Disease Relapse In Patients Research Articles

Hospitalisation for Drug Infusion Did Not Increase Levels of Anxiety and the Risk of Disease Relapse in Patients with Inflammatory Bowel Disease during COVID-19 Outbreak.

During the coronavirus disease 2019 (COVID-19) pandemic, immunomodulatory therapies and hospital admission were suspected to increase the risk of infection. Nevertheless, patients with inflammatory bowel diseases (IBD) treated with intravenous (i.v.) biologics had to move to hospitals for drug infusion. We investigated the impact of hospitalisation in patients with IBD. We conducted a survey including consecutive IBD patients initially in clinical and biochemical remission treated with biologics at the end of the first lockdown period. Patients underwent the normally scheduled clinical visits, performed at hospital for i.v.-treated patients or at home for patients treated with s.c. drugs. We administered to all patients the Hospital Anxiety and Depression Scale (HADS) questionnaire and other 12 questions, specifically related to COVID-19 and its implications. A total of 189 IBD patients were recruited, 112 (59.3%) treated with i.v. drugs and 77 (40.7%) with s.c. ones. No relapses were recorded in either group (hospitalized vs. non-hospitalized, p = ns), as well as which, COVID-19 infections were not demonstrated in patients in contact with people with suspected symptoms or directly experiencing them. The total HADS score obtained by the sum of all items was also almost identical between groups (37.1 ± 2.8 vs. 37.2 ± 2.8; p = 0.98). In patients treated with i.v. drugs receiving a televisit (n = 17), the rate of satisfaction with telemedicine (58.8%) was significantly lower compared with those treated with s.c. drugs (94.8%; p < 0.0005). Our results suggest that hospitalisation during the COVID-19 outbreak does not increase the risk of COVID-19 infection as well as the risk of IBD relapse; moreover, the similar levels of anxiety in both groups could confirm that there is no need to convert patients from i.v. to s.c. therapy.

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer.

