Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.

Combining venetoclax with the hypomethylating agents azacitidine or decitabine has shown high complete response rates (60-70 %) in newly diagnosed (ND) acute myeloid leukemia (AML). However, studies addressing the efficacy of this approach in relapsed/refractory (R/R) AML remain limited. We conducted a retrospective analysis on patients treated with venetoclax-based therapy at a single institution. Objective response rates (ORR) and overall survival (OS) were assessed using logistic regression and Cox regression models, respectively. The total study population exhibited an ORR of 64 % with a complete remission at 34 %, complete remission with incomplete count recovery at 19%, and morphologic leukemia free state at 11 %. Patients with ND AML had a better ORR (71 %) compared to R/R AML (55 %), but the difference was not statistically significant. Median OS for the overall population was 14.4 months (range: 2-26 months). In the ND group, patients had a longer 6-month OS (82 % vs. 55 % in R/R AML), while both cohorts showed similar 12- and 24-month OS. Factors such as the hypomethylating agent chosen, adverse cytogenetics, TP53 mutations, prior hypomethylating agent use, and stem cell transplant status did not significantly affect ORR or OS. These findings support the effectiveness of venetoclax-based treatments in ND and R/R AML.

Acute myeloid leukemia resistant to venetoclax-based therapy: What does the future hold?

Venetoclax is a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, which, combined with a DNA hypomethylating agent or low dose cytarabine, results in high rates of initial responses in patients with acute myeloid leukemia (AML). However, the disease relapses in most patients. Mechanisms of resistance to venetoclax-based therapy include TP53 gene mutations or inactivation of p53 protein, activating kinase mutations such as FLT3 and RAS, and upregulation of other BCL-2 family apoptotic proteins. Current clinical trials are exploring strategies such as doublet or triplet regimens incorporating a p53 activator, an anti-CD47 antibody, or other novel agents that target genes and proteins responsible for resistance to venetoclax. Further studies should focus on identifying predictive biomarkers of response to venetoclax-based therapy and incorporating immunotherapeutic approaches such as checkpoint inhibitors, bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy to improve outcomes for patients with AML.

A Rare Case of Midostaurin-Associated Sweet's Syndrome.

Acute febrile neutrophilic dermatosis which is referred as Sweet's syndrome (SS) is a dermatological condition characterized by fever, erythematous rash, and leukocytosis. SS can be idiopathic or associated with malignancies or medications. We present a rare case of SS which developed shortly after starting midostaurin in a patient with acute myelogenous leukemia (AML).

Utilization of anti-factor Xa levels to guide reversal of oral factor Xa inhibitors in the emergency department.

PURPOSE: Oral factor Xa inhibitors (FXaIs) are increasingly utilized for outpatient anticoagulation therapy; however, laboratory monitoring is not routinely used to assess the safety and efficacy of these agents. We aimed to evaluate the role of chromogenic anti-factor Xa (anti-Xa) assays in the emergency department (ED) in the setting of patients with an acute bleed or requiring emergent procedures. METHODS: A retrospective review of anti-Xa levels obtained in the ED between June 1, 2019, and April 30, 2020, was completed. Data were collected to describe the clinical setting of anti-Xa level collection, oral FXaIs used before admission, administration of reversal agents, and patient disposition to further characterize the role of anti-Xa levels in the management of rivaroxaban and apixaban reversal. RESULTS: Thirty anti-Xa levels were included in the final analysis. The median time from sample collection to anti-Xa assay result was 45.9 minutes (interquartile range, 35.3-54.7 minutes). Eleven patients (37%) received anticoagulation reversal after their anti-Xa levels were determined. Anticoagulation reversal agents included either activated prothrombin complex concentrates (aPCCs) or prothrombin complex concentrates (PCCs). Anti-Xa levels were collected in 2 patients who had received PCCs before arrival at our ED. Of the patients with anti-Xa levels below 30 ng/mL, none received aPCCs or PCCs after their anti-Xa levels were determined. Anti-Xa assays were used to rule out the presence of FXaIs in 3 patients. CONCLUSION: This study illustrates the novel role of anti-Xa levels in managing patients with an emergent need for reversal in the ED. The assay may be used to rule out the presence of oral FXaIs and avoid unnecessary administrations of anticoagulation reversal agents.

