Genetic Risk Stratification and Outcomes Among Treatment-Naive Patients With AML Treated With Venetoclax and Azacitidine.

European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS.

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Establishing a global regulatory floor for children's decisions about participation in clinical research.

BACKGROUND: Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is the best candidate for a global standard but would benefit from additional specification. METHODS: Ethical analysis of ICH guidance for permission and assent for pediatric trials, with recommendations for clarification. RESULTS: ICH guidance regarding permission and assent would be enhanced by additional detail in the following areas: (1) what information should be provided to parents, guardians, and children considering a trial, and how that information should be provided; (2) the definition of "assent," the criteria for when assent should be required, and the need to include children in discussions even when assent is not mandated; (3) criteria for requiring children's signatures indicating agreement; (4) greater specificity regarding children's right to decline or withdraw; and (5) clarification of when children's wish to decline or withdraw from participation may be overridden and of what the overriding process should entail. CONCLUSION: ICH guidance provides a global standard for decision making regarding children's participation in trials. Several clarifications would facilitate the conduct of multinational pediatric research. IMPACT: Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor. Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials. The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research.

Venetoclax and Hypomethylating Agents as First-line Treatment in Newly Diagnosed Patients with AML in a Predominately Community Setting in the US.

BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.

NCCN Guidelines Insights: Survivorship, Version 1.2016.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common consequences of cancer and cancer treatment. They are intended to aid health care professionals who work with survivors of adult-onset cancer in the posttreatment period, including those in general oncology, specialty cancer survivor clinics, and primary care practices. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors. This article summarizes the NCCN Survivorship panel's discussions for the 2016 update of the guidelines regarding the management of anxiety, depression, posttraumatic stress disorder-related symptoms, and emotional distress in survivors.

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Survivorship: pain version 1.2014.

Many posttreatment cancer survivors experience chronic pain, often leading to psychological distress; decreased activity, motivation, and personal interactions; and an overall poor quality of life. This section of the NCCN Guidelines for Survivorship provides screening and management recommendations for pain in survivors. A multidisciplinary approach is recommended, with a combination of pharmacologic treatments, psychosocial and behavioral interventions, physical therapy and exercise, and interventional procedures.

Survivorship: sleep disorders, version 1.2014.

Sleep disorders, including insomnia and excessive sleepiness, affect a significant proportion of patients with cancer and survivors, often in combination with fatigue, anxiety, and depression. Improvements in sleep lead to improvements in fatigue, mood, and quality of life. This section of the NCCN Guidelines for Survivorship provides screening, diagnosis, and management recommendations for sleep disorders in survivors. Management includes combinations of sleep hygiene education, physical activity, psychosocial interventions, and pharmacologic treatments.

Survivorship: screening for cancer and treatment effects, version 2.2014.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocial consequences of cancer and cancer treatment. This portion of the guidelines describes recommendations regarding screening for the effects of cancer and its treatment. The panel created a sample screening tool, specifically for use in combination with the NCCN Guidelines for Survivorship, to guide providers to topics that require more in-depth assessment. Effective screening and assessment can help providers deliver necessary and comprehensive survivorship care.

Survivorship: healthy lifestyles, version 2.2014.

Healthy lifestyle habits have been associated with improved health outcomes and quality of life and, for some cancers, a reduced risk of recurrence and death. The NCCN Guidelines for Survivorship therefore recommend that cancer survivors be encouraged to achieve and maintain a healthy lifestyle, with attention to weight management, physical activity, and dietary habits. This section of the NCCN Guidelines focuses on recommendations regarding physical activity in survivors, including assessment for the risk of exercise-induced adverse events, exercise prescriptions, guidance for resistance training, and considerations for specific populations (eg, survivors with lymphedema, ostomies, peripheral neuropathy). In addition, strategies to encourage health behavioral change in survivors are discussed.

Survivorship: nutrition and weight management, Version 2.2014. Clinical practice guidelines in oncology.

