Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature.

Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Characteristics and outcomes of acute myeloid leukaemia patients with baseline CD7 expression.

Targeted therapy development for acute myeloid leukaemia (AML) requires an understanding of specific expression profiles. We collected flow cytometry data on 901 AML patients and recorded aberrant CD7 expression on leukaemic blasts. 263 (29.2%) had blasts positive for CD7. CD7+ AML was more likely to be adverse risk (64.6% vs. 55.6%, p = 0.0074) and less likely to be favourable risk (15.2% vs. 24.1%, p = 0.0074) by European LeukemiaNet 2022 criteria. Overall survival was inferior (11.9 [95% CI, 9.7-15.9] vs. 19.0 months [95% CI, 16.1-23.0], p = 0.0174). At relapse, 30.4% lost and 19.0% gained CD7, suggesting moderate instability over time.

A phase 2 trial of mini-hyper-CVD, blinatumomab, and ponatinib in Philadelphia positive acute lymphoblastic leukemia.

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%).

Assessing the Impact of a Pulmonary Embolism Response Team and Treatment Protocol on Patients Presenting With Acute Pulmonary Embolism.

BACKGROUND: Pulmonary embolism (PE) care has traditionally been fragmented. The newly introduced Pulmonary Embolism Response Team (PERT) model provides streamlined care based on expedient, multi-disciplinary decision-making. This study aimed to quantify the impact of PERT, as part of a hospital-wide PE treatment protocol, on clinical outcomes. METHODS: Consecutive adult patients with acute PE diagnosed via computed tomography pulmonary angiogram (CTPA) were included. The PERT and treatment protocol were introduced in January 2015. Patient characteristics, therapies, quality measures of CTPA reporting, and clinical outcomes of PE patients treated for 2 years before and after implementation of these changes were evaluated. Primary endpoints were median length of stay in intensive care (ICU) and survival to discharge. RESULTS: A total of 321 consecutive PE patients were enrolled, of which 154 (treated in 2013-2014) and 167 (2015-2016) patients formed the historical control and study groups, respectively. Implementation of the algorithm was associated with less variance in anticoagulation and improved reporting of right heart strain parameters on CTPA. The ICU stay was reduced from a median of 5 to 2 days (p < 0.01). Eligible massive PE patients receiving reperfusion increased from 30% to 92% (p = 0.01), with mean delay from diagnosis to reperfusion decreasing from 763 to 181 minutes (p < 0.01). Bleeding complications were not increased, but overall survival to discharge remained unchanged. CONCLUSIONS: Introducing a PERT and treatment protocol reduced ICU stay, enhanced quality measures, and improved access of massive PE patients to reperfusion therapies, without increasing bleeding complications or health care costs.

SOHO State of the Art Updates and Next Questions | Novel Agents and the Diminishing Role of Allogeneic Stem Cell Transplant in B-Acute Lymphoblastic Leukemia.

Outcomes of patients with B-acute lymphoblastic leukemia (B-ALL) have improved remarkably in the past decade. This has largely been due to the development and introduction of novel immunotherapies such as blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, highly potent tyrosine kinase inhibitors, and improved risk stratification, including better understanding of high risk genomic subgroups and better methods of measurable residual disease (MRD) detection. Historically, allogeneic stem cell transplant (allo-SCT) has been the consolidative treatment of choice in first complete remission for fit adults with B-ALL. However, allo-SCT is associated with significant treatment-related mortality and morbidity. Current research is directed at the incorporation of novel immunotherapies into frontline regimens to improve depth and durability of responses and ultimately increase cure rates. In this review, we will discuss the emerging role of novel immune-based treated strategies in both the frontline and relapsed/refractory settings. We present our approach to newly diagnosed patients with B-ALL and illustrate how the incorporation of novel agents and use of high-sensitivity MRD assays can abrogate the need for allo-SCT in most patients with B-ALL.

Hypertensive Emergency with Thrombotic Microangiopathy or TTP? A Case Series and Literature Review.

Thrombotic microangiopathy (TMA) is associated with both hypertensive emergency and primary thrombocytopenia purpura (TTP). However, their clinical management is vastly different, with the latter necessitating urgent plasma exchange (PEX). We report two cases of hypertension-associated TMA (HTN-TMA) and a literature review of the clinical management of malignant hypertension. We suggest that in patients presenting with hypertensive emergency associated with TMA, a clinical diagnosis of HTN-TMA should be made, with emergent treatment to lower blood pressure started immediately. Although TTP is a differential diagnosis for TMA, PEX should not be started concurrently in the absence of other supporting evidence for TTP.

