De-escalation Strategies Research Articles

"Do No Harm": Promoting Anti-Racist Policing in Pediatric Emergency Departments Through 20 Practice Change Considerations.

Children represent some of the most vulnerable and most valuable members of society. When acutely ill or injured, pediatric emergency departments (EDs) provide first line, specialized care for children and adolescents. Unique and unpredictable, the pediatric ED environment requires a wide range of health care professionals to care for children and their families and often includes hospital-employed security professionals and local law enforcement personnel to ensure safe and protective spaces paramount for optimal patient care. However, an active policing presence within environments designed to promote healing can paradoxically contribute to harm, particularly for Black and Brown patients. As health care systems pledge to dismantle structural racism and achieve health equity, efforts must include anti-racist reforms of threat management systems within clinical environments. We propose assessment and evaluation of current security and police encounters within pediatric EDs. We call for institution of policies that mitigate biases, address medical mistrust, distinguish clinical from criminal aggression, and minimize punitive contact with police. We outline a multitiered, patient-centered approach to disruptive and violent acts that prioritizes prevention, early intervention, and de-escalation strategies with a goal of reducing the perceived need for policing presence in pediatric EDs.

Online communication of European public institutions and NATO during the crisis in Ukraine (February 24, 2022 - December 24, 2022)

The crisis in Ukraine between February 24, 2022 and December 24, 2022 drastically altered the way that European public institutions and NATO used Twitter to communicate with the public. In response to the political, economic, and military escalation in Ukraine, European public institutions and NATO used Twitter to disseminate information to the public about their diplomatic efforts in the region, as well as to discuss potential solutions and strategies for de-escalation and long-term resolution of the crisis. Through Twitter, European public institutions and NATO were also able to communicate their concerns about regional stability and the potential implications of the crisis for the entire European continent. Twitter proved to be an invaluable tool for European public institutions and NATO in their efforts to keep the public informed and to potentially influence the political dynamics of the crisis in Ukraine.

15th Post-ECTRIMS Meeting: a review of the latest developments presented at the 2022 ECTRIMS Congress (Part II)

On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October. To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts. This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

The Optimal Duration and De-escalation Strategy of Antiplatelet Agents and Anticoagulation Agents in Korean Patients Undergoing Percutaneous Coronary Intervention

The Optimal Duration and De-escalation Strategy of Antiplatelet Agents and Anticoagulation Agents in Korean Patients Undergoing Percutaneous Coronary Intervention

Risk factors for lower extremity lymphedema after surgery in cervical and endometrial cancer.

Lower extremity lymphedema (LEL) is a well-known adverse effect related to cervical and endometrial cancer (CEC); however, very few studies have elucidated the clinicopathologic risk factors related to LEL. We investigated the incidence and risk factors in patients who received primary surgery and/or adjuvant radiotherapy (RT) or chemotherapy for CEC. We retrospectively reviewed 2,565 patients who underwent primary surgery following CEC diagnosis between January 2007 and December 2020. LEL diagnosis was based on objective and subjective assessments by experts. We identified important predictors of LEL to construct a nomogram predicting individual risks of LEL. For internal validation of the nomogram, the original data were separated using the split-sample method in a 7:3 ratio of training data and test data. Overall, 858 patients (33.5%) received RT, 586 received external beam RT (EBRT), and 630 received intracavitary RT. During follow-up period, LEL developed in 331 patients, with an overall cumulative 5-year incidence of 13.3%. In multivariate analysis, age at primary treatment, use of docetaxel-based chemotherapy, type of hysterectomy, type of surgical pelvic lymph node (LN) assessment, number of dissected pelvic and para-aortic LNs, and EBRT field were the independent predictors of LEL. We subsequently developed the nomogram showing excellent predictive power for LEL. LEL is associated with various treatment modalities, and their interactions may increase the possibility of occurrences. De-escalation strategies for treatment modalities should be considered to reduce LEL in patients with CEC.