Healthy lifestyle habits have been associated with improved health outcomes and quality of life and, for some cancers, a reduced risk of recurrence and death. The NCCN Guidelines for Survivorship therefore recommend that cancer survivors be encouraged to achieve and maintain a healthy lifestyle, including attention to weight management, physical activity, and dietary habits. This section of the NCCN Guidelines focuses on recommendations regarding nutrition, weight management, and supplement use in survivors. Weight management recommendations are based on the survivor's body mass index and include discussions of nutritional, weight management, and physical activity principles, with referral to community resources, dietitians, and/or weight management programs as needed.

Survivorship: fatigue, version 1.2014.

Many cancer survivors report that fatigue is a disruptive symptom even after treatment ends. Persistent cancer-related fatigue affects quality of life, because individuals become too tired to fully participate in the roles and activities that make life meaningful. Identification and management of fatigue remains an unmet need for many cancer survivors. This section of the NCCN Guidelines for Survivorship provides screening, evaluation, and management recommendations for fatigue in survivors. Management includes education and counseling, physical activity, psychosocial interventions, and pharmacologic treatments.

Survivorship: cognitive function, version 1.2014.

Cognitive impairment is a common complaint among cancer survivors and may be a consequence of the tumors themselves or direct effects of cancer-related treatment (eg, chemotherapy, endocrine therapy, radiation). For some survivors, symptoms persist over the long term and, when more severe, can impact quality of life and function. This section of the NCCN Guidelines for Survivorship provides assessment, evaluation, and management recommendations for cognitive dysfunction in survivors. Nonpharmacologic interventions (eg, instruction in coping strategies; management of distress, pain, sleep disturbances, and fatigue; occupational therapy) are recommended, with pharmacologic interventions as a last line of therapy in survivors for whom other interventions have been insufficient.

Survivorship: immunizations and prevention of infections, version 2.2014.

Cancer survivors are at an elevated risk for infection because of immune suppression associated with prior cancer treatments, and they are at increased risk of complications from vaccine-preventable diseases. This section of the NCCN Guidelines for Survivorship provides recommendations for the prevention of infections in survivors through education, antimicrobial prophylaxis, and the judicious use of vaccines. These guidelines provide information about travel and gardening precautions and safe pet care/avoidance of zoonosis, and include detailed recommendations regarding vaccinations that should be considered and encouraged in cancer and transplant survivors.

Quality of care for chronic conditions: identifying specificities of quality aims based on scoping review and Delphi survey.

There is a growing need to implement high quality chronic care to address the global burden of chronic conditions. However, to our knowledge, there have been no systematic attempts to define and specify aims for chronic care quality. To address this gap, we conducted a scoping review and Delphi survey to establish and validate comprehensive specifications. The Institute of Medicine's (IOM) quality of care definition and aims were used as the foundation. We purposively selected articles from the scientific (n=48) and grey literature (n=26). We sought papers that acknowledged and unpacked the plurality of quality in chronic care and proposed or utilised frameworks, studied their implementation, or investigated at least two IOM quality care aims and implementation. Articles were analysed both deductively and inductively. The findings were validated through a Delphi survey involving 49 international chronic care experts with varied knowledge of, and experience in, low-and-middle-income countries. Considering the natural history of chronic conditions and the journey of a person with a chronic condition, we defined and identified the aims of chronic care quality. The six IOM aims apply with specific meanings. We identified a seventh aim, continuity, which relates to the issue of chronicity. The group endorsed our specifications and several participants gave contextualised interpretations and concrete examples. Chronic conditions pose specific challenges underscoring the relevance of tailoring quality of care aims. The next steps require a tailored definition and specific aims to improve, measure and assure the quality of chronic care.

Main findings: While previously defined aims of good-quality care may also apply to chronic care quality, the nature of chronic conditions and ensuing healthcare needs warrant specifications for good-quality chronic care.Added knowledge: Our proposed definition and specific aims are tailored to the natural history of chronic conditions, and can serve as a guide on determining what can be deemed as good-quality chronic care.Global health impact for policy and action: This work, developed to guide further work on designing purchasing instruments to improve quality of chronic care, particularly in low- and middle-income countries, may also be a source of inspiration for other interventions aiming at improving quality of chronic care.