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulopathy but the optimal prophylactic anticoagulation therapy remains uncertain and may depend on COVID-19 severity. OBJECTIVE: To compare outcomes in hospitalized adults with severe COVID-19 treated with standard prophylactic versus intermediate dose enoxaparin. METHODS: We conducted a multi-center, open-label, randomized controlled trial comparing standard prophylactic dose versus intermediate dose enoxaparin in adults who were hospitalized with COVID-19 and admitted to an intensive care unit (ICU) and/or had laboratory evidence of coagulopathy. Patients were randomly assigned in a 1:1 ratio to receive standard prophylactic dose enoxaparin or intermediate weight-adjusted dose enoxaparin. The primary outcome was all-cause mortality at 30 days. Secondary outcomes included arterial or venous thromboembolism and major bleeding. RESULTS: A total of 176 patients (99 males and 77 females) underwent randomization. In the intention-to-treat population, all-cause mortality at 30 days was 15% for intermediate dose enoxaparin and 21% for standard prophylactic dose enoxaparin (odds ratio, 0.66; 95% confidence interval, 0.30-1.45; P = .31 by Chi-square test). Unadjusted Cox proportional hazards modeling demonstrated no significant difference in mortality between intermediate and standard dose enoxaparin (hazard ratio, 0.67; 95% confidence interval, 0.33-1.37; P = .28). Arterial or venous thrombosis occurred in 13% of patients assigned to intermediate dose enoxaparin and 9% of patients assigned to standard dose enoxaparin. Major bleeding occurred in 2% of patients in each arm. CONCLUSION: In hospitalized adults with severe COVID-19, standard prophylactic dose and intermediate dose enoxaparin did not differ significantly in preventing death or thrombosis at 30 days.

Pilot trial of semi-automated medical note writing using lexeme hypotheses.

Clinicians write a billion free text notes per year. These notes are typically replete with errors of all types. No established automated method can extract data from this treasure trove. The practice of medicine therefore remains haphazard and chaotic, resulting in vast economic waste. The lexeme hypotheses are based on our analysis of how records are created. They enable a computer system to predict what issue a clinician will need to address next, based on the environment in which the clinician is working, and what responses the clinician has selected to date. The system uses a lexicon storing the issues (queries) and a range of responses to the issues. When the clinician selects a response, a text fragment is added to the output file. In the first phase of this work, the notes of 69 returning hemophilia patients were scrutinized, and the lexicon was expanded to 847 lexeme queries and 7995 responses to enable the construction of completed notes. The quality of lexeme-generated notes from 20 consecutive subjects was then compared to the clinicians' conventional clinic notes. The system generated grammatically correct notes. In comparison to the traditional clinic note, the lexeme-generated notes were more complete (88 % compared with 62 %), and had less typographical and grammatical errors (0.8 versus 3.5 errors per note). The system notes and traditional notes averaged about 800 words, but the traditional notes had a much wider distribution of lengths. The note-creation rate from marshalling the data to completion using the system averaged 80 wpm, twice as fast as the typical clinician can type. The lexeme method generates more complete, grammatical and organized notes faster than traditional methods. The notes are completely computerized at inception, and they incorporate prompts for clinicians to address otherwise overlooked items. This pilot justifies further exploration of this methodology.

Prevalence and the impact of hypogammaglobulinemia in newly diagnosed chronic lymphocytic lymphoma patients.