Cost-Effectiveness Analysis of Ultra-Hypofractionated Whole Breast Radiation Therapy Alone Versus Hormone Therapy Alone or Combined Treatment for Low-Risk ER-Positive Early Stage Breast Cancer in Women Aged 65 Years and Older

The optimal management of early-stage, low-risk, hormone-positive breast cancer in older women remains controversial. Recent trials have shown that 5-fraction ultrahypofractionated whole-breast irradiation (U-WBI) has similar outcomes to longer courses, reducing the cost and inconvenience of treatment. We performed a cost-utility analysis to compare U-WBI to hormone therapy alone or their combination. We simulated 3 different treatment approaches for women age 65 years or older with pT1-2N0 ER-positive invasive ductal carcinoma treated with lumpectomy with negative margins using a Markov microsimulation model. The strategies were U-WBI performed with a 3-dimensional conformal technique over 5 fractions without a boost ("radiation therapy [RT] alone"), adjuvant hormone therapy (anastrozole for 5 years) without RT ("aromatase-inhibitor [AI] alone"), or the combination of the 2. The combination strategy was calibrated to match trial results, and the relative effectiveness of the RT alone and AI alone strategies were inferred from previous randomized trials. The primary endpoint was the cost-effectiveness of the 3 strategies over a lifetime horizon as measured by the incremental cost-effectiveness ratio (ICER), with a value of $100,000/quality-adjusted life-year deemed "cost-effective." The model results compared with the prespecified target outcomes. On average, RT alone was the least expensive strategy ($14,775), with AI alone slightly more ($14,998), and combination therapy the costliest ($19,802). RT alone dominated AI alone (the incremental cost-effectiveness ratio [ICER] -$5089). Combination therapy, compared with RT alone, was slightly more expensive than our definition of cost-effective (ICER $113,468) but was cost-effective compared with AI alone (ICER $54,451). Probabilistic sensitivity analysis demonstrated RT alone to be cost-effective in 50% of trials, with combination therapy in 36% and AI alone in 14%. U-WBI alone appears the more cost-effective de-escalation strategy for these low-risk patients, compared with AI alone. Combining U-WBI and AI appears more costly but may be preferred by some patients.

What is the future of treatment de-escalation for HPV-positive oropharyngeal cancer? A review of ongoing clinical trials.

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased in incidence in recent decades. With higher cure rates in younger populations, long-term survivors may live with acute- and long-term toxicity, leading to increased interest in de-escalation treatment strategies for HPV-related OPSCC. Herein, we have examined the current landscape of clinical trials in this context. A review of active clinical trials related to de-escalation of HPV-associated OPSCC treatment was performed using the clinicaltrials.gov database from inception to January 2022. A search using the key words "oropharyngeal cancer" and "HPV" was completed. Three investigators independently reviewed each trial, with any discrepancies settled by a fourth. Data collected from each study included study phase, study design, primary, and secondary endpoints, and de-escalation treatment strategies. A final 24 articles were selected for full text review. Many trials (n=19, 79%) were non-randomized, and most studies employed a phase II design (n=14, 58%). Only 13% (n=3) were randomized trials, and 8% (n=2) included a phase III component. The most frequent primary endpoint was progression-free survival (PFS) (n=9, 37.5%). With regards to the identified de-escalation strategies, all the studies (n=24) had at least one component assessing changes in RT dose/fractionation and/or a reduction in RT volumes. A smaller percentage of trials assessed surgical interventions (n=9, 37.5%) and/or changes in systemic therapy (n=8, 33.3%). A small number of randomized trials are underway, and a transition to more randomized phase III trials in the future will be important to change clinical practice.