Acute kidney injury in acute promyelocytic leukemia: a possible adverse effect of high dose arsenic trioxide in obese patients.

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.

Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

Reducing Chemotherapy Waiting Times in the Ambulatory Setting of a Tertiary Cancer Centre Using a Design Thinking Approach.

INTRODUCTION: Chemotherapy is complex. We hypothesized that a design thinking approach could redesign preparatory processes and reduce wait times. METHODS: A multidisciplinary process mapping exercise was undertaken to understand the current processes, followed by proposing and testing solutions. Proposals were selected based on desirability and feasibility. These focused on starting the morning treatments on time and scheduling pre-made regimens in these slots. The primary outcome measure was the time from the appointment to starting treatment. Treatments in the post-intervention study group were compared against a historical control group. RESULTS: The median time to start morning treatment decreased by 46%, from 83 min (with an interquartile range 50-127) in the control group to 45 min (with an interquartile range of 24-81 min) in the study group (p < 0.001). This translated into an overall improvement for the day, with the median time to start treatment decreasing from 77 min (with an interquartile range of 40-120 min) to 47 min (with an interquartile range of 20-79 min) (p < 0.001). Pre-makes increased by 258%, from 908 (28.5%) to 2340 (71.7%) regimens (p < 0.001). The number of patients starting treatment within an hour of their appointment increased from 1688 (32.8%) to 3355 (62.3%, p < 0.001). CONCLUSION: We have shown that a data-driven, design thinking approach can improve waiting times. This can be adapted to improve other processes in an empathetic, sustainable manner.

Factors Affecting Patient and Caregiver Preferences for Treatment of Myeloma and Indolent Lymphoma.

PURPOSE: Treatment options for myeloma and indolent lymphoma are increasing exponentially, with distinct efficacy, side effects, and cost. We aim to determine the factors influencing patient and caregiver treatment preferences. METHODS: Patients and caregivers of patients with myeloma and indolent lymphoma were recruited from two cancer centers in Singapore. Preferences were elicited using a discrete choice experiment. Attributes and levels were selected based on a previous qualitative study. The relative preference for levels within each attribute (part worth utility values) and the extent to which an attribute would influence decision making (relative importance) were calculated. Patient and caregiver participation in the treatment plan selection process were assessed using the Control Preference Scale. RESULTS: One hundred ninety-nine patients and 169 caregivers were recruited. Patients placed the highest importance on out-of-pocket costs (relative importance = 35%), followed by efficacy (25%), persistent side effects (19%), administration route (8%), treatment duration (7%), and short-term side effects (5%). Caregivers ranked efficacy (27%) as the most important attribute, over out-of-pocket costs (24%). Most patients preferred a collaborative role in the shared decision-making process, while similar proportions of caregivers favored active and collaborative roles. CONCLUSION: Our study demonstrates that both patients and caregivers consider cost seriously when making treatment decisions. Furthermore, as patient and caregiver preferences may differ, there are implications for treatment selection and counseling, especially in cultures where caregivers have more prominent roles in treatment planning.

Venous thromboembolism in an Asian COVID-19 cohort across 3 infection waves-a retrospective observational study.

Background: A high incidence of venous thromboembolism (VTE) in COVID-19 has led to international recommendations for thromboprophylaxis. With limited data on Asian patients with COVID-19, the role of thromboprophylaxis remains unclear. Objectives: To investigate the in-hospital incidence of VTE in an Asian COVID-19 cohort, describe the VTE trend through successive COVID-19 waves (wild-type, delta, and omicron), and characterize the risk factors for VTE. Methods: We performed a retrospective observational cohort study of hospitalized COVID-19 adults from January 2020 to February 2022. Objectively confirmed VTE were reviewed to obtain VTE incidence and trend. Subset analysis of critical (intensive care), moderate (oxygen supplementation), and mild cases hospitalized ≥5 days was performed to investigate risk factors and in-hospital hazards of VTE. Results: Sixteen VTE events occurred among 3574 patients. Overall, VTE incidence was 0.45%, or 0.21% in mild, 3.60% in moderate, and 5.38% in critical infection. The maximum cumulative risk of VTE was 1.14% at 14 days for mild, 8.13% at 21 days for moderate, and 11.55% at 35 days for critical infection. Thromboprophylaxis use in mild, moderate, and critical cases was 5.7%, 28.8%, and 81.7%, respectively. In multivariable analysis, the severity of infection remained the strongest independent predictor of VTE. Compared with mild infection, the relative risk was 8.26 (95% CI, 2.26-30.16) for critical infection and 6.29 (95% CI, 1.54-25.67) for moderate infection. Conclusion: Overall, VTE incidence in Asian patients with COVID-19 is <1% across successive waves. Patients with moderate and critical infections are at greater risk for VTE and should be considered for routine thromboprophylaxis.

