Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial

Background The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. Methods The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. Discussion From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. Trial registration The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293. Date of registration September 30, 2018.

High Level of Successful TKI Discontinuation in Chronic Myeloid Leukemia (CML) Patients: Preliminary Results of AST-Argentina Stop Trial

Introduction: Treatment-free remission (TFR) is an emerging treatment goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). Current evidence shows that 40%-60% of patients relapse while in TFR; and nearly all regain response once tyrosine kinase inhibitors (TKIs) treatment are reinitiated. However a robust predictor of prolonged TFR has not been reported yet. Considering real-life setting, 2 key factors may affect TFR outcome if not properly done: Access to serial molecular monitoring at optimal timepoints and quality laboratory terms as accuracy, sensitivity and rapid results. This motivated the creation of the AST study in our region to guarantee adequate molecular monitoring for TFR in Argentina and characterize new prognostic biomarkers helpful to identify more accurately patients who will be able to sustain TFR. We aimed to assess the proportion of patients with sustained major molecular response (MMR) after TKIs discontinuation and define precise conditions for stopping treatment. Methods: This prospective, multicentre Argentina Stop Trial (AST) trial is recruiting chronic phase CML patients under TKI treatment for at least ≥ 4 years, in DMR (≥MR4.0) sustained for ≥ 2 years in standardized laboratory, confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2 and aged > 18 years. Molecular tests are centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the first year, and every 3 months during the second year. If patients lost MMR, TKI was restarted immediately. Molecular relapse Free Survival was estimated by Kaplan-Meier method. Difference between survival variables was evaluated through log-rank test. Multivariate analysis was performed through Cox proportional hazards model. The cutoffs of the numerical variables were considered according to the log-rank test. Results: Between February 2019 and July 2020, we evaluated 50 CML patients of whom 46 were enrolled from 7 centers in Argentina and 4 were screening failures. Recruitment was interrupted due to COVID-19 pandemic. Patient median age was 57.5 years (range 24-85). Before discontinuation, TKI treatment was as follows: Imatinib 37/46 (80%), Nilotinib 5/46 (11%) and Dasatinib 4/46 (9%), 2G-TKI as 1st line, 11% of the patients received non-branded treatment. Sokal risk score showed to be low in 22 patients (48%), intermediate in 14 (30%) and high in 10 (22%). Median follow-up was 10 months (range 4-17) and the estimated molecular relapse-free survival was 80.2% (95%CI 69-93) at 6 months Fig 1. Longer DMR durations before discontinuation were associated with increased probability of maintaining response at 6 and 12 months: 83.2% for patients who had >54 months in DMR vs 70% with <54 months and 72% vs 23.3% respectively (p=0.0453) Fig 2. Cox multivariate analysis was performed including different variables as age at diagnosis, time in DMR, time in TKI previous to discontinuation and Sokal risk. The only significant variable associated to improved prognosis was time in DMR (HR 2.8 95%CI 1.002-8.07 p=0.0495). Our cohort had a long time on TKI treatment previous to discontinuation, median 10.5 years (4.16-17.5) probably considering it a favorable factor for the high TFR rates described at 6 months. Among the 46 patients included, 15 (33%) lost MMR, all restarted treatment with the same TKI used before discontinuation, 12/15 (80%) regained MMR with a median time of 3 months (range1-8) and 9/15(60%) obtained MR 4.0 with a median time of 3 months (range1-5). Conclusion: This is the first multicenter study of TKI discontinuation in CML patients in Argentina showing that TKI can be safely discontinued in those who achieve and maintain a DMR before discontinuation. We observed high rates of molecular relapse free survival, although longer follow-up is needed. We must continue with this approach for patients participating in TFR trials or TFR programs in order to decrease the risk of relapse and make this goal a fact in our region. This discontinuation study will allow in a near future significant saving of economic resources and might improve patients quality of life specially in those who are currently experiencing treatment adverse events. Disclosures Pavlovsky: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau; Pint Pharma: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Varifarma: Speakers Bureau. Moiraghi:BMS: Speakers Bureau; Novartis: Speakers Bureau.