Objective: To examine the prevalence of hypogammaglobulinemia in chronic lymphocytic lymphoma (CLL) patients and to test the hypothesis that patients with hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: Immunoglobulin levels (IgA, IgG, IgM, IgE) were measured in newly diagnosed, treatment naïve banked samples of 150 patients with CLL followed prospectively for outcomes. Cox regression models were used to assess the effects of clinical variables on overall survival (OS). Results: The median age of the selected CLL cohort was 64 years with a male predominance; 96.2% of the patients were white. Fifty-nine deaths occurred during a median follow up of 6.8 years. Hypogammaglobulinemia in CLL was common in our cohort with 88 (58.7%, 95% CI: 50.4-66.6%) patients having a measurable isotype deficiency. The most common Ig deficiency was IgM (44.0%). IgA deficiency or low IgE was associated with higher Rai stages as well as with higher white blood cell counts at presentation. Any immunoglobulin deficiency was not associated with overall survival. Conclusion: A significant proportion of treatment-naïve CLL patients had underlying Ig deficiencies - both in isolation and in isotype combinations. Although a deficiency of IgA or IgE was associated with more severe disease at presentation, the impact of this association was mild.

Novel treatment approaches and future perspectives in follicular lymphoma.

Follicular lymphoma (FL) is a common B-cell malignancy characterized by relatively indolent growth and incurability with an expected lifetime course of serial intermittent treatment courses. Many patients with FL have lives shortened by the disease and despite a relatively favorable prognosis relative to other incurable systemic malignancies, optimal management of FL has not been achieved. This review focuses on identifying both patients for whom novel therapies might be most beneficial as well as systematically reviewing novel strategies at various levels of investigation. Prognostic markers incorporating clinical measurements and tumor genetics are discussed, yet at the time of diagnosis do not yet powerfully discriminate patients for whom specific strategies are beneficial. Reassessment of prognosis after evaluating the response to initial therapy is the most powerful identifier of those in need of novel management strategies. For initial therapy of high burden systemic disease, anti-CD20 antibody along with chemotherapy or immunomodulators all offer relatively similar effects on overall survival with subtly different effects on progression-free survival and quality of life. Several new agents currently under investigation in the upfront setting are discussed. Perhaps the best testing ground for novel therapies is in patients with early relapse following initial immunochemotherapy. Ongoing research in multiple therapy classes including, novel monoclonal antibodies, antibody drug conjugates, immunomodulatory agents, intracellular pathway inhibitors, immune checkpoint inhibitors, and epigenetic regulators are discussed herein.

Clinical use of FLT3 inhibitors in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is one of the two most common driver mutations and the presence of FLT3-ITD delivers poor prognosis. A number of ongoing clinical efforts are focused on FLT3 inhibitor use to improve the outcomes of this otherwise difficult leukemia. Midostaurin has been shown to improve outcomes in FLT3-mutated AML in the frontline setting. Several FLT3 inhibitors, especially second-generation agents, have shown clinically meaningful activity in relapsed or refractory AML and in patients not amenable to intensive therapy. In this article, we briefly review the biology of FLT3 in the physiological state and its role in leukemogenesis. We present a detailed review of current clinical evidence of FLT3 inhibitors and their use in the induction, treatment of relapsed or refractory disease, and maintenance setting.

A systematic review and meta-analysis of the association between vitamin A intake, serum vitamin A, and risk of liver cancer.

BACKGROUND: Previous evidence supports that vitamin A decreases the risk of several types of cancer. However, the association between vitamin A and liver cancer is inconclusive. AIM: This systematic review and meta-analysis summarizes the existing literature, discussing the association between vitamin A intake, serum vitamin A, and liver cancer in adult populations. METHODS: A systematic literature review was performed by searching the EMBASE, PubMed, Scopus and International Pharmaceutical Abstract databases using terms related to vitamin A (e.g. retinol, α-carotene, ß-carotene, and ß-cryptoxanthin) and hepatic cancer without applying any time restriction. A meta-analysis was performed using random effect models. RESULTS: The meta-analysis of five studies showed no association between serum retinol and liver cancer (pooled risk ratio = 1.90 (0.40-9.02); n = 5 studies, I2 = 92%). In addition, the systematic review of studies from 1955 to July 2017 found studies that indicated no association between the intake and serum level of α-carotene ( n = 2) and ß-cryptoxanthin ( n = 1) and the risk of liver cancer. Further, the associations between retinol intake ( n = 3), ß-carotene intake ( n = 3), or serum ß-carotene ( n = 3) and liver cancer were inconclusive. CONCLUSIONS: Current information on the association between vitamin A intake and liver cancer or serum vitamin A and liver cancer are limited. Most studies demonstrated no association between dietary vitamin A and the risk of liver cancer. However, the finding was based on a small number of studies with potential publication bias. Therefore, large observational studies should be conducted to confirm these associations.