The role of point-of-Care Musculoskeletal Ultrasound for Routine Joint evaluation and management in the Hemophilia Clinic - A Real World Experience

BackgroundThe use of musculoskeletal ultrasound (MSKUS) for point-of-care (POC) evaluation of hemophilic arthropathy is growing rapidly. However, the extent to which MSKUS influences clinical treatment decisions is unknown.MethodsWe conducted a three-year, prospective, multi-center study at three hemophilia treatment centers in the United States to evaluate the utilization of POC-MSKUS for routine clinical decision-making in adult persons with hemophilic arthropathy. Bilateral elbows, knees and ankles were assessed clinically [Hemophilia Joint Health Score (HJHS)] and with POC-MSKUS by the Joint TissueActivity and Damage Exam (JADE) protocol at baseline and approximately annually for two additional times. Treatment decisions, including physical therapy (PT) and “medical” (joint injections/aspirations, referrals to orthopedics, changes/adjustments of hemostatic plans, and use of oral anti-inflammatory medications) were recorded in relation to POC-MSKUS.ResultsForty-four persons [median age 37 years (IQR 29, 51)], mostly with severe Hemophilia A on clotting factor prophylaxis, completed 129 visits, yielding 792 joint exams by POC-MSKUS and HJHS [median at baseline 27 (IQR 18, 42)] over a median follow up of 584 days (range: 363 to 1072). Among 157 management decisions, 70% were related to PT plans (n = 110) and 30% were “medical”. Point-of-care MSKUS influenced 47/110 (43%) PT plans, mostly informing treatment of specific arthropathic joints (45/47 plans) in patients with high HJHS. Physical therapy plans influenced by POC-MSKUS directed more manual therapy/therapeutic exercises, while plans based on physical exam were focused more on global exercises and wellness. Treatment decisions were mostly based on the identification of specific musculoskeletal abnormalities visualized by POC-MSKUS. Of note 20/47 (43%) POC-MSKUS plans included de-escalation strategies, thereby reducing exercise intensity, mostly for joint instability and subclinical hemarthroses. Point-of-care MSKUS also informed 68% (32/47) of “medical” decisions, surprisingly mostly for injections/aspirations and referrals to orthopedics, and not for adjustments of hemostatic treatment. Although not formally studied, ultrasound images were used frequently for patient education.ConclusionRoutine joint evaluations with POC-MSKUS resulted in few changes regarding medical management decisions but had a profound effect on the formulation of PT plans. Based on these findings, new studies are essential to determine the benefit of MSKUS-informed management plans on joint health outcomes.

Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010-2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

518 DUAL ANTIPLATELET THERAPY DE-ESCALATION MODALITIES IN ACUTE CORONARY SYNDROME PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION

Abstract Background Dual antiplatelet therapy (DAPT) is usually recommended for 12 months after an acute coronary syndrome (ACS). A major drawback of DAPT is represented by an increased risk of bleeding events, which have a detrimental impact on short and long-term prognosis. To minimize this risk, bleeding modulation strategies can be adopted, including de-escalating to a lower intensity DAPT regimen (i.e., halving the dose of a potent P2Y12-inhibitor or switching to clopidogrel). Whether either DAPT de-escalation modality is associated with improved clinical outcomes is unknown. Purpose To investigate the role of DAPT de-escalation in ACS patients undergoing PCI as compared to standard DAPT, and to indirectly compare two DAPT de-escalation modalities (i.e., by halving P2Y12-inhibitor dose or switching from a potent P2Y12-inhibitor to clopidogrel) by means of a network meta-analysis using standard DAPT as a common comparator. Methods MEDLINE, Cochrane and Web Of Science were searched for randomised trials of DAPT de-escalation strategies in ACS patients undergoing PCI. The primary outcome was all-cause death, while secondary outcomes included net adverse cardiovascular events (NACE), major adverse cardiovascular events (MACE), and their individual components. A network meta-analysis was performed to indirectly compare different DAPT de-escalation modalities (i.e., halving the dose of a potent P2Y12-inhibitor or switching to clopidogrel). Results A total of 12,813 from ten studies were included for the purposes of this analysis. In the pairwise meta-analysis, there were no significant differences between DAPT de-escalation and standard DAPT in terms of all-cause death (risk ratio [RR] 0.85, 95% confidence interval [CI] 0.62 to 1.18), MACE (RR 0.83, 95% CI 0.69 to 1.00), cardiovascular death (RR 0.78, 95% CI 0.56 to 1.07), myocardial infarction (RR 0.80, 95% CI 0.58 to 1.09), stent thrombosis (RR 0.74, 95% CI 0.37 to 1.47) and major bleeding (RR 0.88, 95% CI 0.66 to 1.17). Compared to standard DAPT, de-escalation was associated with a lower risk of NACE (RR 0.76, 95% CI 0.68 to 0.85), clinically relevant bleeding (RR 0.65, 95% CI 0.51 to 0.84) and minor bleeding (RR 0.63, 95% CI 0.54 to 0.74). In the indirect comparison, there were no significant differences between de-escalation by switching to clopidogrel and de-escalation by halving the P2Y12-inhibitor dose in terms of all-cause death (RR 1.24, 95% CI 0.51 to 2.99), NACE (RR 1.10, 95% CI 0.81 to 1.48), MACE (RR 1.10, 95% CI 0.59 to 2.06) and clinically relevant bleeding (RR 1.16, 95% CI 0.60 to 2.21). Conclusions DAPT de-escalation was associated with a lower risk of NACE, clinically relevant bleeding and minor bleeding compared to standard DAPT in ACS patients undergoing PCI. There is no consensus on the optimal DAPT de-escalation modality and further research in this field is warranted since halving the dose of a potent P2Y12-inhibitor and switching to clopidogrel resulted to be similar in terms of net clinical benefit and both ischemic and bleeding events, therefore representing two viable options in ACS patients undergoing PCI.