In Pursuit of Surrogate Markers for Treatment-Free Remission in Patients with Chronic Myeloid Leukemia from Argentina Stop Trial

INTRODUCTION: Long-term survival of patients with chronic myeloid leukemia (CML) has significantly improved since the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). Several considerations about the side effects, risks and cost associated with the lifetime treatment, have led patients and physicians to explore the possibility of TKI discontinuation after achievement of a sustained deep molecular response (DMR), so-called treatment-free remission (TFR). Several clinical trials show that approximately half of patients who achieve a sustained DMR during TKI treatment maintain molecular remission after suspension of TKIs. There is currently no biomarker that reliably predicts TFR in CML, mainly due to different study designs that have generated inconsistent data. Thus, further investigations are needed to identify factors that consistently favor achievement of TFR. With the aim of developing a biomarker for TFR prediction we analyzed the phenotype of Natural Killer (NK) cells and their relation to successful TKI cessation. METHODS: This analysis was conducted as a substudy of the Argentina Stop Trial. Altogether, 50 consecutive chronic phase CML patients who participated in the clinical trial were recruited from 7 Argentinian centers. Peripheral blood samples were collected before stopping TKI treatment, at month 3, 12 and at any time when MR3.0 was lost. Freshly isolated mononuclear cells from 46 patients were immunophenotyped by staining with CD3, CD16, CD25, CD56, CD57, CD158, NKp30, NKp44, NKp46, NKG2A, NKG2C, NKG2D and PD-1 antibodies and NK cells subpopulations were analyzed by flow cytometry (BD FACS Canto™II). Molecular recurrence-free survival was estimated by the Kaplan-Meier method and compared within groups by the log-rank test. The cutoffs of the numerical variables were optimized according to the log-rank test. Quantitative variables were dichotomized according to receiver operating characteristics (ROC) curves in order to describe sensibility and specificity. Multivariate analysis was performed through Cox proportional hazards model. Main results are provided with hazard ratio (HR) at 6 months and 95% confidence intervals (95% CI). RESULTS: At the time of discontinuation the median proportion of NK cells (CD3-CD56+) among lymphocytes was significantly increased in patients compared with controls (15% vs 9%, P = 0.0016). A significant difference between molecular relapsed vs no-relapsed patients was observed when optimal cutoff (0.43) for CD56bright low and high was determined (at 6 months 74% vs 100% respectively, log rank test, p=0.023). At this time of follow up, no significant difference was observed for CD56dim NK cells. Phenotypic markers for adaptive-like NK cells were analyzed, however, no significant differences were observed between the non-relapsing and relapsing groups. Nevertheless, molecular non-relapsing patients had significantly higher frequencies of PD-1+ NK cells as compared with molecular relapsing patients (at 6 months 85% vs 64%, Log Rank test, P=0.009). Based on the ROC and Youden Index analysis, at 6 months the 1.2 cutoff shows an 80% specificity and 50% sensitivity. Moreover, after multivariable Cox proportional analysis, including age, time of treatment, deep molecular response time, Sokal risk, NK cells and PD-1+ NK cells, the last subpopulation was identified as an independent prognostic factor for molecular-relapse-free survival (Hazard ratio = 3.63; 95% CI 1.3 - 10.1; P=0.014). CONCLUSIONS: The clinical impact of NK cells in patients who have discontinued TKIs is controversial. The effects of TKIs against immune cells, including NK cell subsets, could depend on the type of TKIs; this aspect is particularly relevant in Argentinian treated patients real world, since many different copies of TKIs are routinely used in the clinical setting. Our study is the first, to our knowledge, to report a significant increase in PD-1 expression in NK cells at TKI cessation in patients who do not relapse. Accordingly to recent reports, PD-1 expression is more abundant on NK cells with an activated and more responsive phenotype and does not mark NK cells with an exhausted phenotype. To fully understand how PD-1 on NK cells modulates immune responses we are planning to carry out functional studies. In the future, we are also planning a comprehensive study of immune suppressors, including regulatory T cells and myeloid-derived suppressor cells. Disclosures Moiraghi: Novartis: Speakers Bureau; BMS: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Protocol for a mixed methods process evaluation of the Smoking Treatment Optimisation in Pharmacies (STOP) trial

IntroductionAssessing the fidelity of complex behavioural interventions and examining the contextual reasons why such interventions succeed, or fail are important activities but challenging and rarely reported. The Smoking Treatment Optimisation in Pharmacies (STOP) trial is a cluster randomised trial evaluating the effectiveness of a complex intervention to optimise the National Health Service (NHS) Stop Smoking Service delivered in community pharmacies. This complex intervention comprises a training package for pharmacy staff involving motivational interviewing and communication skills aimed at increasing smoking cessation knowledge and proactive client engagement. We report on a process evaluation which was planned alongside the trial to offer findings that will assist in the interpretation of the main trial results and help inform potential implementation in community pharmacy settings on a wider scale.Methods and analysisQuantitative data on recruitment and retention process of pharmacies, pharmacy staff and service users has been collected during the trial along with data on dose and fidelity of the intervention delivery from participating intervention arm pharmacies to identify potential implementation issues. Simulated client data on behaviour change skills and display of intervention materials from both control and intervention pharmacies is being assessed. These data will be combined with qualitative data; including adviser-smoker consultation recordings that provide a snapshot of behaviour skills delivery by stop smoking advisers and semi-structured interviews with pharmacy staff and services users from the intervention arm.DiscussionPublished protocols for process evaluations of complex health interventions are still rare despite increasing funding for this work to facilitate understanding of trial outcomes from an implementation perspective. This mixed methods protocol will contribute to the developing literature around the conduct of process evaluation and the value they add to health services research.Trial registration numberISRCTN16351033.Strengths and limitations of this studyA planned mixed methods process evaluation that draws together data from different sources to help explain the trial results and establish the feasibility of scaling this complex intervention up in community pharmacy settings.A strength is the use of a previously tested mystery shopping method to assess fidelity of skills performance at the pharmacy counterThe process evaluation relies on willing pharmacy staff and service users involved in the trial to collect some of the data, which may introduce bias.This paper also provides a detailed example of how to use the MRC framework for process evaluation of complex interventions to design an extensive process evaluation within trial settings.

The value of Transcranial Doppler sonography in children with sickle cell disease compared to non-transfusion depenendent thalassemias: Cohort Randomized study

Background Transcranial Doppler ultrasonography is the only method provides a relatively inexpensive, noninvasive real-time measurement of blood flow characteristics and cerebrovascular hemodynamics within the basal arteries of the brain, adding physiologic information to the anatomic images. It seems ideally suited to screening for large-vessel disease, because it is safe, noninvasive, relatively low in cost, and well tolerated by children. Objective Is to measure the blood velocity in cerebral vessels by Transcranial Doppler in patients with sickle cell anaemia according to transfusion status and in patients with non transfusion dependent thalassemia. Patients and Methods Cohort study of sixty patients on children following up paediatric haematology clinic at children hospital, Ain shams university from March 2018 till September 2018. Results according to the STOP trial the Doppler velocity of the right MCA among the 60 patients are 55 patients were normal (91%), 1 patient was very low (1.7%),1 patient was conditional (1.7%) and 3 patients were abnormal ( 5.0%) and 5 patients are at risk (8.3%),and the Doppler velocity of the left MCA among the 60 patients are 54 patients were normal (90.0%), 2 patients were very low (3.3%), 3patients were conditional (5.0%) and 1 patient was abnormal (1.7%). Conclusion TCD is the recommended method of assessing stroke risk in SCD patients and NTDT, it is particularly useful in children because it is painless, noninvasive, available relatively inexpensive, easy to perform, and requires no sedation or contrast media or radiation exposure.