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine.

The prognostic value of measurable residual disease (MRD) by flow cytometry in acute myeloid leukemia (AML) patients treated with non-intensive therapy is relatively unexplored. The clinical value of MRD threshold below 0.1% is also unknown after non-intensive therapy. In this study, MRD to a sensitivity of 0.01% was analyzed in sixty-three patients in remission after azacitidine/venetoclax treatment. Multivariable cox regression analysis identified prognostic factors associated with cumulative incidence of relapse (CIR), progression-free survival (PFS) and overall survival (OS). Patients who achieved MRD < 0.1% had a lower relapse rate than those who were MRD ≥ 0.1% at 18 months (13% versus 57%, p = 0.006). Patients who achieved an MRD-negative CR had longer median PFS and OS (not reached and 26.5 months) than those who were MRD-positive (12.6 and 10.3 months, respectively). MRD < 0.1% was an independent predictor for CIR, PFS, and OS, after adjusting for European Leukemia Net (ELN) risk, complex karyotype, and transplant (HR 5.92, 95% CI 1.34−26.09, p = 0.019 for PFS; HR 2.60, 95% CI 1.02−6.63, p = 0.046 for OS). Only an MRD threshold of 0.1%, and not 0.01%, was predictive for OS. Our results validate the recommended ELN MRD cut-off of 0.1% to discriminate between patients with improved CIR, PFS, and OS after azacitidine/venetoclax therapy.

Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.

Qualitative Study of Factors Affecting Patient, Caregiver and Physician Preferences for Treatment of Myeloma and Indolent Lymphoma.

INTRODUCTION: The number of treatment options for myeloma and indolent lymphoma are expanding at an exponential rate, with few direct head-to-head comparisons on which to base efficacy measures. We sought to understand how patients, their caregivers and physicians weigh treatment characteristics in order to come to a decision on which treatment option to pursue. METHODS: Patients, their caregivers and physicians were recruited and interviewed until data saturation was reached. A qualitative, thematic analysis was done to identify themes important to each stakeholder. RESULTS: We found that, while all three groups valued efficacy the most, the consideration of other secondary characteristics of the treatment, such as cost, toxicity and logistical issues all differed subtly between the different groups. Patients valued minimising cost and toxicity, even at small trade-offs in efficacy. Caregivers and physicians valued efficacy foremost. CONCLUSION: Acknowledging and managing these differences is paramount because they influence shared decision-making and may affect patient outcomes in the short term, as well as their more general well-being in the long term.

Remote monitoring of marginalised populations affected by COVID-19: a retrospective review.

OBJECTIVES: The COVID-19 outbreak in Singapore has largely centred around migrant worker dormitories, comprising over 90% of all cases in the country. Dormitories are home to a culturally and linguistically distinct, low-income population, without on-site healthcare after-hours. The primary objective of this study was to assess the engagement and utilisation of a simple, low-cost, accessible, mobile health solution for remote self-reporting of vital parameters in dormitory residents with COVID-19. DESIGN: Retrospective review of medical care. SETTING: Two large migrant worker dormitories with a combined population of 31 546. PARTICIPANTS: All COVID-19-affected residents housed in dormitories during the study period. INTERVENTION: All residents were taught to use a chat assistant to self-report their temperature, heart rate and oxygen saturations. Results flowed into a dashboard, which alerted clinicians of abnormal results. OUTCOMES: The primary outcome measure was engagement rate. This was derived from the total number of residents who registered on the platform over the total number of COVID-19-affected residents in the dormitories during the study period. Secondary outcome measures included outcomes of the alerts and subsequent escalations of care. RESULTS: 800 of the 931 COVID-19-affected residents (85.9%) engaged with the platform to log a total of 12 511 discrete episodes of vital signs. Among 372 abnormal readings, 96 teleconsultations were initiated, of which 7 (1.8%) were escalated to emergency services and 18 (4.9%) were triaged to earlier physical medical review on-site. CONCLUSIONS: A chat-assistant-based self-reporting platform is an effective and safe community-based intervention to monitor marginalised populations with distinct cultural and linguistic backgrounds, living communally and affected by COVID-19. Lessons learnt from this approach may be applied to develop safe and cost-effective telemedicine solutions across similar settings.