Molecular Pathways of Breast Cancer in Systemic Sclerosis: Exploratory Immunohistochemical Analysis from the Sclero-Breast Study.

Several authors reported an increased risk of cancer in SSc patients, including breast cancer (BC). Nevertheless, the mechanisms underlying this association have not yet been clarified. SSc and BC share several molecular pathways, which seem to play a common etiopathogenetic role. The previously published Sclero-Breast study demonstrated the development of BC with a good prognosis among these patients, which could be explained by an autoimmune background as a possible mechanism for limiting tumor extension. Here, we report the results of an IHC analysis of molecular pathways known to be common drivers for both diseases, with the aim to better define the mechanisms underlying a good prognosis of BC in patients affected by SSc. The analysis demonstrated higher TILs rates in all BC subgroups, with a high rate of PD-L1 expression especially in TNBC and HER2-positive BC, suggesting a less aggressive behavior in these patients compared to the general population. These results support a possible de-escalation strategy of cancer therapies in these fragile patients. These data could represent a starting point for future prospective studies based on the clinical application of these biomarkers with a larger sample size to promote a personalized and targeted oncological treatment for this specific subset of patients.

Circulating Human Papillomavirus DNA in Head and Neck Squamous Cell Carcinoma: Possible Applications and Future Directions

There has been a rising trend in HPV-induced head and neck cancers in the last several decades. This subgroup of squamous cell carcinoma is mostly located in the oropharynx and comprises a subset of patients who are typically younger and without the usual risk factors of smoking and alcohol use. As the prognosis of HPV-induced OPC is more favorable, there is a desire to properly select these patients for de-intensification protocols while identifying individuals who may suffer treatment failure. Here, we describe recent developments in circulating tumor HPV DNA as a marker of HPV-positive oropharyngeal cancer that can potentially be used as a diagnostic tool to stratify patients for de-escalation strategies and to survey for recurrence.

Stakeholder outcome prioritization in the Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA) trial.

The Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA) study is a randomized, pragmatic trial investigating different tumour necrosis factor inhibitor de-escalation strategies for children with sustained inactive disease. In this project, we elicited concept rankings that aided in the selection of the patient-reported outcome (PRO) measures that should be examined as part of the BACK-OFF JSpA trial. We conducted a discrete choice experiment to evaluate individuals' preferences regarding PROs. Stakeholders assessed a discrete list of 21 outcome concepts, each of which had a Patient-Reported Outcome Measurement Information System (PROMIS) measure associated with it. PROMIS measures are self- or proxy-reported instruments that are universally applicable to the general population and all chronic conditions. Stakeholders were required to make choices instead of expressing the strength of a preference. Fourteen caregivers, 12 patients (9-22 years old), 16 rheumatologists and three executives from health insurance companies completed the exercise, which took approximately 10 min. The discrete choice experiment resulted in an estimate of the relative importance of each outcome and rank. All stakeholder groups agreed that the primary PRO should be 'Pain Interference', a measure that evaluates the effect of pain on a child's everyday activities, including its impact on social, emotional, mental and physical functioning. Patients and caregivers were mostly aligned in their top priorities, with patients valuing physical health (50% of the top 10) whereas caregivers were more interested in mental health (60% of the top 10). Rheumatologists and health insurance executives were most interested in physical health outcomes, which were ranked 80% and 60% of their top 10 PROs, respectively. Overall, the patients had the most diverse set of prioritized outcomes, including at least one of each category in their top 10 rank order of importance. Patients were also the only stakeholders to prioritize 'social' health. Patients and caregivers were mostly aligned in their outcome priority rankings. The rank-order list directly informed the creation of a profile of PRO measures for our upcoming trial. Stakeholder partners helped with acquisition of data and lead parent partners helped interpret data.

Protocol for the postoperative radiotherapy in N1 breast cancer patients (PORT-N1) trial, a prospective multicenter, randomized, controlled, non-inferiority trial of patients receiving breast-conserving surgery or mastectomy

BackgroundPostoperative radiotherapy (PORT) could be useful for pN1 breast cancer patients who have undergone breast-conserving surgery (BCS) or mastectomy. However, the value of regional nodal irradiation (RNI) for BCS patients, and the indications for post-mastectomy radiotherapy (PMRT) for pN1 breast cancer mastectomy patients, have recently been challenged due to the absence of relevant trials in the era of modern systemic therapy. “PORT de-escalation” should be assessed in patients with pN1 breast cancer.MethodsThe PORT-N1 trial is a multicenter, randomized, phase 3 clinical trial for patients with pN1 breast cancer that compares the outcomes of control [whole-breast irradiation (WBI) and RNI/PMRT] and experimental (WBI alone/no PMRT) groups. PORT-N1 aims to demonstrate non-inferiority of the experimental group by comparing 7-year disease-free survival rates with the control group. Female breast cancer patients with pT1-3 N1 status after BCS or mastectomy are eligible. Participants will be randomly assigned to the two groups in a 1:1 ratio. Randomization will be stratified by surgery type (BCS vs. mastectomy) and histologic subtype (triple-negative vs. non-triple-negative). In patients who receive mastectomy, dissection of ≥5 nodes is required when there is one positive node, and axillary lymph node dissection when there are two or three positive nodes. Patients receiving neoadjuvant chemotherapy are not eligible. RNI includes a “high-tangent” or wider irradiation field. This study will aim to recruit 1106 patients.DiscussionThe PORT-N1 trial aims to verify that PORT de-escalation after BCS or mastectomy is safe for pN1 breast cancer patients in terms of oncologic outcomes and capable of reducing toxicity rates. This trial will provide information crucial for designing PORT de-escalation strategies for patients with pN1 breast cancer.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT05440149) on June 30, 2022.

Risk-Adapted Therapy Directed According to Response (RADAR, UK-MRA Myeloma XV) - Comparing MRD-Guided Treatment Escalation and De-Escalation Strategies in Patients with Newly Diagnosed Myeloma Suitable for Stem Cell Transplantation

