of performance status (ECOG PS), hemoglobin, platelets, neutrophil count (estimated as total WBC-lymphocyte count), liver function (ALAT, bilirubin) and kidney function (estimated by eGFR) on OS were assessed. Shapley-values measuring an average decrease in 5-year restricted mean survival difference by omitting a criterion were used to assess the impact of the inclusion criteria on the OS difference between eligible and ineligible patients. Results A total of 3,702 adults were diagnosed with FL, of those 1,183 were included in the study. Median age was 63 and male:female ratio was 1.1. Firstline treatments were R-Bendamustin (20.3%), R-CVP (35.4%) and R-CHOP (44.3%), proportion treated with R-Bendamustin increasing to 50% after 2016. Rituximab maintenance was used in 47.3%. The 5-year OS for all patients was 82% with no differences between patients treated with R-Bendamustine (5-year OS, 79%, CI: 73-86%), R-CVP (81%, CI: 77-85%) and R-CHOP (84%, CI: 80-87%) (Table 1). 1,036 patients were relevant for the GALLIUM trial based on age (≥18 years) and Ann Arbor disease stage (2 with bulky disease, 3 or 4) alone. Of 870 patients with available data on in/exclusion criteria, 778 (89%) were trial eligible, 92 (11%) were ineligible. The outcome of eligible patients was superior to the outcome of ineligible patients with 5-year OS of 83% vs 56% (P<0.0001, Fig. 1) with results similar when stratifying on treatment. Adjustments for age differences between eligible and ineligible patients did not impact results (5-year OS difference of 24%, CI: 13-35%). Results were consistent for the other trials with 5-year OS for eligible and ineligible patients of 83 vs 62% for RELEVANCE (P<0.0001), 84% vs 66% for BRIGHT (P<0.0001) and 81% vs 53% for StiL NHL1 (P<0.0001). POD24 was observed more frequently in ineligible patients (except in RELEVANCE), even though deaths without disease progression were treated as a competing risk to reduce impact of comorbidity related deaths. According to the Shapley-values, ECOG PS (ranging from 5.64 to 9.98 months) and creatinine (ranging from 1.27 to 11.0 months) were the most important contributors to the observed OS differences between eligible and ineligible patients. The main reason for ineligibility for GALLIUM, RELEVANCE and BRIGHT was low creatinine clearance with 38%, 69% and 47% of ineligible patients violating this criterion respectively (24% in StiL NHL1). In StiL NHL1, 45% and 39% of ineligible patients did not fulfill the ECOG PS and ALAT criteria. Conclusions This study shows that commonly used in/exclusion criteria in clinical trials of FL lead to exclusion of a group of patients with 5-year OS outcomes significantly worse than trial eligible patients. A higher proportion of POD 24 events in the group of ineligible patients also suggests that disease control was inferior in those patients. Collectively, these results show that a high unmet need remains for better 1st line therapies for the minority of FL patients ineligible for clinical trials with narrow in/exclusion criteria. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal