Requiring Treatment Change Research Articles

Dermal lesions associated with anti-tumor necrosis factor α therapy in patients with inflammatory bowel disease (IBD): findings from a tertiary IBD center in Poland.

There are scarce data on the occurrence of dermal lesions in patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor α (anti-TNF‑α) antibodies. Characteristics of the skin lesions, their clinical course, and impact on treatment are of high importance. The aim of this study was to assess the prevalence, risk factors, and clinical sequelae of dermal lesions in IBD patients treated with anti-TNF‑α antibodies. This retrospective, single‑center study evaluated 541 IBD patients treated with anti-TNF‑α drugs and 688 IBD individuals with no history of anti-TNF‑α treatment. Higher prevalence of dermal lesions was noted in the patients on anti-TNF‑α therapy than in the individuals not receiving such treatment (30.9% vs 16.4%; P <0.001). Risk factors for dermal lesions included higher body mass index (BMI), Crohn disease located in the small intestine, and longer duration of therapy. Some types of dermal lesions were associated with anti-TNF‑α therapy; these included infusion reactions and injection site reactions, cutaneous infection, psorasiform reactions, and lupus‑like symptoms. Overall, 5.9% of the patients on anti-TNF‑α therapy required treatment change or discontinuation due to dermal lesions (alopecia, lupus‑like symptoms, melanoma, and psoriasis). We observed a higher prevalence of dermal lesions in patients with IBD undergoing anti-TNF‑α therapy than in the treatment-naive group, although development of such lesions rarely necessitated a change in or discontinuation of treatment. Patients with IBD should regularly undergo follow-up dermatologic evaluation, which may improve detection of dermal lesions. Moreover, biologic therapy in IBD patients requires close collaboration with an experienced dermatologist.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6months. However, in routine care, it is often extended to 12months, despite lacking robust supporting data. GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. For glioblastoma patients, extending post-radiation temozolomide from 6 to 12months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Outcomes of Chronic Myeloid Leukemia Patients after Therapeutic Failure to Asciminib, a Multicenter Observational Study

Introduction: Asciminib has recently entered the market as a promising option for patients with chronic myeloid leukemia (CML) and therapeutic failure to ³ 2 tyrosine kinase inhibitors (TKIs). It presents a relevant rate of therapeutic success thanks to its different mechanism of action, being the first in its class to produce an allosteric inhibition on the myristoylated pocket of ABL. However, a percentage of patients fail this drug due to intolerance or resistance. This group constitutes a highly polytreated population with few therapeutic options. The aim of this analysis is to determine the most frequent treatment strategies in this setting, as well as to ascertain the prognosis in this difficult to treat group. Material and methods: a retrospective descriptive multicenter observational study was carried out. Eligible patients were those with a diagnosis of CML, &amp;gt;18 years and who had presented a therapeutic failure to asciminib, due to resistance or intolerance. Patients were selected from a cohort of 85 CML patients who received asciminib through a managed-access program. Results: A total of 19 patients were recruited from 17 centers in Spain. Median age at the time of therapeutic failure to asciminib was 61.7 years. Median time from diagnosis to asciminib failure was 7.9 years (range 1.7-25.5), median number of previous lines was 5. 47% of patients had previously received ponatinib and 15.8% (3/19) had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) prior to asciminib. Median time on asciminib was 5.6 months (range 0.7- 40.9). 42% of patients (8/19) failed treatment due to intolerance and 58% (11/19) due to resistance. Four of them had progression to accelerated/blastic phase at the time of withdrawal. Of the intolerant patients, the most frequent reason for discontinuation was pancreatitis (50%, 4/8). The remaining causes were renal failure (1), pleural effusion (1), fatigue (1), and neurological symptoms (1). Regarding the intolerant group, 2 patients did not require restart of treatment due to a sustained deep molecular response (MR). The rest (6/8) required treatment, which in all cases involved restarting a classic TKI that they had already received (2 imatinib, 2 dasatinib, 2 nilotinib). In 50% (3/6) dose reductions were used to control adverse events (AEs), which in 2/3 patients compromised efficacy. In another case, low-dose corticosteroid therapy was used for the management of pleural effusion, maintaining standard dose. Only 1/8 intolerant patients required an additional change of treatment, and all of them are still alive and without progression to advanced stages at the last follow-up. Regarding the patients that required treatment change due to progression to advanced phases, one patient underwent allo-HSCT. The rest were not candidates due to age or clinical impairment (1 received dasatinib, 1 hydroxyurea (HU), 1 without treatment). Only the patient who underwent HSCT is alive more than one year after the procedure with a grade 5 MR. In the rest the median overall survival (OS) was less than 1 month. Of the remaining resistant patients, 4/7 (57%) received ponatinib (1 of 4 had received it previously), 1 imatinib, 1 allo-HSCT and the other patient received cytarabine + interferon + HU. Three of 7 patients required additional lines including change of TKI (asciminib, nilotinib, dasatinib) and other strategies (HU, busulfan, interferon, cytarabine). In terms of response, only the patient undergoing HSCT maintained a mayor MR (1/7). One patient maintained a complete cytogenetic response and the other 2 patients were unable to improve response despite treatment (maintaining worse response than CHR at the end of follow-up). Two patients died (1 acute myocardial infarction, 1 digestive neoplasia). With a median follow-up of 11.2 months, OS of the global cohort is 73%; 100% for intolerant patients, 71% for resistant patients and 25% for those in accelerated/blastic phase. Conclusions: Patients who fail asciminib are a particularly difficult to manage group. In intolerant patients, dose reductions and symptomatic management of AEs may be an appropriate strategy. Resistant patients currently represent an unmet therapeutic need, with low cytogenetic and molecular response rates and poor survival with current strategies. Patients with progression to advanced phases have a dismal prognosis, HSCT may be the only option that provides long-term survival in this group.

Lowering the bar for consideration of neoadjuvant chemotherapy in early-stage HER2-positive breast cancers.

e12534 Background: The use of neoadjuvant chemotherapy (NAC) has contributed to increased rates of disease-free survival (DFS) as well as overall survival in breast cancer patients, specifically those with HER2-positive disease. Stage 2 patients with HER2-positive disease including tumors &gt; 2cm as well as node positive disease receive neoadjuvant chemotherapy as per current NCCN guidelines. The aim of our study was to understand outcomes in patients with early breast cancer receiving chemotherapy. Methods: We extracted data on patients with initial clinical stages IA-IB breast cancer who had HER2-positive status on initial biopsy and received chemotherapy plus anti-HER2 therapy in the Henry Ford Health System between January 2016 to June 2020. Patients with T2 or above and/or node positive disease were excluded. Results: Of the 229 total patients that met eligibility criteria, 159 (71%) were white, 65 (28%) were African American. 99% were females. The median age at diagnosis was 61 years. Estrogen receptor positivity was noted in 85% (196/229) of the patients. NAC was given to 56 patients (24%) of which 26 (46%) were African American and 45 (80%) were hormone receptor positive. 5 (9%) patients achieved pathological complete remission (CR). Remaining 51 patients (91%) did not have pathological CR. Of these, 17 (33%) patients had the same stage at surgery after NAC and 34 (66%) were upstaged on final pathological evaluation. 21 patients with residual disease (41%) underwent treatment change in the form of either ado-trastuzumab emtasine (TDM-1) or additional radiation therapy or repeat surgery. Of note, 34 of the 51 patients were treated for residual disease after 2019 with TDM-1. 54 (95%) patients are alive currently. Of the 173 patients that received adjuvant chemotherapy (76%), 39 (23%) were African American and 150 (87%) had hormone receptor positive disease. 19 of these (11%) were upstaged at surgery compared to the initial biopsy requiring treatment change. 163 (94%) are alive currently with no disease recurrence. Conclusions: Our study results suggest that NAC is used in minority of breast cancer patients, especially with stages 1A and 1B. Pathological CR rate in our study population was low and majority of patients who got NAC as well as a small percent of those who received adjuvant chemotherapy had disease upstaged based on surgical pathology results. We believe that this could be because of inaccurate initial staging due to limitations of imaging techniques and our population being mostly hormone receptor positive. With approval of TDM-1 in patients with residual disease post NAC, we may be able to improve outcomes in terms of recurrences and survival in these patients. Thus, consideration of NAC for early stage HER2-positive breast cancers appears attractive and data like our study may support ongoing prospective clinical trials.

Incidence and Related Factors of L-asparaginase-induced Hypersensitivity Reactions Requiring Treatment Changes in Pediatric Patients with Acute Lymphoblastic Leukemia

Incidence and Related Factors of L-asparaginase-induced Hypersensitivity Reactions Requiring Treatment Changes in Pediatric Patients with Acute Lymphoblastic Leukemia

Venetoclax combined with low dose cytarabine compared to standard of care intensive chemotherapy for the treatment of favourable risk adult acute myeloid leukaemia (VICTOR): Study protocol for an international, open-label, multicentre, molecularly-guided randomised, phase II trial

BackgroundFor patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC.MethodsVICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years.DiscussionThe principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients.Trial registrationEudraCT: 2020–000,273-24; 21-Aug-2020.ISRCTN: 15,567,173; 08-Dec-2020.

OA08 A case of Recalcitrant Psoriatic Disease- should new treatment strategies be considered?

Introduction/BackgroundDespite the advent of numerous biologic therapies and small molecular drugs targeting specific immune pathways, at least 40% of PsA patients exhibit poor response.Given the complexity and heterogeneity of signalling pathways resulting in synovio-entheseal disease in PsA; new treatment strategies must be evaluated to induce deep and sustainable clinical responses in all the phenotypic domains.In patients who do not achieve remission in all disease aspects on biologic monotherapy or combination of a biologic therapy with an oral synthetic agent; dual targeted anti-cytokines strategies or combined biologic with a targeted oral small molecule are a possible treatment option.Description/MethodA 40-year-old attended our rheumatology department in 2010 with peripheral synovitis, dactylitis and scalp psoriasis. A clinical diagnosis of PsA was made and she was commenced on combination methotrexate and sulphasalazine.In 2011, therapy was escalated to include etanercept and methotrexate due to persistent active disease clinically and on nuclear medicine bone scan.Between 2011 to 2015, sequential bDMARD switches including certolizumab, infliximab and adalimumab, failed to put the disease in remission.Due to loss of effect, adalimumab was switched to secukinumab in early 2016. A few months later, while on secukinumab, she developed new onset Crohn’s disease and required treatment change to ustekinumab.In August 2018 following a prolonged flare, ustekinumab was stopped and tofacitinib was started. The disease went in LDA until September 2020 when hospital admission for a severe PsA flare was required. She had dactylitis of 3 digits, a left temporomandibular joint effusion on ultrasound and elevated acute phase reactants. A treatment change to abatacept resulted in primary failure and abatacept was replaced with baricitinib.In March 2021, she attended clinic with new nail changes, dactylitis of 3 digits and a large left knee effusion. She underwent a diagnostic arthroscopy of the left knee and wash-out in May 2021 which showed a macroscopic synovitis score and vascularity score of 100% respectively. Synovial histology showed evidence of chronic synovitis with abundant plasma cells.Following the arthroscopy and careful discussion, it was decided to initiate combination therapy with adalimumab biosimilar and tofacitinib in June 2021. The patient was assessed at 2 months following starting combination therapy and a dramatic clinical and biochemical was noted. CRP had improved from 139.9mg/L to 6.3mg/L. She was mobilising without an aid for the first time in years. Both her psoriasis and Crohn’s disease were also well controlled.Discussion/ResultsWhile the outcomes of patients with psoriasis have dramatically improved with monoclonal antibody therapies targeting IL-23 and IL-17A; achieving a measurable low disease activity state such as minimal disease activity (MDA) for musculoskeletal manifestations of psoriatic disease is infrequent. Due to the heterogeneity of disease in PsA, multiple cellular pathways are involved in the pathogenesis resulting in recalcitrant disease in a subgroup of patients. These patients, like our case, exhibit poor response to the current therapeutic paradigm in PsA.In such patients, treating one disease domain, one type of cell or a single pathway at a time is unlikely to result in meaningful disease control and remission may be unachievable thus subjecting patients to sustained joint inflammation and damage seen in PsA. Very little data exist regarding the safety of dual immunomodulator therapies for concomitant psoriasis and psoriatic arthritis. Safety concerns such as infectious risks are important considerations with such strategies; however, the targeted second-generation anti-cytokine biologics and targeted JAK-I have exhibited improved safety profiles with regards to infections.In this case, following careful discussion with our patient, she felt that the prospect of possible reduction in her musculoskeletal symptoms outweighed the potential safety concerns.Multiple cases are reported in the literature regarding the use combined biologic strategies in psoriatic disease; the most common combination reported being anti-TNF therapy and ustekinumab with varying degrees of response. Prospective, high-quality studies are needed to identify safe and efficacious dual strategies in PsA to pinpoint dosages, sequence and frequency of therapies.Key learning points/ConclusionThis case truly highlights the heterogeneity and complexity that accompanies psoriatic disease and as such, modulating a single pathway may not be sufficient to address all the phenotypic domains (skin, synovium, entheses, and axial).While physicians are often, understandably, hesitant to prescribe combined immunomodulatory therapies due to concerns regarding potential complications, such strategies should be considered in debilitating cases of psoriatic disease who fail to respond to conventional treatment as they have the potential to foster deep and long-lasting remission.Our case highlights that a patient-centred approach with patient involvement in clinical decisions regarding their disease is required. With such strategies, patients and clinicians, both, should balance the potential associated risks particularly infectious risk.Further studies are required to better determine the efficacy and safety profile of combined immunomodulatory therapies in psoriatic disease.

Assessment of Treatment Response to Lenvatinib in Thyroid Cancer Monitored by F-18 FDG PET/CT Using PERCIST 1.0, Modified PERCIST and EORTC Criteria-Which One Is Most Suitable?

Simple SummaryIn patients with progressive metastatic radioiodine-refractory differentiated thyroid cancer, tyrosine kinase inhibitor (TKI) therapy with lenvatinib improves progression-free survival. Early identification of patients with therapeutic responses to the TKI therapy is clinically relevant due to common side effects and toxicity. The use of metabolic response criteria derived from F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging can help to identify those patients who benefit from treatment. In our study, we evaluated different response criteria, namely, the Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST) and European Organization for Research and Treatment of Cancer (EORTC) criteria, to find out which system might be more reliable and suitable in everyday clinical practice. The EORTC criteria could be applied to all patients, and the different PERCIST criteria, in 80% and 88%, respectively. Regarding their survival and treatment responses, patients with a progressive disease could be reliably identified by using all the criteria.Background: We aimed to compare the established metabolic response criteria PERCIST and EORTC for their applicability and predictive value in terms of clinical response assessment early after the initiation of lenvatinib therapy in patients with metastatic radioiodine-refractory (RAI) thyroid cancer (TC). Methods: In 25 patients treated with lenvatinib, baseline and 4-month follow-up F-18 FDG PET/CT images were analyzed using PERCIST 1.0, modified PERCIST (using SUVpeak or SUVmax) and EORTC criteria. Two groups were defined: disease control (DC) and progressive disease (PD), which were correlated with PFS and OS. Results: PERCIST, mPERCIST, PERCISTmax and EORTC could be applied in 80%, 80%, 88% and 100% of the patients based on the requirements of lesion assessment criteria, respectively. With PERCIST, mPERCIST, PERCISTmax and EORTC, the patients classified as DC and PD ranged from 65 to 68% and from 32 to 35%, respectively. Patients with DC exhibited a longer median PFS than patients with PD for EORTC (p < 0.014) and for PERCIST and mPERCIST (p = 0.037), respectively. Conclusion: EORTC and the different PERCIST criteria performed equally regarding the identification of patients with PD requiring treatment changes. However, the applicability of PERCIST 1.0 using SULpeak seems restricted due to the significant proportion of small tumor lesions.