Automated Lugano Metabolic Response Assessment in 18F-Fluorodeoxyglucose-Avid Non-Hodgkin Lymphoma With Deep Learning on 18F-Fluorodeoxyglucose-Positron Emission Tomography.

PURPOSE: Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic. METHODS: Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers NCT02257567, NCT02500407; 20% holdout in ClinicalTrials.gov identifier NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review. RESULTS: The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses. CONCLUSION: These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.

The effectiveness of text messages support for diabetes self-management: protocol of the TEXT4DSM study in the democratic Republic of Congo, Cambodia and the Philippines.

BACKGROUND: People with diabetes find it difficult to sustain adequate self-management behaviour. Self-Management Support strategies, including the use of mobile technology, have shown potential benefit. This study evaluates the effectiveness of a mobile phone support intervention on top of an existing strategy in three countries, DR Congo, Cambodia and the Philippines to improve health outcomes, access to care and enablement of people with diabetes, with 480 people with diabetes in each country who are randomised to either standard support or to the intervention. DESIGN/METHODS: The study consists of three sub-studies with a similar design in three countries to be independently implemented and analysed. The design is a two-arm Randomised Controlled Trial, in which a total of 480 adults with diabetes participating in an existing DSME programme will be randomly allocated to either usual care in the existing programme or to usual care plus a mobile phone self-management support intervention. Participants in both arms complete assessments at baseline, one year and two years after inclusion.Glycosylated haemoglobin blood pressure, height, weight, waist circumference will be measured. Individual interviews will be conducted to determine the patients' assessment of chronic illness care, degree of self-enablement, and access to care before implementation of the intervention, at intermediate moments and at the end of the study.Analyses of quantitative data including assessment of differences in changes in outcomes between the intervention and usual care group will be done. A probability of <0.05 is considered statistically significant. Outcome indicators will be plotted over time. All data are analysed for confounding and interaction in multivariate regression analyses taking potential clustering effects into account.Differences in outcome measures will be analysed per country and realistic evaluation to assess processes and context factors that influence implementation in order to understand why it works, for whom, under which circumstances. A costing study will be performed. DISCUSSION: The intervention addresses the problem that the greater part of diabetes management takes place without external support and that many challenges, unforeseen problems and questions occur at moments in between scheduled contacts with the support system, by exploiting communication technology. TRIAL REGISTRATION: ISRCTN86247213.

Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Polatuzumab vedotin, marketed under the trade name POLIVY®, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin's lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.

Descriptive assessment of COVID-19 responses and lessons learnt in Cambodia, January 2020 to June 2022.

As a member state of the International Health Regulations 2005, Cambodia is continuously strengthening its capacity to respond to health emergencies and prevent the international spread of diseases. Despite this, Cambodia's capacity to prevent, detect and rapidly respond to public health threats remained limited at the onset of the pandemic, as was the case in most countries. This paper describes epidemiological phases, response phases, strategy and lessons learnt in Cambodia between 27 January 2020 and 30 June 2022. We classified epidemiological phases in Cambodia into three phases, in which Cambodia responded using eight measures: (1) detect, isolate/quarantine; (2) face coverings, hand hygiene and physical distancing measures; (3) risk communication and community engagement; (4) school closures; (5) border closures; (6) public event and gathering cancellation; (7) vaccination; and (8) lockdown. The measures corresponded to six strategies: (1) setting up and managing a new response system, (2) containing the spread with early response, (3) strengthening the identification of cases and contacts, (4) strengthening care for patients with COVID-19, (5) boosting vaccination coverage and (6) supporting disadvantaged groups. Thirteen lessons were learnt for future health emergency responses. Findings suggest that Cambodia successfully contained the spread of SARS-CoV-2 in the first year and quickly attained high vaccine coverage by the second year of the response. The core of this success was the strong political will and high level of cooperation from the public. However, Cambodia needs to further improve its infrastructure for quarantining and isolating cases and close contacts and laboratory capacity for future health emergencies.

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.