Simple SummaryOver the last two decades, our improved understanding of the pathobiology of androgen-addicted prostate cancer (PCa), and documented therapeutic advances/breakthroughs have not translated into any substantial or sustained curative benefit for patients treated with traditional ADT or novel immune checkpoint blockade therapeutics. This is invariably connected with the peculiar biology and intratumoral heterogeneity of PCa. Castration-resistant PCa, constituting ~30% of all PCa, remains a clinically enigmatic and therapeutically challenging disease sub-type, that is therapy-refractory and characterized by high risk for recurrence after initial response. Our findings highlight the role and exploitability of testosterone metabolic reprogramming in prostate TME for patient stratification and personalized/precision medicine based on the differential but concerted expression of molecular components of the proposed testosterone tetrad in patients with therapy-refractory, locally advanced, or recurrent PCa. The therapeutic exploitability and clinical feasibility of our proposed approach is suggested by our preclinical findings.Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Selinexor Maintenance Is Feasible and Tolerable after Allogeneic Stem Cell Transplant (allo-SCT) for Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent in relapsed/refractory AML. We hypothesized that selinexor could be used as maintenance therapy after allo-SCT to prevent disease relapse in patients with AML and MDS.Methods: This phase I trial tests selinexor as a maintenance therapy in patients with AML/MDS undergoing allo-SCT (NCT02485535). The primary endpoint was to determine the maximum tolerated dose (MTD) of selinexor after allo-SCT. Patients were enrolled between day 60 to day 100 post allo-SCT if there was no GVHD or disease relapse. Once weekly oral selinexor started approximately 100 days post allo-SCT, and continued for 12 months if tolerated, and there was no relapse of disease. Dose limiting toxicity (DLT) was defined as any grade 3 or higher treatment-related adverse event (AE) that occurred within the first treatment cycle (28 days).Results: From January 2016 to March 2017, nine patients were enrolled including seven with AML and two with MDS. Selinexor dose levels were 60mg weekly (n=6) and 80mg weekly (n=3). Per stem cell transplant disease risk index (DRI), three patients had high risk and five had intermediate risk. Six patients with AML entered allo-SCT in CR (five CR1, one CR2) and one patient had refractory AML. Two MDS patients had active disease at the time of transplant. Four patients had matched related donors (MRD), two had matched unrelated donors (MUD), and three had haplo/cord SCT. One patient had myeloablative conditioning, and eight had RIC. The median time from allo-SCT to first dose of selinexor was 97 days (range: 66-102). One of the first three patients treated at 60mg weekly developed grade 3 nausea, thus three more patients were enrolled to the 60mg weekly dose level. After no additional DLTs at 60mg weekly, patients were enrolled to 80mg weekly dose level. While there was no DLT during the first cycle treatment at 80mg weekly, the dose of selinexor was decreased to 60mg weekly at the beginning of cycle 2 due to decreased chimerism in one patient and in one in cycle 3 due to neutropenia; one patient stopped treatment in the middle of cycle 2 due to leg cramping. The MTD of selinexor post allo-SCT was determined to be 60mg weekly. The most common AEs were fatigue (67%), anorexia (56%), nausea (56%), vomiting (33%) and diarrhea (22%) which were grades 1-2 with the exception of one case of grade 3 nausea. These AEs were manageable with adequate supportive care, including ondansetron, dexamethasone, megestrol and short hold of drug. One patient is finishing 12 months of treatment without major complications. One patient developed grade 1 skin GVHD during tapering immunosuppression not related to selinexor, and 2 patients developed skin and/or liver GVHD after donor lymphocyte infusion (DLI) for low chimerism, which was not related to selinexor. With median follow-up of 359 (219-639) days from transplant, two patients had disease relapse after 2 and 4 cycles of treatment, of which one patient died from disease progression. Three patients are still on treatment, three patients are off study due to tolerability (Neutropenia=1, fatigue=1; and leg cramping=1), and one patient is off study due to liver GVHD after donor lymphocyte infusion (DLI). The median remission duration from the start of Selinexor treatment was 199 (59-542) days. Correlative studies for MRD monitoring and immune reconstitution are on-going.Conclusions: Selinexor maintenance after allo-SCT is feasible and tolerable without increased risk of GVHD. The recommended phase II dose of selinexor maintenance post allo-SCT is 60mg weekly. Additional patients are being enrolled to the expansion cohort at the dose of 60mg weekly for better understanding of the toxicities and efficacy. DisclosuresLiu:BMS: Research Funding; Karyopharm: Research Funding. Larson:Daiichi Sankyo: Consultancy, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Stock:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy.

Proteomic Profiling Identifies c-KIT and 53BP1 As Resistance Factors of AML Relapse Post Allogeneic Stem Cell Transplantation with G-CSF/Plerixafor/Busulfan-Fludarabine Conditioning

The CXCR4 inhibitor plerixafor in combination with G-CSF disrupts stroma-leukemia interactions, mobilizing leukemia cells from their niche microenvironment. This combination in conjunction with chemotherapy has been investigated in clinical trials in AML. We recently reported a phase 1/2 study of CXCR4 inhibition combined with chemotherapy prior to allogeneic stem cell transplantation (allo-SCT) (G-CSF-plerixafor (G+P) plus busulfan-fludarabine (Bu+Flu), Konopleva, et al. BMT 2015) and confirmed that patients who had not achieved remission at the time of transplant (“non-CR”) had poorer outcome than patients who were in remission at the time of allo-SCT (“CR”). Similar results have been reported in other clinical studies. Risk factors, such as the presence of circulating blasts and unfavorable cytogenetics are associated with poor outcome, but the molecular responses in patients treated with CXCR4 inhibitor and conditioning chemotherapy prior to allo-SCT are unknown. We investigated the hypothesis that the CXCR4 inhibition-driven preparative regimen modulates distinct signaling networks, which vary depending on disease status.Utilizing reverse phase protein array (RPPA), we profiled 157 proteins in 36 cellular signaling and functional groups in samples collected from ten AML patients who were studied in the phase 1/2 trial (Table1). Five CR patients had less than 1% blasts in bone marrow (BM) and no blasts in peripheral blood (PB) before conditioning regimen (baseline, day -9). Five non-CR patients had BM blasts ranging from 10-72% and PB blasts from 0-45%. Here we denote samples from “CR” patients as “normal” and from “non-CR” patient as “AML”. All “AML” patients with blasts had persistent blasts after G+P plus conditioning, ranging from 4-64%. However, four of five “AML” and five “normal” patients achieved complete response to allo-SCT. Engraftment was observed in all patients. Disease progression following allo-SCT was observed in four of five “AML” but not in “normal” patients. Overall survival in “AML” was significantly shorter than in “normal” patients (non-CR = 260 ± 55 days, CR = 2028 ± 103 days, P < 0.001).RPPA analysis of samples prior to conditioning (day -9) revealed that 9 proteins in 9 signaling pathways were expressed differently in “normal” and “AML” samples. Among them, c-KIT, 53BP1, a P53-binding DNA repair protein, and CIAP (a SMAC and IAP family member) had significantly higher expression in “AML”.G+P treatment significantly modulated 7 proteins in 4 pathways in “AML” samples, and 22 proteins in 13 signaling and functional groups in “normal” samples (Fig 1A). As a result, 22 proteins in 14 signaling and functional groups were differentially expressed in “AML” and “normal” samples post G+P treatment (day -7) (Fig 1B). Among the top 10 distinct proteins, PI3Kp110A, P53BP1, SMAD1 and p-C-JUN S73 had higher expression, and P38MAPK, p-HER2 Y1248, P-CADHERIN, SYK, P21 and TAU had lower expression in “AML” samples.Treatment with G+P plus Bu+Flu conditioning modulated 10 proteins in 7 signaling pathways in “AML” samples, and altered 40 proteins in 13 signaling pathways in “normal” samples (Fig 1C). As a result, G+P plus Bu+Flu conditioning caused significant differences in expression of 16 proteins in 14 signaling and functional groups in “AML” vs. “normal” samples (day -3) (Fig 1D). Among the top 10 distinct proteins, PI3Kp110A, XRCC1, p-ERA S118, 53BP1, and BCL2 had higher expression, and MIG6, SYK, TAU, p-AKT T308 and MEK1 had lower expression in “AML” samples. Notably, c-KIT and 53BP1 in “AML” baseline samples were persistently expressed at high levels in samples from G+P and G+P plus Bu+Flu treated patients, suggesting that c-KIT and 53BP1 mediated signaling might play a role in therapeutic resistance and disease relapse in patients with active disease at the time of transplant.In summary, CXCR4 inhibition combined with Bu+Flu conditioning triggered distinct molecular responses, resulting in differential signaling between “normal” and “AML” cells prior to allo-SCT. The persistence of c-KIT and 53BP1 might play a role in resistance and contribute to relapse in AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

JAK2V617F mutant endothelial cells promote neoplastic hematopoiesis in a mixed vascular microenvironment

The chronic myeloproliferative neoplasms (MPNs) are clonal stem cell disorders. The hematopoietic stem/progenitor cell (HSPC) compartment in patients with MPNs is heterogeneous with the presence of both wild-type and JAK2V617F mutant cells. Mechanisms responsible for mutant stem cell expansion in MPNs are not fully understood. Vascular endothelial cells (ECs) are an essential component of the hematopoietic microenvironment. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. Utilizing an ex vivo EC-HSPC co-culture system with mixed wild-type and JAK2V617F mutant ECs, we show that even small numbers of JAK2V617F mutant ECs can promote the expansion of JAK2V617F mutant HSPCs in preference to wild-type HSPCs during irradiation or cytotoxic chemotherapy, the two treatments commonly used in the conditioning regimen for stem cell transplantation, the only curative treatment for patients with MPNs. Mechanistically, we found that both cell-cell interactions and secreted factors are important for JAK2V617F mutant EC-mediated neoplastic hematopoiesis. Further understanding of how the JAK2V617F mutation alters vascular niche function will help identify new strategies to not only control neoplastic cell expansion but also prevent disease relapse in patients with MPNs.

P223 Degree of Histological Activity is not Associated with Vedolizumab Therapy Outcome in Ulcerative Colitis

Abstract Background Histological inflammation is known to be associated with increased risk of disease relapse in patients with ulcerative colitis (UC). Vedolizumab (VDZ) is a gut selective anti-integrin which inhibits intestinal immune cell-trafficking. Whether the degree of histological activity at the time of VDZ therapy initiation is associated with therapy outcome is not known. We aimed to determine if there is an association between histological activity at the time of VDZ initiation and outcome of therapy. Methods A retrospective review was performed to identify UC patients treated with VDZ who had undergone an endoscopic assessment prior to therapy commencement. Baseline demographic data, information on therapy outcome and Mayo endoscopic sub score (MES) was collected for all patients. Endoscopic biopsies were retrieved and were scored for histological activity using the Geboes Score (GS). For Kaplan Meir analyses of primary endpoint, the cohort was dichotomised around a GS grade of 5. Primary endpoint was VDZ therapy outcome defined as persistence on VDZ therapy over time. Secondary endpoints included association between GS and MES and the association between a combined endoscopic and histological endpoint (MES = 3 &amp; GS grade 5) and VDZ therapy outcome. Results 33 patients were included [median age 44.3 years (range 17.2 -84.3); 36% male gender]. 24%, 43% and 33% of the cohort had proctitis, left-sided colitis and extensive colitis respectively. 67% of subjects had prior anti-TNF exposure. Median time from endoscopy to commencement of VDZ was 9 weeks. Median study follow-up was 68 weeks (range 6.1 – 228.7). 3%, 21%, 42% and 33% had MES of 0, 1, 2 and 3 respectively. GS grade was significantly associated with MES (p = 0.04) (Figure 1). GS grade was not associated with time to discontinuation of VDZ (p=0.64) (Figure 2). Combined endoscopic and histological endpoint was not associated with time to discontinuation of VDZ (p=0.43) (Figure 3). The presence of lamina propria eosinophils was not associated with time to discontinuation of VDZ (p=0.92). Conclusion GS grade is associated significantly with MES which has been demonstrated previously. Neither histological activity alone nor in combination endoscopic activity were associated with outcome of VDZ therapy. Assessment of histological activity does not appear to provide additional information when selecting patients for VDZ therapy.

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer.

The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. Patients with a high CEA-R (≥ 2) exhibited significantly worse 2year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.

Recurrent Nephritis and/or Pulmonary Hemorrhage in Patients with Anti-Glomerular Basement Membrane Disease with and without ANCA Positivity

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is characterized by rapidly progressive glomerular nephritis with or without pulmonary hemorrhage with disease severity correlating with antibody titer. Following treatment, relapse is rare but has been reported in the literature. The objective of this study was to assess for clinical, serologic, and histologic differences associated with disease relapse in patients with anti-GBM disease. Methods: Patients seen at our facility between 1997 and 2017 were screened for anti-GBM disease by ICD 9/10 codes. They were included if the diagnosis was confirmed by a board-certified rheumatologist or nephrologist and had positive antibodies and/or biopsy results consistent with anti-GBM disease. Relapsing disease was defined as recurrence of pulmonary or renal manifestations after achieving remission following the initial presentation. All charts were reviewed for baseline demographics, clinical manifestations, and antibody positivity and compared between groups. Results: 40 patients were confirmed as having anti-GBM disease. Mean follow-up from disease onset to the date of last follow-up was 56.2 months. 8 patients had relapsing disease and 32 patients had nonrelapsing disease. Baseline characteristics and clinical manifestations were similar between groups. Patients with relapsing disease had a high incidence of anti-neutrophilic cytoplasmic antibody (ANCA) co-positivity as compared to nonrelapsing patients (50 vs. 15.6%, respectively, p = 0.059), but this did not reach statistical significance. In patients with relapsing disease, only one had positive anti-GBM antibodies at time of relapse. Conclusions: In this study, patients with relapsing disease had a high incidence of ANCA co-positivity (50%). In patients with newly diagnosed anti-GBM disease, ANCAs should be obtained to assess for the risk of relapse and to help guide long-term follow-up and treatment.

Does the use of herbal medicine affect adherence to medication - a cross sectional study of outpatients with chronic disease?

IntroductionThe use of herbal medicine is common and is increasing globally but it is unknown whether this affects patients’ use of western medicine. The aim of this study was to investigate whether herbal medicine (HM) use may effect medication adherence in Turkish patients with chronic disease attending internal medicine outpatient clinics. MethodsPatients prescribed medication by a medical doctor for longer than one year for a chronic disease and with any symptoms were identified from the register of patients attending a general internal medicine outpatient clinic. Medication adherence was measured using the Morisky Medication Adherence Scale (MMAS) score. Patients were questioned about whether they had used any HMs. ResultsOut of 912 patients examined, 516 patients (51.7% female patients, mean age 52.4) met the inclusion criteria. Use of the HMs was positively correlated with educational status and monthly income and negatively correlated with the MMAS score. Multivariate logistic regression analysis demonstrated that use of herbs and/or herbal products was significantly associated with the MMAS score (OR: 0.85, 95% CI 0.78-0.93, p < 0.001). ConclusionLow medication adherence was found to be independently associated with the use of HMs in this study population. Medication non-adherence is an important public health problem for all departments of medicine. Hospitalizations, drug resistance and disease relapse in patients with chronic diseases could be prevented if medication adherence is achieved

How to recognize and respond to viral re-positivity and disease relapse in patients with COVID-19.

How to recognize and respond to viral re-positivity and disease relapse in patients with COVID-19.

Circulating Tumor DNA as Surveillance Following Resection of Colorectal Liver Metastases - Results from a Prospective Single Center Trial

Background: Following curative intended liver surgery an intensive surveillance program using CT-scans is used to detect disease recurrence. This is a relative expensive and resource demanding approach. In patients with known CRC, circulating tumor-DNA (ctDNA) can be found in the blood and correlates with tumor burden. The aim of this study was to investigate whether ctDNA, could detect disease relapse in patients operated for CRC liver metastases.

Efficacy and safety of immunosuppressive therapy in myelin oligodendrocyte glycoprotein antibody-associated disease: a systematic review and meta-analysis.

Background:A considerable number of patients with myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) will experience a relapse, but the effect of maintenance therapies on re-attack rates is currently unknown.Objective:To investigate the efficacy and safety of immunosuppressive therapy for preventing disease relapses in patients with MOGAD, including rituximab (RTX), mycophenolate mofetil (MMF), and azathioprine (AZA).Methods:English-language studies published prior to August 31, 2020, were searched in the NCBI (PubMed), ISI Web of Science, and the Cochrane Library databases. Patient characteristics, treatment regimens, outcome measures, and adverse effects were retrieved.Results:We enrolled 11 studies in the final meta-analysis, including 346 patients with MOGAD. RTX therapy was demonstrated to result in reduced mean annualized relapse rate (ARR) by 1.35 (95% confidence interval (CI): 0.85–1.85) and reduced mean Expanded Disability Status Scale score by 0.80 (95% CI: 0.53–1.08) in patients with MOGAD. MMF therapy was associated with the mean ARR decreasing by 0.83 (95% CI: 0.31–1.35), and AZA was related to the mean ARR decreasing by 1.71 (95% CI: 0.83–2.58). The reported discontinuation rates of RTX, MMF, and AZA therapy due to adverse effects were 3/197 (1.52%), 3/39 (7.69%), and 4/37 (10.81%), respectively.Conclusion:The study provided evidence to support the efficacy of RTX, MMF, and AZA on the preventive treatment in patients with MOGAD. However, large randomized controlled trials are still needed in the future.

Risk of relapse in patients receiving azithromycin after allogeneic HSCT.

Following publication of the ALLOZITHRO trial, the FDA released a safety announcement warning that azithromycin should not be given long-term to prevent BOS in patients with a blood or lymph cancer who have undergone allogeneic HSCT. Our site typically initiated azithromycin when patients were diagnosed with BOS post-transplant rather than empirically as prevention. The purpose of our study was to discern whether the use of azithromycin at the time of diagnosis of BOS increased risk of disease relapse in patients who received an allogeneic HSCT for malignant disease. We retrospectively reviewed 432 patients in 3 cohorts: Cohort (1) patients who received greater than or equal to 2 weeks of azithromycin therapy (n = 98); Cohort (2) patients who received azithromycin therapy for less than 2 weeks (n = 63); and Cohort (3) patients who never received azithromycin therapy (n = 271). Neither patients in Cohort 1 (HR 0.44; 95% CI, 0.12-1.53, P = 0.19) nor Cohort 2 (HR 0.66; 95% CI, 0.2-2.19, P = 0.49) were associated with an increased risk of relapse when compared to those who had never received azithromycin. Our data indicate that the prolonged use of azithromycin after allogeneic HSCT is not associated with an increased rate of hematologic relapse.

Immunotherapy choice and maintenance for generalized myasthenia gravis in China.

AimsTo compare long‐term efficacy and safety of immunotherapeutic strategies as maintenance to prevent disease relapses of generalized myasthenia gravis (MG) in real‐world settings.MethodsThis is a retrospective cohort study on generalized MG conducted in seven major neurological centers across China. Eligible participants were patients with generalized MG who were under minimal manifestation status or better. Main outcome measures were probability of patients free of relapses and causes of drug discontinuation.ResultsAmong 1064 patients enrolled, the median (interquartile range) age was 50.3 (37.0‐62.5) years and 641 (60.2%) were women. Disease relapse was significantly lower for rituximab (6.1%) compared with all the other monotherapies (hazard ratio [HR] = 0.18, 95% confidence interval [CI] 0.06 to 0.56, P = .0030). As combination therapies, tacrolimus in combination with corticosteroids reduced risk of disease relapses compared with azathioprine with corticosteroids (HR = 0.45, 95% CI 0.25 to 0.81, P = .0077) or mycophenolate mofetil with corticosteroids (HR = 0.32, 95% CI 0.15 to 0.67, P = .0020). Otherwise, lower‐dose corticosteroids or azathioprine as monotherapy significantly increased risk of disease relapses (HR = 2.78, 95% CI 1.94 to 3.99, P < .0001; HR = 2.14, 95% CI 1.42 to 3.23, P = .0003, respectively). The proportion of discontinuation was lowest in patients with rituximab (20.4%) as monotherapy and tacrolimus with corticosteroids (23.6%). Overall, combination treatment of immunosuppressants with corticosteroids had a lower rate of discontinuation compared with corresponding monotherapy (HR = 0.51, 95% CI 0.36 to 0.71, P < .0001).ConclusionsRituximab as monotherapy and tacrolimus with corticosteroids displayed better clinical efficacy as well as drug maintenance to prevent disease relapses in patients with generalized MG.

S3210 Assessment of Factors Which May Predict Crohn’s Disease Relapse in Patients Initiating Ustekinumab Therapy

INTRODUCTION: Ustekinumab is a biologic agent, acting against the p40 subunit of IL 12 and IL 23, approved for use in Crohn’s disease (CD). Currently, ustekinumab is approved for every 8 week dosing following initiation. However, we have clinically observed the need for every 4 week dosing, in a cohort of patients not achieving control with every 8 week administration. Of note, such a subset of CD patients was not assessed in the UNITI trial. The aim of our study was to identify patient or clinical factors that could indicate the need for a shorter ustekinumab dosing interval to obtain and maintain remission of CD. METHODS: The pharmacy database was searched for all patients initiating ustekinumab for histologically confirmed CD. Patients were then divided into 2 groups following initiation based on occurrence of next dose, either standard schedule (8 weeks after initial dose) or early administration (4 weeks following). Data collected for all included demographic information, smoking status, extent of disease and disease duration. Stepwise logistic regression was used to identify predictors for early dosing. Potential predictors not identified by the logistic model were forced in. Beta coefficients/odds ratios and 95% confidence intervals were calculated to estimate the magnitude of the effect. RESULTS: A total of 57 CD patients were eligible for study. The majority of patients overall were female (68%) and non-Hispanic white (52%). A total of 44 patients were in the standard group and 13 patients were in the early administration group. No difference in age, gender, race, smoking status or disease duration was present between groups. Colonic CD disease extent was significantly different between standard and early groups (one colonic segment involved in 36.4% of standard vs 84.6% of early patients, P < 0.003). We further forced in age, sex, race, smoking status, and duration of disease as likely to impact occurrence of early ustekinumab dosing. Again, only extent of disease on colonoscopy showed a statistically significant result (OR 9.56, CI 1.41–64.88, P < 0.01). CONCLUSION: Extent of colonic disease may identify those CD patients at risk for earlier than 8 week dosing following initiation of ustekinumab. We identified that patients with one colonic segment involvement have higher odds to be on early administration than those that have multiple colonic segment involvement. Further evaluation of this clinical phenomenon is warranted to completely understand ustekinumab use in CD.

11C-choline positron emission tomography/computed tomography for detection of disease relapse in patients with history of biochemically recurrent prostate cancer and prostate-specific antigen ≤0.1 ng/ml.

The objective was to evaluate the diagnostic performance of surveillance11 C-choline positron emission tomography/computed tomography (PET/CT) for the detection of disease relapse in patients with a history of biochemically recurrent (BCR) prostate cancer (PCa) and prostate-specific antigen (PSA) ≤0.1 ng/ml. We included patients who had been treated for BCR PCa and had a surveillance11 C-choline PET/CT at serum PSA ≤0.1 ng/ml. Positive surveillance PET/CT was defined as a study that identified a new tracer-avid lesion or new tracer uptake in a previously treated lesion or both. Findings were confirmed against a composite radiologic-pathologic gold standard. Time to recurrence association analyses were performed for disease relapse risk with the use of Cox proportional hazards regression. In total, 13 (12.1%) of the 107 patients had positive surveillance PET/CT scans, confirmed on pathologic assessment (n = 5) and subsequent imaging (n = 8). Among these 13 patients, ten had distant metastases, two had local recurrence, and one had both. Nine of the ten patients with metastases had oligometastatic disease defined as the presence of ≤3 metastases. Serum PSA became detectable again in only seven patients with positive surveillance PET/CT, after a mean interval from surveillance PET/CT of 292 days (range: 105-543 days). We identified an association of N stage with increased risk of recurrence (hazard ratio = 3.85; P = 0.036) although this was not significant after accounting for multiple testing. Surveillance11 C-choline PET/CT can detect early disease relapse at serum PSA ≤0.1 ng/ml in patients with a history of BCR PCa.

1437P Can FDG-PET predict early disease relapse in patients receiving peri-operative FLOT for localised oesophago-gastric adenocarcinoma?

1437P Can FDG-PET predict early disease relapse in patients receiving peri-operative FLOT for localised oesophago-gastric adenocarcinoma?