Ulcerative colitis: understanding the impact of ulcerative colitis on everyday life and exploring the unmet needs of patients

Background Ulcerative colitis (UC) is a life-long disease characterised by flare ups and periods of remission. This market research sponsored by Janssen-Cilag Ltd was designed to gain an understanding of the impact of UC from the patient’s perspective and to establish the main unmet needs associated with it. Methods The market research was conducted by telephone among 30 patients in the UK with a diagnosis of moderate to severe UC. Results Delayed referral from primary care to secondary care was identified as the key unmet need. Hospital appointments were often unavailable for months and in some cases, it was 6 months before a procedure was performed. Specialists rarely involved the patient in discussions regarding diagnosis and initial treatment. Communications improved when treatment changes became necessary but gaps still existed particularly regarding the continued emotional impact of UC. All patients required treatment changes to regain or maintain control and the response to medications varied between patients. Patients who had transitioned through multiple treatments feared they would run out of options and therefore require surgery. The UC “journey” was highly individualized and patients experienced many emotional “ups and downs”. Conclusions Healthcare bodies should aim to improve earlier referral to secondary care and waiting times for investigation need to be reduced significantly. Patients felt that specialists could support them in understanding their condition by discussing it with them immediately following diagnosis and by involving them in the development of their individual treatment plans. There is a need for more effective and better tolerated medications to expand the armamentarium and thus reduce the need for surgery.

Barriers to clinical trial enrollment among gynecologic oncology patients at a National Cancer Institute Comprehensive Cancer Center

<h3>Objectives:</h3> The objective of this retrospective review was to assess barriers to successful clinical trial enrollment among gynecologic cancer patients at a comprehensive cancer center. <h3>Methods:</h3> A retrospective chart review was performed of all new patients and established patients requiring treatment changes seen in a clinic setting by physicians in the gynecologic oncology department at a national cancer institute between July 1, 2019, and June 30, 2020. Demographic information collected for each patient included age, race, language, distance from the cancer center, insurance type, marital status, education, performance status and medical history. Demographic factors were compared between patients who enrolled in trials and those who were deemed eligible for clinical trials but did not enroll. Patients who did not enroll in a clinical trial were stratified by the reason for not enrolling as physician factor, patient factor, trial factor, and screening failure. Data was collected in a secure REDCap database. Data was analyzed using the Wilcoxon rank sum test and Fisher's exact test. <h3>Results:</h3> 960 records were reviewed and 165 patients were found to be eligible for a clinical trial at the time of their visit. 35 of these 165 patients (21.2%) enrolled in a clinical trial. Among patients who did not enroll in a clinical trial, the reasons for not doing so were due to a physician factor (71/130 or 55%), patient factor (42/130 or 32%), screening failure (13/130 or 10%), or a trial factor (4/130 or 3%). There were no significant differences in demographics between patients who enrolled in trials and those who did not. Patients who did not enroll secondary to a physician factor differed significantly from those enrolled or attempted to enroll in age and insurance type. Patients who did not enroll secondary to a physician factor were older when compared to those who enrolled or attempted to enroll in a clinical trial but failed the screening process (median of 70 vs 61.5 years old, p=0.014). They were also more likely to have Medicare and less likely to have private insurance (p=0.044). Patients who did not enroll secondary to a patient factor did not appear to differ significantly from patients who did enroll or who failed screening. Although patients who did not enroll secondary to a patient factor lived a mean distance almost twice as far away as those who enrolled or attempted to enroll (mean of 184 vs 91 miles), this was not statistically significant (p=0.107). <h3>Conclusions:</h3> Based on a one year time span of retrospective review, including the COVID 19 pandemic time, physician factor and concern for a patient's age appears to be the biggest barrier to clinical trial enrollment. Exploring additional reasons behind physicians' reluctance to enroll patients in trials may be the key to increasing clinical trial enrollment of eligible patients.

Ten-Day Decitabine Treatment in AML Associated with Reversible Non-Ischemic Cardiomyopathy

Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferase inhibitor, is used to treat patients with IPSS intermediate 1 or higher Myelodysplastic Syndrome (MDS) and elderly patients with Acute Myeloid Leukemia (AML) not able to receive standard treatment (Blum et al., 2010). Decitabine induced non ischemic cardiomyopathy (NICM) has not been observed in large trials, however, isolated cases of reversible cardiomyopathy have been published (De C et al., 2012). We present two cases of NICM resulting from ten-day course of decitabine treatment for AML; one of which had improved cardiac function with aggressive cardiac management and reduced five-day decitabine course.Case 1A 69 year old African American male with history of hypertension presented with fatigue and thrombocytopenia (platelet 18k/uL). Bone marrow biopsy showed MDS. Treatment was delayed by 2 months due to lack of insurance and he had worsening cytopenias. Repeat bone marrow biopsy showed AML transformation from MDS (60% myeloblasts). FISH revealed deletion 7 and deletion 5. Echocardiogram (echo) done prior treatment showed borderline concentric left ventricular hypertrophy with ejection fraction (EF) of 55%.Treatment was initiated with Decitabine 20mg/m2 ten-day course every twenty-eight days. On cycle 2 day 23, patient presented with lower extremity edema, and fatigue. Repeat echo revealed severe reduced left ventricular ejection fraction (LVEF) 30% and moderate mitral regurgitation. EKG did not reveal ischemia. Troponin was 0.100ng/mL and NT-proBNP was raised at 14,609pg/mL. Cardiac MRI with and without contrast revealed ventricular dysfunction but did not show myocarditis or myocardial infarction.Bone marrow biopsy at the end of cycle two showed remission with underlying MDS changes. Treatment was switched to Azacitidine 75mg/m2 for 5 days. Repeat echo to reassess is pending at the time of this report.Case 262 year old African American female with history of alcohol abuse presented with pancytopenia (WBC 2.7/uL, Hb 9.1g/dl, platelets 35/uL). Bone marrow biopsy revealed 30% myeloblasts, dyspoetic megakaryocytes and 15% ringed sideroblasts. Cytogenetics were complex including deletion 7. Molecular testing was negative for FLT3, NPM and CEBPA mutations. Echo showed EF of 60% with diastolic dysfunction.Decitabine 20mg/m2 x 10 days was given for two cycles. She presented with increasing fatigue and dyspnea on day 15 of cycle 2. Physical exam showed jugular venous distention and peripheral edema. NT-proBNP was markedly elevated at 78,705(pg/mL) and troponin I was 0.254 ng/mL. EKG did not reveal ischemia. Echo demonstrated severely reduced LVEF to <20% with moderate mitral regurgitation. Cardiac MRI, performed without gadolinium because of acute kidney injury, confirmed the echo findings. Patient was started on standard cardiac medications by our cardio-oncologist. Repeat bone marrow prior to cycle three-showed remission. The shorter course decitabine (20mg/m2x 5 days) with close cardiology monitoring was initiated. Patient went on to receive cycles 3- 5 without clinical symptoms or signs of heart failure (HF). Repeat echo after three short course decitabine cycles showed improved LVEF to 45% and resolution of mitral regurgitation. The patient progressed after 6 cycles of Decitabine requiring treatment change to Azacitadine and Revlimid. She died from severe sepsis three months later.ConclusionCardiac dysfunction caused by permanent myocardial cell injury is a serious side effect of conventional chemotherapies including anthracyclines and antimetabolites. We report two cases of ten-day decitabine regimen causing severe LV systolic dysfunction that were treated with heart failure therapy. Reversal of cardiac complications were seen despite continued therapy with shorter course decitabine suggest that this may be a toxicity of the extended ten-day treatment. DisclosuresNo relevant conflicts of interest to declare.

Molecular testing in advanced lung adenocarcinoma: A single-center experience.

e21157 Background: Standard of care testing prior to first-line therapy for advanced lung non-small cell lung cancer (NSCLC) includes EGFR mutations, ALK rearrangements, and PD-L1 expression. There is limited real-world evidence on NSCLC molecular testing patterns in underrepresented racial and ethnic populations. Methods: We identified adult patients newly diagnosed with stage IV lung adenocarcinoma at the University of Illinois Hospital &amp; Health Sciences System between January 1, 2015 and October 1, 2019. Rates of biomarker testing for EGFR, ALK, and PD-L1 were determined, as well as the median time from tissue biopsy to each result. Data were stratified by race and ethnicity. Timelines of molecular testing were studied in relation to cancer therapy initiation. Results: Among 80 patients diagnosed with advanced NSCLC, 70 (87.5%) received EGFR testing, 69 (86.3%) received ALK testing, and 40 (50%) received PD-L1 testing from 2015-2019. Thirty-one (81.6%) patients diagnosed from 2017-2019 had PD-L1 testing. Median time from biopsy to molecular test result in the overall population was 3.0 weeks for EGFR, 3.0 weeks for ALK, and 2.0 weeks for PD-L1. There was no significant difference in EGFR and ALK testing rates between Black and non-Black patients. PD-L1 testing was decreased in Black patients compared to non-Black patients ( p = 0.02) from 2015-2019, but there was no significant difference from 2017-2019. All three biomarkers had similar testing rates between White and non-White patients and between Hispanic and non-Hispanic patients. Median time from biopsy to PD-L1 result decreased from over 12 weeks in 2015 and 2016 to 2 weeks in 2018 and 2019. Six (7.5%) patients received first-line treatment before results were available. Two (2.5%) required treatment changes based on results. Conclusions: In an urban, academic center we found similar EGFR and ALK testing rates among race and ethnicity subgroups. PD-L1 testing was lower in Black patients from 2015-2019 but not after national guidelines recommended PD-L1 testing in 2017. Treatment was initiated without full biomarker data in multiple cases, sometimes leading to changes in therapy after results were obtained. Further studies are indicated to determine strategies for comprehensive, timely, and equitable biomarker testing in advanced NSCLC.[Table: see text]

Efficacy and tolerability of the updosing of second-generation non-sedating H1 antihistamines in children with chronic spontaneous urticaria.

Chronic urticaria (CU), daily wheals or angioedema that lasts more than 6 weeks, is a common skin disease; CU is classified as spontaneous (no specific eliciting factor involved) or inducible (specific eliciting factor involved). Recent EAACI guidelines for management of CSU recommend second-generation non-sedating H1 antihistamines (sgAH1 s) as initial treatment in children (weight-adjusted) as in adults, followed by increased doses (up to 4 times) if the standard dose is not effective. The efficacy and tolerability of fourfold updosing in adults are known, but there is little documentation regarding updosing in the pediatric population. This retrospective study evaluates the efficacy and tolerability of the updosing of sgAH1 s in children with CSU in a tertiary care pediatric hospital. The electronic charts of patients diagnosed with CSU and referred to the Allergy Unit of Meyer Children's University hospital were reviewed during a period of 4 years. For each patient, an examination of demographic characteristics, diagnostic workup, efficacy, and tolerability of the treatment was performed. Disease activity was monitored using UAS7. Sixty-six cases of CSU were identified, and all of them were treated initially with a standard dose of sgAH1 s, followed by increased doses up to fourfold when standard dosing was not effective. 44/66 patients (66.7%) treated with sgAH1 s responded: 25 with a standard dose, 16 with a double, 2 with threefold dose, and 1 with fourfold dose. 12/66 (18.2%) patients began a therapy with omalizumab. As for the remaining patients, 10/66 (15.1%), they are still undergoing therapy with sgAH1 s because of the relapse of the symptoms after the stepped-down dosage. Regarding tolerability, 9/66 (13.6%) patients treated with sgAH1 s experienced side effects: three that required treatment change and six that did not. Our data were consistent with the tolerability of updosing of sgAH1 s in children with CSU, although the efficacy appears to be limited to double the standard dose.

First postoperative day review in eyes undergoing pars plana vitrectomy, encirclement and endotamponade to check intraocular pressure: Is it necessary?

To assess the proportion of patients with raised intraocular pressure (IOP) (≥ 30 mmHg) on the first postoperative day following pars plana vitrectomy (PPV), encirclement and endotamponade and assess the number requiring alteration in management to address elevated IOP. To establish whether review on day one is required. Retrospective case note review of consecutive patients who underwent 23-gauge PPV, 276-encirclement and endotamponade under the care of a single surgeon. All patients as standard received prophylactic anti-glaucoma medication post-surgery (eye drops) to take home but initiate only after day-one review. Statistical analysis was carried out using student t tests and Fisher's exact tests. Sixty-six patients were examined over a 2-year period. Mean day-one IOP was 22.2 mmHg (SD 7.3, 95% CI 20.4-24.0). Eleven patients (16.7%) had IOP ≥ 30 mmHg. Five patients (7.6%) had management changing decisions made at the day-one postoperative visit. Lens status, endotamponade, preoperative IOP, surgeon grade, cryopexy versus laser retinopexy or preoperative administration of once only 500 mg dose of intravenous acetazolamide did not influence IOP, with no significant difference between these subgroups. No cases of hypotony occurred. A significant minority of patients had elevation of IOP above 30 mmHg, a number of whom required treatment changes to address this. No preoperative risk factors were identified indicating those at risk of high IOP. It is important to identify these potentially harmful IOP elevations, and therefore day-one review is imperative and should be continued.

Cardiotoxicity manifestations in metastatic breast cancer patients treated with trastuzumab as first line.

e13011 Background: Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). Its use may result in cardiotoxicity. There are no formal guidelines for left ventricular ejection fraction (LVEF) monitoring in patients with metastatic disease treated with trastuzumab. Our local guideline include an echocardiogram every 3 months for these patients. Methods: We collected data from electronic records and hard copy files of patients treated with Trastuzumab as first line, between the years 2011-2014. Results: One hundred patients met the inclusion criteria. Median treatment duration of all patients was 30 months, with an average of 12 echocardiogram follow-ups per patient. Ninety-nine patients (99%) received additional chemotherapy. Thirty patients (30%) also received Pertuzumab. Ten (10%) of the eligible 100 patients showed significant decline in EF (≥10%) to a final LVEF of &lt; 50%. The median follow-up duration of these patients was 52 months. Median EF at the beginning of treatment was 61.5% in all patients. Cardiotoxicity occurred at an average of 23 months [median 18 months] after beginning of Trastuzumab treatment (range; 3-54 months), with an average EF decline of 14% (range; 10-18%). Three patients (30%) required treatment change due to the decline in EF. Temporary cessation of treatment was necessary in 4 (40%) of the patients for a period of time between 4 weeks to 8 months. The remaining 3 patients (30%), although developing significant decline in EF, did not require treatment cessation or change. None of the 10 patients presented any other clinical sign of cardiotoxicity. In the group with cardiac events, there were no previous reports of congestive heart failure (CHF), ischemic heart failure (IHF), myocardial infraction (MI) or diabetes. Only one patient was a smoker and another received hormone replacement therapy. The average age of this group at the time of diagnosis of metastatic disease was younger (50.6 vs. 55.8, P-value 0.5). Conclusions: Monitoring heart function by trimonthly echocardiogram does not seem to be the optimal monitoring modality in metastatic breast cancer patients who receive a trastuzumab-containing regimen as first line. This study results suggest that less frequent monitoring may be sufficient, thus diminishing patients' inconvenience and allowing better allocation of health care resources.