Intravenous maintenance fluid tonicity and hyponatremia after major surgery- a cohort study.

BACKGROUND: Intravenous maintenance fluid (IMF) tonicity and composition influence plasma electrolyte balance. OBJECTIVE: To determine if hypotonic IMF therapy contributes to post-surgical hyponatremia. SETTING: Single-center tertiary institution. PARTICIPANTS: Adults who underwent major surgery and received peri-surgical IMF, with exclusive administration of hypotonic pre-mixed 0.33% saline, 5% dextrose and potassium chloride (DK0.33%S), or isotonic 0.9% saline with or without 5% dextrose (NS/DNS). OUTCOMES AND MEASURES: We examined post-surgical hyponatremia, hypokalemia and acute kidney injury (AKI), associated with use of either IMF. RESULTS: We studied 659 patients, of whom 161 patients (24%) developed post-surgical hyponatremia. DK0.33%S (versus NS/DNS) IMF was administered in 52% of patients who developed hyponatremia, compared to 38% of patients with stable natremia (p = 0.001). More patients with hyponatremia underwent gastrointestinal-hepatobiliary or abdominal (GI/HBS/Abd) surgery versus other surgical-sites (p = 0.001). Hypokalemia developed in 1% versus 10% of patients who received DK0.33%S and NS/DNS IMF respectively (p< 0.001), with corresponding AKI rates of 3% versus 7% (p = 0.02). On multivariate analysis, adjusted for timing of biochemistry post-surgery, IMF infusion rate and volume; independent factors associated with post-surgical hyponatremia included DK0.33%S administration, GI/HBS/Abd surgery (versus other sites), and post-surgical AKI (p < 0.05). Subgroup analysis by surgical sites showed that association of DK0.33%S administration with hyponatremia was most evident in GI/HBS/Abd surgery. CONCLUSIONS: Administration of DK0.33%S IMF, compared with NS/DNS, is associated with post-surgical hyponatremia in adults after major surgery, but with less hypokalemia. The higher rate of AKI observed with NS/DNS IMF requires further evaluation.

A New Model for Risk Stratification of Patients With Acute Pulmonary Embolism.

Pulmonary embolism (PE) is associated with mortality. There are many clinical prediction tools to predict early mortality in acute PE but little consensus on which is best. Our study aims to validate existing prediction tools and derive a predictive model that can be applied to all patients with acute PE in both inpatient and outpatient settings. This is a retrospective cohort study of patients with acute PE. For each patient, the Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI), European Society of Cardiology (ESC), and Angriman scores were calculated. Scores were assessed by the area under the receive-operating curve (AUC) for 30-day, all-cause mortality. To develop a new prognostic model, elastic logistic regression was used on the derivation cohort to estimate ß-coefficients of 8 different variables; these were normalized to weigh them. A total of 321 patients (mean age 60±17 years) were included. Overall 30-day mortality was 10.3%. None of the scores performed well; the AUCs for the PESI, sPESI, ESC, and Angriman scores were 0.67 (95% confidence interval [CI], 0.57-0.77), 0.58 (0.48-0.69), 0.65 (0.55-0.75), and 0.67 (0.57-0.76), respectively. Our new prediction model outperformed PESI, with an AUC of 0.82 (95% CI, 0.76-0.88). At a cutoff score of 100, 195 (60.1%) patients were classified as low risk. Thirty-day mortality was 2.1% (95% CI, 0.8%-5.2%) and 23.0% (16.5%-31.1%) for low- and high-risk groups, respectively (P < .001). In conclusion, we have developed a new model that outperforms existing prediction tools in all comers with PE. However, further validation on external cohorts is required before application.