The 2020 BMT CTN Myeloma Intergroup Workshop on Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma.

The fifth annual Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma was conducted as one of the American Society of Hematology Annual Meeting Scientific Workshops on Thursday December 3, 2020. This workshop focused on four main topics: (1) integrating minimal residual disease into clinical trial design and practice; (2) the molecular and immunobiology of disease evolution and progression in myeloma; (3) adaptation of next-generation sequencing, next-generation flow cytometry, and cytometry by time of flight techniques; and (4) chimeric antigen receptor T-cell and other cellular therapies for myeloma. In this report, we provide a summary of the workshop presentations and discuss future directions in the field.

Can a Multistakeholder Prioritization Structure Support Regulatory Decision Making? A Review of Pediatric Oncology Strategy Forums Reflecting on Challenges and Opportunities of this Concept.

Timely and successful drug development for rare cancer populations, such as pediatric oncology, requires consolidated efforts in the spirit of shared responsibility. In order to advance tailored development efforts, the concept of multistakeholder Strategy Forum involving industry, academia, patient organizations, and regulators has been developed. In this study, we review the first five pediatric oncology Strategy Forums co-organized by the European Medicines Agency between 2017 and 2020, reflecting on the outcomes and the evolution of the concept over time and providing an outline of how a "safe space" for multistakeholder engagement facilitated by regulators could be of potential value beyond pediatric oncology drug development.

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.

ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children.

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets.

The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy.

On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression-free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0.69; 95% confidence interval, 0.57-0.83; one-sided log-rank p value < .0001). The most frequently observed toxicity (grade ≥3, treatment arm vs. control arm) in the phase III trial included neutropenia (29.6% vs. 26.5%), anemia (17.9% vs. 17.7%), thrombocytopenia (16.8% vs. 12.3%), pneumonia (12.5% vs. 10.5%), fatigue (7.7% vs. 6.4%), hypertension (4.6% vs. 2.1%), diarrhea (3.8% vs. 4.1%), and respiratory tract infection (4.1% vs. 2.1%).The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the European Union. The scientific review concluded that the gain in PFS of 8.7 months observed with the combination of CRd was considered clinically meaningful and was supported by a clear trend in overall survival benefit, although the data were not mature. The delay in disease progression appeared superior to available alternatives in the setting of relapsed MM at the time of the marketing authorization of carfilzomib. Therefore, given the overall accepted safety profile, which was considered manageable in the current context, the benefit risk for CRd was considered positive. IMPLICATIONS FOR PRACTICE: Carfilzomib (Kyprolis) was approved in the European Union in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The addition of carfilzomib to lenalidomide and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression-free survival compared with lenalidomide and dexamethasone, which was supported by a clear trend in overall survival benefit, although the data were not mature. At the time of the marketing authorization of carfilzomib, the delay in disease progression appeared superior to available alternatives in the setting of relapsed multiple myeloma. In terms of safety, the overall accepted safety profile was considered manageable.

The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use.

On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day. The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83]; p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

UNLABELLED: : On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme. The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n = 242) was compared with patient's choice with physician's advice (n = 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p = .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p = .0373). Secondary endpoints, including response rates, progression-free survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Acute myeloid leukemia (AML) remains an area of significant unmet need, especially in older patients. Older patients and those with comorbidities are often considered ineligible for standard induction therapy, and outcome for these patients is poor. Decitabine has favorable effects in terms of overall survival, which were considered clinically meaningful in the context of a manageable toxicity profile and after consideration of the lack of therapeutic alternatives for these patients. Decitabine is widely used in the treatment of AML in patients aged >60 years, as per current guidelines, including the European LeukemiaNet and the U.S. National Cancer Comprehensive Network.

The European Medicines Agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: summary of the scientific assessment of the Committee for Medicinal Products for Human Use (CHMP).

BACKGROUND: The European Commission has recently issued a marketing authorisation valid throughout the European Union for ingenol mebutate (Picato) in the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults. OBJECTIVES: The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU. The full scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (www.ema.europa.eu). MATERIAL & METHODS: The application was supported by 25 clinical studies, of which 18 were performed in patients with actinic keratosis. RESULTS: The active substance is a pure ingenol angelate obtained from the aerial parts of the plant species Euphorbia peplus by extraction and purification. One tube of ingenol mebutate 150 mcg/g gel or 500 mcg/g gel should be applied once daily to the affected area for 3 or 2 consecutive days on the 'face and scalp' or 'trunk and extremities', respectively. Complete response rate is 42.2% on the 'face and scalp' and 34.1% on the 'trunk and extremities'. The most common side effects are local skin responses including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application site. CONCLUSIONS: The benefits of ingenol mebutate are its ability to improve the complete response rate of actinic keratosis, the short duration of treatment and the ease of self-application.

The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use.

On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application, a 2.4-month longer median overall survival time and a 30% lower risk for death were observed for cabazitaxel, compared with mitoxantrone. The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).

Comparative validation of the growth hormone-releasing hormone and arginine test for the diagnosis of adult growth hormone deficiency using a growth hormone assay conforming to recent international recommendations.