Outcomes of pregnant women with refractory epilepsy

PurposeEpilepsy is the most common neurological disorder requiring medical treatment during pregnancy. However, very few studies are specially dedicated to pregnant women with refractory epilepsy. This study was carried out with the aim of describing obstetrical and neurological outcomes of pregnant women with refractory epilepsy in Brazil. MethodsPregnant women with refractory epilepsy were enrolled in longitudinal cohort study between January 2005 and January 2018. They were regularly followed by a neurologist until the end of pregnancy. Neurological outcomes included seizure control, status epilepticus and adherence to antiepileptic medications. Obstetrical outcomes included major congenital malformations and obstetrical complications. ResultsA total of eighty two patients with a mean age of 24.5 ± 5.5 were included in our study. A significant number of women experienced an increase in seizure frequency and the prevalence of status epilepticus was 8.5%. More than half were non-adherent to antiepileptic drugs. Most of patients required treatment changes during pregnancy, in dose and/or in number of antiepileptic drugs. Cesarean section was the preferred way of delivery and five cases of major congenital malformations were detected. Obstetrical complications were significantly associated with polytherapy, multiple comorbidities, poor adherence to treatment and seizure deterioration during pregnancy (p < 0.05). ConclusionsWomen with refractory epilepsy can have a significant risk of obstetric and neurological complications during pregnancy. Treatment of refractory epilepsy in pregnancy is a real challenge for neurologists.

Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses.

To evaluate specific myelopathy diagnoses made in patients with suspected idiopathic transverse myelitis (ITM). A total of 226 patients 18 years and older were referred to Mayo Clinic Neurology for suspected ITM from December 1, 2010, to December 31, 2015. Electronic medical records were reviewed for detailed clinical presentation and course, laboratory and electrophysiologic investigations, and neuroimaging to determine the etiology. Current diagnostic criteria for ITM and alternative myelopathy diagnoses were applied. All cases where any discrepancy was suspected from the final reported clinical diagnosis were reviewed by each author and a consensus final diagnosis was made. The diagnostic criteria for ITM were met in 41 of 226 patients (18.1%). In 158 patients (69.9%), an alternative specific myelopathy diagnosis was made: multiple sclerosis or clinically isolated syndrome, 75; vascular myelopathy, 41; neurosarcoidosis, 12; neuromyelitis optica spectrum disorder, 12; myelin oligodendrocyte glycoprotein myelopathy, 5; neoplastic, 4; compressive, 3; nutritional, 3; infectious, 2; and other, 2. A myelopathy was not confirmed in 27 patients. Time from symptom onset to final clinical diagnosis in patients without ITM was a median of 9 months (range 0-288). Fifty-five patients (24%) required treatment changes according to their final clinical diagnosis. The majority of patients with suspected ITM have an alternative specific myelopathy diagnosis. A presumptive diagnosis of ITM can lead to premature diagnostic conclusions affecting patient treatment.

Predictors of early treatment failure following initial therapy for systemic immunoglobulin light-chain amyloidosis

We analysed factors predicting early treatment failure (ETF), after first-line therapy for light-chain amyloidosis (AL). AL amyloidosis patients seen at Mayo Clinic within 90 days of diagnosis, from 2006 to 2015, excluding those who died within 3 months of initial therapy, were analysed retrospectively. ETF was defined as progression requiring treatment change or death within 12 (ETF12) or 24 (ETF24) months of first-line treatment. Non-ETF included those with a follow-up of more than 12 or 24 months who had progression beyond 12 or 24 months. A total of 724 patients met the study criteria; 244 (33.7%) had ETF12 and 388 (53.6%) had ETF24. Patients with ETF12 were older (64.1 vs. 62.2 years) with higher prevalence of cardiac (81 vs. 64.1%) and multi-organ involvement (67.2 vs. 45.4%) and higher proportion of patients with t(11; 14) (58.5 vs. 44.3%) or in higher Mayo 2012 stage (58.5 vs. 41.1%).The median follow-up was 5.4 years from start of initial therapy. In multivariate analysis, presence of t(11; 14) and non-incorporation of autologous transplant in initial therapy are significant predictors of ETF12 (p = .01and p = .003) and ETF24 (p = .0001 and p = .005) while Mayo stage is predictive of ETF24 (p = .002), but not ETF12.

Bortezomib Versus Non-Bortezomib Based Initial Treatment for Transplant Ineligible Patients with Light Chain Amyloidosis