Predictor of 90-Day Readmission Rate for Hepatic Encephalopathy.

OBJECTIVES: The purpose of our study was to identify clinical parameters associated with readmissions within 90 days in patients with hepatic encephalopathy (HE). METHODS: We reviewed electronic medical records of patients admitted between January 1, 2010 and September 30, 2013 at University Medical Center, Lubbock, Texas. Inclusion criteria were admission to the hospital with diagnosis of HE in patients older than 18 years. We compared the patients with readmission within 90 days with patients with no readmission using routine clinical data. RESULTS: A total of 140 admissions met inclusion criteria; 35% were white, 59.3% were Hispanic, and their mean age was 55.6 ± 10.5 years. The median admission Model for End-Stage Liver Disease score was 15.5 (4-38). Univariate analysis demonstrated that a history of diabetes mellitus, a history of hypertension, prior transjugular intrahepatic portosystemic shunt placement, a history of prior HE, and the use of lactulose posthospitalization were associated with increased readmission rates and the presence of gastrointestinal bleeding was associated with decreased readmission rates (P < 0.05 for each factor). Multivariate logistic regression demonstrated that history of hypertension (P = 0.02) predicted an increased readmission rate. CONCLUSIONS: Our study demonstrates that hypertension increased the risk of readmission in patients with HE. More intensive interventions in these patients may decrease readmission rates and improve outcomes.

Factors Associated With Reintubation in Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase morbidity, mortality, and health care costs in COPD patients. Patients who require mechanical ventilation and fail extubation often have longer hospital stays and/or increased mortality. Determining predictors to identify patients who might require reintubation could help respiratory care teams manage these patients better. METHODS: We retrospectively reviewed data of COPD patients over a 3-year period. Inclusion criteria were patients with acute exacerbations of COPD, age more than 45 years, and patients on mechanical ventilation. Exclusion criteria were ventilated via tracheostomy, unplanned extubation, and reintubation for reasons other than respiratory failure. RESULTS: This study included 88 patients; 61 patients were successfully extubated, 11 patients were extubated and required reintubation, and 16 patients were not extubated during their intensive care unit stay. There were no differences in demographic or clinical characteristics between the patients with successful extubation and failed extubation. Patients with successful extubation were more likely to have a "good cough" assessment and to not receive any sedatives or analgesics in the 24 hours prior to extubation than patients who failed extubation (P < .05). Multiple variable logistic regression demonstrated that reintubation was significantly associated with sedatives/analgesics given prior to extubation (odds ratio = 8.6; 95% confidence interval, 1.23-60.8). Intensive care unit and hospital lengths of stay, tracheostomy events, and mortality rates were higher in the reintubation group (P < .001). CONCLUSION: Sedative and analgesic drug use prior to extubation was associated with more frequent reintubation in patients with acute exacerbations of COPD. This study suggests that the judicious withdrawal of sedatives prior to extubation may reduce reintubations.

Diverticulitis in the young.

BACKGROUND: Colonic diverticulitis is relatively uncommon in young patients, especially those younger than 40 years. We compared demographic data, clinical presentation, management, and clinical course of diverticulitis in patients ≤40 years old compared with patients >40 years old. METHODS: This study included all patients who presented to the emergency department with a diagnosis of diverticulitis between October 1, 2009 and September 30, 2010. Patients were divided into 2 groups: group 1 (≤40 years old) and group 2 (>40 years old). Demographic characteristics, clinical presentation and management, and short-term outcomes were compared. RESULTS: Ninety-four patients were included in the study (37 patients in group 1 and 57 patients in group 2). A higher percentage of obese and Hispanic men was found in group 1 (P > .05). The rate of discharge from the emergency department was significantly higher in group 1 (56.8% in group 1 vs 7.0% in group 2, P < .01). Group 2 patients had a shorter median length of stay than group 1 patients (3.1 vs 5.7 days, P = .16). There were no differences in vital signs, laboratory data (including complete blood count and basic metabolic panel), and in-hospital mortality rates between the 2 groups. CONCLUSIONS: This study demonstrates that young Hispanic men develop diverticulitis and that this diagnosis needs to be considered when they present to emergency rooms with abdominal symptoms. A longitudinal study is needed to determine the long-term outcomes in these patients and to investigate the pathogenesis.