Background. Outcomes in newly diagnosed multiple myeloma (MM) are influenced by genetic risk by FISH or molecular profiling determined prior to therapy (Shah. V et al, 2022, DOI: 10.1038/leu.2017.179), and depth of response after therapy as determined by IMWG and minimal residual disease (MRD, De Tute, RM et al, 2022, DOI: 10.1200/JCO.21.02228). Results of OPTIMUM/MUKnine (NCT03188172) provide compelling evidence for intensification of therapy in patients with genetically determined high-risk disease, but strategies to incorporate MRD as a predictive tool to reactively adapt therapy according to response are yet to be proven. Study Design / Methods. The UK-MRA RADAR study is a national, multi-centre, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial which will recruit 1400 patients with newly diagnosed MM eligible for ASCT. Eligible patients receive induction with 4 cycles of RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. In the current protocol, post-ASCT treatment is determined by genetic risk classification and MRD status (Figure 1). Genetic risk classification in RADAR is performed using standard-of-care NHS FISH testing at local sites. Laboratory reports are reviewed by the Trial Management Group and participants enter the standard or high-risk pathway based on the presence of at least two of the markers: t(4;14), t(14;16), t(14:20), del(17p) and gain(1q). Participants who cannot be categorised after two attempts are classed as "Unable to Determine" and treated on the standard-risk pathway. MRD analysis in RADAR uses a multi-parametric flow panel with CD319 and CD229 used to augment post-Isatuximab sample analysis at a central laboratory, with negativity defined at threshold of 10-5. For standard-risk patients, the study addresses two pivotal MRD-related questions: 1) For those with sustained MRD negativity after 12 months of isatuximab maintenance, can treatment be stopped safely to allow patients a treatment-free interval thereby reducing treatment burden? 2) For patients with persistent detectable disease after ASCT, does intensification of consolidation and maintenance therapy augment conversion to MRD negativity compared to lenalidomide maintenance? For high-risk participants the original study question was: do intensified consolidation and maintenance regimens post-ASCT show activity in prolonging disease control? With new data from OPTIMUM, however, RADAR was amended so that high risk participants receive isatuximab with cycles 2-4 of induction, 4 cycles of RBorIsaD consolidation and R-Isa maintenance until progression (Figure 1). At the same time del(1p) was added as a high-risk marker. The amended question for the high-risk pathway is: does induction, consolidation and maintenance incorporating isatuximab, show activity of prolonging disease control? Trial Progress. RADAR opened to recruitment in May 2021 and is currently recruiting at 37 NHS sites with a further 40 sites in setup. 156 patients have been recruited; 20 are classified as high risk on FISH analysis (116 standard risk, 5 unable to determine, 15 TBC). Proportions of patients with each high-risk lesion are shown in Table 1. 27 patients have completed ASCT, and 10 have reached D+100 MRD assessment. Of the standard risk patients reaching the D+100 timepoint, 4 are MRD positive and 4 MRD negative and have been randomised to consolidation and maintenance options accordingly. Assessments of COVID-19 vaccination, immunity and infection are being recorded within the RADAR trial and the effect of isatuximab will be examined. Discussion. The RADAR study simultaneously tests escalation and de-escalation strategies, according to disease response, and using MRD to guide therapy in transplant-eligible MM. Use of local results for genetic risk stratification has proven feasible in 96.5% of patients to date. Recruitment is on target and outcomes will provide RCT-level evidence for the adaptive use of MRD in treatment allocation. Finally, the platform design enabled adaptation, in this case, to include CD38 antibody for high-risk patients, ensuring up-to-date treatment based on latest evidence, keeping pace with evolving standard of care in the UK, and without altering the scientific MRD-related questions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Survival of Acute Myeloid Leukemia Responding Patients Who Stopped Azacytidine and/or Venetoclax Because of Poor Tolerance or Physician Choice: A Retrospective Multicenter Study from the French Innovative Leukemia Organization (FILO)