Abstract 720: Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer

Abstract The therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer is usually assessed by the reduction of tumor size and lymph nodes. The pathologic complete response (pCR) is considered as a marker related to good prognosis. However, patients who can achieve pCR is a minor population, and pCR may be not a robust marker predicting prognosis in patients with ER-positive breast cancer. Additional markers allowing the assessment of prognosis is needed. Circulating tumor DNA (ctDNA) has been proved as a marker to detect disease progression in metastatic breast cancer and predict relapse in patients after resection of breast cancer. Therefore, we would like to assess the value of ctDNA in breast cancer patients receiving neoadjuvant therapy. The ctDNA was collected before and after completion of the neoadjuvant chemotherapy (Tend). The presence of ctDNA was detected by ultra-deep targeted next-generation sequencing. We enrolled 82 patients and 62 patients were found to have ctDNA as the biomarkers. The presence of ctDNA included nonsynonymous variants and copy number variations in TP53, PIK3CA, HER2, CDH1, PTEN, S100A, CCND1 and c-MYC. Among the 62 patients, there were 24 patients with hormone receptor (+)/Her2(-), 20 with Her2(+) and 18 with triple-negative breast cancer (TNBC). Pathologic complete response (pCR) occurred in 9 patients, partial response in 32 patients and stable/progression in 21 patients, according to the RECIST 1.1 criteria. Univariate analysis showed tumor reduction&amp;gt;50% (p=0.032), number of metastatic lymph node (p=0.039), and status of ctDNA at Tend (p&amp;lt;0.001) were significantly associated with disease-free survival (DFS). The 5-year DFS of patients with undetectable ctDNA at Tend (74.0%, 95% confidence interval (CI) range 98%-50%) was significantly superior to those with detected ctDNA (16.8%, 95% CI range 36.1%-0%). Multivariate analysis revealed that status of ctDNA at Tend was the only one independent factor predicting relapse (hazard ratio 7.74, 95% CI 2.81-21.35). Two patients had pCR and were found to have alterations of ctDNA at Tend; one with TNBC had distant metastases at 6 months after mastectomy and the other with Her2 (+) breast cancer had brain metastasis at the end of adjuvant trastuzumab treatment. Therefore, we concluded that the presence of ctDNA at the end of the neoadjuvant chemotherapy was a poor prognostic factor predicting relapse in patients with stage II-III breast cancer. Citation Format: Po-Han Lin, Sung-Sheng Kuo, Chiun-Sheng Huang. Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 720.

Abstract LB-047: CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a very aggressive hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation is sustained by strong oncogenic drivers, notably NOTCH1 and MYC, whose activation is present in more than half of all T-ALL cases. However, although it is known that post-translational modifications, such as ubiquitination by the E3-ligase FBXW7, regulate NOTCH1 and MYC protein stability and activity, regulatory proteins involved in their stability remain unestablished. The Charged multivesicular body protein 5 (CHMP5), an accessory protein of the ESCRT (endosomal sorting complex required for transport) pathway, has been shown to regulate the stability of client proteins in thymocytes through the recruitment of de-ubiquitinating enzymes. Here, we report that CHMP5 protein is not only highly expressed in T-ALL cells, but also promotes the stability of transactivating intracellular NOTCH1 (ICN1) and MYC. We found that depletion of CHMP5 significantly reduced the abundance of ICN1 and MYC, and the transcription of their target genes in vitro, as well as suppressed the development of T-ALL in vivo in a murine model of NOTCH1 driven T-ALL. Additionally, loss of CHMP5 restored T-ALL cell susceptibility to chemotherapeutic agents, including glucocorticoids and gamma secretase inhibitors, resistance to which contributes to disease relapse in patients. We further reveal CHMP5 as an adaptor protein required to orchestrate T-ALL client protein deubiquitination and stability. Altogether, our data suggest that CHMP5 is a non-oncogenic dependency of T-ALL and its depletion may be an effective therapeutic strategy for T-ALL. Citation Format: Katharine Umphred-Wilson, Stanley Adoro. CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-047.

A CpG Methylation Classifier to Predict Relapse in Adults with T-Cell Lymphoblastic Lymphoma.

Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.