Introduction: Chemotherapeutic options for patients with systemic light chain amyloidosis (AL) who are not transplant candidates include bortezomib based therapy, melphalan with dexamethasone, and less commonly, immunomodulatory drugs (IMiDs). However, prospective clinical trial data comparing these regimens are lacking. This study aims to compare efficacy of bortezomib-based treatment to other therapies. Methods: All patients with AL seen within 90 days of diagnosis at our institution over a 10-year period (2006 to 2015) who did not undergo a stem cell transplant were identified from our institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Analyses were carried out by chi-square and Fisher9s exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to death, progression requiring treatment change or relapse requiring re-institution of treatment. PFS and overall survival was analyzed via the Kaplan-Meier method. Results: Seven hundred and twenty five patients met the inclusion criteria, of which 38% (n=275) received bortezomib containing regimens and 62% (n=450) received non-bortezomib based therapies. Bortezomib was used with dexamethasone in 24% (n=67) patients; and with other drugs, most commonly cyclophosphamide, in 76% (n=208) patients. Non-bortezomib treatment regimens included melphalan-based treatment in the majority (92%, n=414) followed by IMiDs with steroids and other drugs (8%, n=36). Baseline variables similar in both groups and their distribution in the entire cohort was as follows: gender distribution (63.3% males, n=459), median age of diagnosis (66.3 years, range 32.2 to 93.6), type of involved free light chain (FLC) (lambda 73%, n=523) and median plasma cell burden (10%, range 0 to 91). Median difference between the involved and uninvolved free light chain (dFLC) was higher in the bortezomib group (29 mg/dL vs. 23 mg/dL; p=0.017). There was no difference in organ involvement. In the bortezomib group, organ involvement was as follows: cardiac (81%, n=219), renal (62%, n=168) and hepatic (18%, n=48). In the non-bortezomib group, the rates of organ involvement were similar: cardiac (78%, n=346), renal (57%, n=247) and hepatic (19%, n=85). Median duration of first line treatment was similar in the 2 groups, with 178 days in the bortezomib cohort and 187 days in the non-bortezomib cohort. Response rates are illustrated in Table 1. Rates of very good partial response (VGPR) or better response were higher in the bortezomib group (64 % vs. 54%, p=0.0002). Patients treated with bortezomib achieved VGPR faster with higher rates of VGPR or better response seen at 3 months (48% vs. 27%, p Relapse or progression requiring change in therapy was more common in patients treated with non-bortezomib based therapy (38%, n=143/372) compared to bortezomib-based treatment (28%, n=67/236); p =0.01). However, no difference in overall survival was observed in patients treated with bortezomib (2.2 years; 95% confidence interval (CI): 1.7 to 3.3) vs. non-bortezomib therapies (1.7 years; 95% CI: 1.3 to 2.5). Conclusion: Treatment with bortezomib-based regimens results in a deeper response including higher rates of early VGPR at 3 and 6 months from starting therapy. Moreover, these patients achieve cardiac response faster and have lower rate of relapse. However, no difference in overall survival was seen, which may be explained by subsequent use of bortezomib-based therapies in this population. Disclosures Dispenzieri:Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; Jannsen: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity9s Board of Directors or advisory committees; Prothena: Membership on an entity9s Board of Directors or advisory committees. Kumar:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

The Molecular Response at 3 Months, Measured Using a Genxpert Platform, Predicts Further Outcomes in Chronic Myeloid Patients, but the Cutoff Differs from the 10% Cutoff Commonly Used with the EUTOS Method

Backgroung: In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels ≤10% measured using conventional RQ-PCR (IS) have consistently been correlated with further outcomes. Monitoring molecular responses using the Xpert BCR-ABL1 MonitorTM PCR system has demonstrated an optimal correlation with standardized RT-qPCR (IS), however, it is not known whether both methods are also equivalent when measuring BCR-ABL1 levels higher than 10%. We previously showed how the cutoff of 10% was not correlate with subsequent responses when using Xpert BCR-ABL1 in a cohort of 125 consecutive CML patients treated with imatinib (58%) and second generation TKI (2GTKI) (42%) as frontline treatment. By contrast, by using a receiver operating characteristic curve, a new cutoff of 1.5% was correlated with probabilities to achieve complete cytogenetic response (CCR) and major molecular response (MMR. The aim of this study is to validate the new cutoff of 1.5% at 3 months in patients treated with second generation 2GTKI.Methods: We have studied 57 new consecutive CML-CP patients treated 2GTKI from from Andalusian CML Group Registry. BCR-ABL1 transcript quantification was performed using the automated method Xpert BCR-ABL1 Monitor™, Cepheid, aligned to the 0.1% BCR-ABL1 ratio according to the standards of the World Health Organization. The samples were not centrally collected. All analyses were performed on an intention-to-treat basis unless otherwise stated. The proportions of patients who achieved MMR and CCyR after first-line treatment for 1 year and the response at 3 months were compared by applying Pearson’s chi-square test or Fisher’s exact test The study was approved by the Ethics Committee.Results: The median age at diagnosed was 48 years (18-74). The ratio of men to women was 59/41, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median follow up was 38 months (3-56). First-line treatment consisted of nilotinib and dasatinib in 58% and 42% of patients, respectively. Overall, the probability of achieving CCyR and MMR at 12 months was 92% (48/52) and 82% (39/47), respectively. Ten patients (17%) required treatment changes as a result of resistance (n=3), not achieving MMR (n=3) or intolerance (n=4). No patients progressed to advanced phases, and only 1 patient died during follow-up (not CML related). The overall median value of BCR-ABL1 at 3 months was 0.16%. Consistent with the original cohort of patients treated with first-line 2GTKI, all patients achieved a BCR-ABL1 level ≤10% at 3 months; therefore, this cutoff did not predict further evolution. We classified this new cohort based on the new cutoff observed in the primary population (BCR-ABL1 level at 3 months ≤1.5%); 77% of patients achieved BCR-ABL1 levels ≤1.5%, whereas 23% of patients did not. This cutoff also predicted the probability to obtain MMR by 12 months (91% vs. 44% (p=0.025).Conclusions: We have shown that when using the current version of GeneXpert, a BCR-ABL1cutoff of 10% at 3 months may underestimate the probability of not achieving an ulterior optimal response. We have shown that a new cutoff of 1.5% at 3 months can better identify patients with lower risk to achieve an optimal response at 12 months. This information should be taken into considerations when using this practical and widespread platform to monitor CML patients. DisclosuresGarcía Gutiérrez:Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ramirez:Bristol-Myers-Squibb: Honoraria; Janssen: Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria. Steegmann:BMS: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group.