Background: Acute myeloid leukemia (AML) patients treated upfront with venetoclax and azacitidine (VEN-AZA) achieved a 66.4% composite complete response (CRc) including 36.7% complete response (CR) and 29.7% CR with incomplete hematologic recovery (CRi) in the VIALE-A trial (DiNardo et al., 2020). Median event-free survival (EFS) and duration of response were 9.8 months (95% CI, 8.4 to 11.8) and 17.8 months, respectively. These good results are mitigated by an 82% rate of hematologic adverse events and a 42 to 54% risk of febrile neutropenia both in clinical trial and real-life studies. A recent report of a small cohort of 13 patients in CRc for ≥12 months who interrupted VEN-AZA showed that these patients maintained long treatment-free remission period (Chua et al., 2022) suggesting that treatment interruptions might be considered. To evaluate the impact and the safety of this strategy, we designed a retrospective multicentric study of responding patients who stopped VEN and/or AZA. Methods: Eligible patients had to 1) have been treated with VEN-AZA for previously untreated or pretreated AML, 2) have stopped VEN or AZA for more than 3 months because of poor tolerance and/or physician choice, 3) be in response (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) be aged ≥18 years. Main endpoints were overall survival (OS), event-free survival (EFS), and treatment-free remission (TFR). We measured the impact of prognostic factors on long-term survival by calculating hazard ratios (HR) in univariate and multivariate analyses. Results: We included 51 patients from 12 centers of the FILO group treated with VEN-AZA upfront (n=35, 68.6%) or as salvage treatment (n=16, 31.4%), between 01/19 and 02/22. Next Generation Sequencing (NGS) and minimal residual disease (MRD) data were available for 38 (74.5%) and 28 (55%) patients, respectively. Median age was 75 (ranges, 22-89). WHO classification AML was de novo, AML with myelodysplastic-related changes and therapy-related AML for 27 (52.9%), 21 (41.2%) and 3 (5.9%) patients, respectively. Median platelet count, total white blood cell count and median absolute neutrophile count were 52 G/L (ranges, 7-259), 1.9 (ranges, 0.5-95.5) and 0.7 (ranges, 0-31.6), respectively. Median bone marrow blasts involvement was 32% (range, 7-99). Fourteen patients (27.5%) had adverse cytogenetics. NPM1 and FLT3 mutations were found in 9 (17.6%) and 4 (7.8%) patients, respectively. Twenty (39.2%) patients had a IDH mutation (IDH1, n=5 [9.8%]; IDH2R140 n=9 [17.6%] and IDH2R172, n=6 [11.8%]). TP53 mutation was mutated in 5 (9.8%) cases. Patients received a median of 4 cycles of VEN-AZA (ranges, 1-15); response were CR, CRi and MLFS for 33 (64.7%), 14 (27.5%) and 11 (21.6%) before interrupting VEN-AZA. Complete response with negative MRD was found for 24 out of the 28 evaluable patient (85.7%). Discontinuation of VEN and/or AZA treatments was based on physician choice because of hematological and/or non-hematological toxicities in 36 (71.6%) and 9 (17.6%) cases. Treatment interrupted was VEN, AZA or both in 26 (51%), 1 (2%) and 24 cases (47.1%), respectively. Median follow-up was 17.8 (15.2-20.4) months. Median EFS and OS were 16.7 (12.8-20.6) and 26.8 (14.1-39.5) months, respectively (Figure). Median duration of treatment-free remission (TFR) was 10.1 (7.1-13.1) months (Figure). Twelve patients resumed VEN and/or AZA treatment. For these patients, CRc, MLFS and SD/PD was obtained in 6 (50%), 2 (16.6%) and 5 (41.6%) cases. Obtaining a CR/CRi following the first VEN-AZA cycle and number of prior VEN-AZA cycles >4 were the main prognostic factors associated with a longer EFS and OS in univariate and/or multivariate analyses (Table). None of these factors were predictive for a better TFR, except the achievement of CR/CRi after cycle 1 (HR=2.2, p=0.05). The type of interrupted treatment (VEN versus VEN-AZA) did not influence EFS, OS nor TFS. Conclusion: Our findings confirm the high efficacy of VEN-AZA treatment in AML. Discontinuation of VEN and/or AZA treatment in responders was associated with durable responses and survival. Strategies of de-escalation based on clinical response, MRD and/or molecular profiling may be envisaged but will require a prospective evaluation in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

De-escalation of Therapy in Patients with Quiescent Inflammatory Bowel Disease.

Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.