Sympathomimetic syndrome, choreoathetosis, and acute kidney injury following "bath salts" injection.

"Bath salts" is a well known street drug which can cause several cardiovascular and neuropsychiatric symptoms. However, only one case of acute kidney injury has been reported in the literature. We present a case with sympathomimetic syndrome, choreoathetosis, gustatory and olfactory hallucinations, and acute kidney injury following the use of bath salts. A 37-year-old man with past medical history of hypertension and depression was brought to the emergency center with body shaking. Three days before admission he injected 3 doses of bath salts intravenously and felt eye pain with blurry vision followed by a metallic taste, strange smells, profuse sweating, and body shaking. At presentation he had a sympathomimetic syndrome including high blood pressure, tachycardia, tachypnea, and hyperhydrosis with choreoathetotic movements. Laboratory testing revealed leukocytosis and acute kidney injury with a BUN of 95 mg/ dL and a creatinine of 15.2 mg/dL. Creatine kinase was 4,457 IU/dL. Urine drug screen is negative for amphetamine, cannabinoids, and cocaine; blood alcohol level was zero. During his ICU stay he became disoriented and agitated. Supportive treatment with 7.2 liters of intravenous fluid over 3 days, haloperidol, and lorazepam gradually improved his symptoms and his renal failure. Bath salts contain 3,4-methylenedioxypyrovalerone, a psychoactive norepinephrine and dopamine reuptake inhibitor. Choreoathetosis in this patient could be explained through dopaminergic effect of bath salts or uremic encephalopathy. The mechanism for acute kidney injury from bath salts may involve direct drug effects though norepinephrine and dopamine-induced vasoconstriction (renal ischemia), rhabdomyolysis, hyperthermia, and/or volume contraction.

Meningitis-retention syndrome as a presentation of west nile virus meningitis.

A 26-year-old previously healthy man presented with fever, urinary retention, nuchal rigidity, and hyperreflexia but with a clear sensorium. His initial spinal fluid results were consistent with aseptic meningitis from West Nile virus infection, and this was confirmed by serological studies on blood and cerebrospinal fluid. Computed tomography and magnetic resonance imaging studies were unremarkable. He received supportive care and urinary catheterization to prevent bladder injury from overdistension. He was discharged home without recurrence of urinary retention after five days of hospitalization. Therefore, this case report describes the first case of West Nile virus meningitis in a patient with the meningitis-retention syndrome.

Reactive Thrombocytosis Associated with Acute Myocardial Infarction following STEMI with Percutaneous Coronary Intervention.

The etiology of thrombocytosis can be classified into reactive and essential forms. The rate of thromboembolic events is higher in essential thrombocytosis, and these events include strokes, transient ischemic attacks, retinal artery or retinal vein occlusions, digital ischemia, and acute coronary syndrome. In a study of 732 medical and surgical patients with thrombocytosis, 88% had reactive thrombocytosis. Patients with reactive thrombocytosis do not require cytoreductive medications or antiplatelet treatment. We report a healthy 40-year-old man without any medical problems who developed a new episode of myocardial infarction associated with thrombocytosis after an episode of myocardial infarction followed by percutaneous coronary intervention. He had thrombocytosis, and his platelet function test did not reveal adequate inhibition. To treat his acute coronary syndrome, therapeutic enoxaparin was added, and clopidrogel was substituted with ticagrelor. We decided to start hydroxyurea to reduce platelets counts. Enoxaparin and hydroxyurea were discontinued when platelet count returned to baseline. JAK-2 and BCR/ABL mutations were negative. This case report highlights a clinical dilemma (reactive thrombocytosis), which is challenging in terms of management and pathophysiology.