Molecular testing to deliver personalized chemotherapy recommendations: risking over and undertreatment

BackgroundIn the adjuvant setting of cancer treatment, de-escalation strategies have the goal of omitting or minimizing treatment in patients, without compromising outcomes. Historically, eligibility for adjuvant treatment solely relied on the patient’s clinical and tumor’s pathological characteristics. At the turn of the century, based on new biological understanding, molecular-based strategies were tested and sometimes implemented.Main bodyHowever, we illustrate how molecularly based de-escalation strategies may paradoxically lead to overtreatment. This may happen when the novel approach is tested in lieu of standard management and may not yield the same results when being implemented in addition to usual practice. In the DYNAMIC trial, adjuvant chemotherapy decision in stage II colon cancer was compared between a circulating tumor DNA (ctDNA)-based approach and the standard care. We show this may result in more patients receiving oxaliplatin-based chemotherapy and may expose a similar proportion of patients to chemotherapy if the novel strategy is implemented in addition to usual practice. The other potential risk is undertreatment. We provide an illustration of early breast cancer, where the decision of adjuvant chemotherapy based on the gene expression signature MammaPrint may lead to inferior outcomes as compared with the clinico-pathologic strategy. This may also happen when non-inferiority designs have large margins. Among solutions, it should be acknowledged that clinico-pathological features, like T4 in colon cancer, may not be abandoned and replaced by novel strategies in real-life practice. Therefore, novel strategies should be tested in addition to standard of care, and not in lieu of. Second, de-escalation trials should focus on the settings where the standard of care has a widespread agreement. This would avoid the risk of testing non-inferiority against an ineffective therapy, which guarantees successes without providing informative data.ConclusionSimply because a molecular test is rational does not mean it can improve patient outcomes. Here, we highlight how molecular test-based strategies may result in either overtreatment or undertreatment. In the rapidly evolving field of medicine, where technological advances may be transformative, our piece highlights scientific pitfalls to be aware of when considering running such trials or before implementing novel strategies in daily practice.

Abstract 12107: Short-Term and De-Escalation Dual Antiplatelet Therapy for Patients With Acute Coronary Syndrome: A Systematic Review and Network Meta-Analysis

Background: Short-term (<6 month) or de-escalation (e.g. switching potent P2Y 12 inhibitors to less potent/lower-dose agents a month after the event) dual antiplatelet therapy (DAPT) have become an attractive therapeutic strategy for patients with acute coronary syndrome (ACS). However, these strategies have never been randomly compared. Methods: PubMed, EMBASE, and Cochrane Central were searched in April 2022. Randomized controlled trials (RCTs) or their subgroup analyses that included ACS patients, with standard (12 months), extended (≥18 months), short-term and unguided de-escalation DAPT strategy, along with the guided DAPT strategy with genotype or platelet function tests were identified. The efficacy outcome (major adverse cardiovascular events: MACE) was defined as a composite of cardiovascular death, myocardial infarction, or stroke. The safety outcomes were mainly defined as major or minor bleeding, and major bleeding. Results: This network meta-analysis included 32 RCTs with 103,497 patients. While there was no significant difference in efficacy among the short DAPT, unguided de-escalation and guided-selection strategy, the unguided de-escalation strategy alone was associated with reduced risks of MACE compared with standard DAPT (e.g. versus DAPT with clopidogrel; HR [95% CI]: 0.66 [0.48-0.91]). Both the short DAPT and de-escalation strategies were associated with reduced risks of major or minor bleeding compared with other strategies including the guided-selection (HR [95% CI]: 0.66 [0.47-0.93], 0.48 [0.33-0.71], respectively); the short DAPT strategy alone was associated with a reduced risk of major bleeding compared with standard, extended and guided-selection DAPT (HR [95%CI]: 0.55 [0.33-0.92]). Conclusions: In ACS patients, the unguided de-escalation strategy was associated with reduced risks of MACE, while the short DAPT strategy was associated with decreased rates of major bleeding compared with standard DAPT, suggesting both strategies can be used in select patients by balancing patients’ ischemic and bleeding risks.