CONTEXT: The GHRH plus arginine (GHRH+Arg) test is a promising alternative to the insulin tolerance test (ITT) for diagnosis of adult GH deficiency (AGHD). OBJECTIVES: The objectives of the study were to validate the GHRH+Arg test for diagnosis of AGHD, using the ITT as comparator and a GH assay calibrated according to recent international recommendations, and to study the repeatability and tolerance of both tests. DESIGN: This was a multicenter, randomized, open-label, phase III study. SETTING: The study was conducted at 10 French university hospitals. SUBJECTS: Sixty-nine subjects (38 and 15 with high and low probability of GH deficiency, respectively, and 16 healthy controls) were randomized: 35 to the GHRH+Arg-GHRH+Arg-ITT test sequence and 34 to the ITT-ITT-GHRH+Arg test sequence. INTERVENTIONS: Each subject underwent three tests of GH secretion separated by 24 h or more. MAIN OUTCOME MEASURES: The primary variable used for response assessments was serum peak GH response. Test results were compared with the final AGHD diagnosis. RESULTS: Peak GH responses in the two tests were strongly correlated. A cutoff value of 7.89 microg/liter for GHRH+Arg corresponding to 3 microg/liter for ITT was calculated. The cutoff value leading to 95% specificity with the GHRH+Arg test was measured at about 3.67 microg/liter (sensitivity 79.0%). Intermethod agreement and repeatability were high. Both tests were well tolerated. A preference for the GHRH+Arg test was expressed by 74% of subjects. CONCLUSIONS: The GHRH+Arg test demonstrated good accuracy and repeatability, was at least as sensitive as the ITT, and was associated with better subject acceptability. The GHRH+Arg test represents a good alternative to the ITT for the diagnosis of AGHD.

Protocolisation, use and development of anti-cancer drugs in the context of T2A (case-mix based payment system) set-up.

Drugs used in oncology represent more than half of the innovative and costly drugs which are not covered by a Group Homogène de Soins (DRG type classification) within the context of the case-mix based payment system (termed T2A). For these drugs, good practice reference guidelines have been drawn up by scientific societies and registration agencies. Recognised indications, relevant indications and situations where the treatment should not be prescribed are defined by the National Institute of Cancer. The reference guidelines should lead towards the good use of these drugs and allow the sick funds to control prescriptions. They should evolve with time, which means that bibliographic monitoring and independent expert opinion is necessary to update them as science provides new data. Manufacturers are involved in this process which in no case should undermine developmental efforts leading to registration. The objective of this protocolisation is to allow all patients early and legitimate access to drugs representing real therapeutic progress. These reference guidelines should be integrated into the life-cycle of a drug and should give rise to new developments allowing the good use of cancer products in situations which have been properly validated.

Protocolisation, Use and Development of Anti-Cancer Drugs in the Context of T2A (Case-Mix Based Payment System) Set-Up.

Drugs used in oncology represent more than half of the innovative and costly drugs which are not covered by a Group Homogène de Soins (DRG type classification) within the context of the case-mix based payment system (termed T2A). For these drugs, good practice reference guidelines have been drawn up by scientific societies and registration agencies. Recognised indications, relevant indications and situations where the treatment should not be prescribed are defined by the National Institute of Cancer. The reference guidelines should lead towards the good use of these drugs and allow the sick funds to control prescriptions. They should evolve with time, which means that bibliographic monitoring and independent expert opinion is necessary to update them as science provides new data. Manufacturers are involved in this process which in no case should undermine developmental efforts leading to registration. The objective of this protocolisation is to allow all patients early and legitimate access to drugs representing real therapeutic progress. These reference guidelines should be integrated into the life-cycle of a drug and should give rise to new developments allowing the good use of cancer products in situations which have been properly validated.

Evolution of the postoperative pericardial effusion after day 15: the problem of the late tamponade.

STUDY OBJECTIVES: To evaluate, through clinical and transthoracic echocardiography (TTE) follow-up, the natural history of persistent pericardial effusion (PE) after postoperative day 15 in patients who were given and were not given anticoagulant therapy. DESIGN AND PATIENTS: We retrospectively studied a cohort of 1,277 patients who were hospitalized between May 1997 and May 1999 in our center a mean (+/- SD) time period of 15 +/- 3 days after undergoing coronary artery bypass graft (CABG) surgery (856 patients) or valve replacement (VR) surgery (421 patients). MEASUREMENTS: TTE was performed on mean (+/- SD) postoperative day 20 +/- 1 (TTE(1)) and postoperative day 30 +/- 2 (TTE(2)). PE severity was classified on a scale from grade 1 to grade 4. RESULTS: On postoperative day 20 +/- 1, PE was present in 22% of the 1,277 patients and was more frequent after patients underwent CABG surgery than after undergoing VR surgery (25% vs 17%, respectively; p < 0.01). On postoperative day 30 +/- 2, the overall incidence of late tamponade in patients with PE was 4%. The incidence increased with the severity grade of PE at TTE(1) (p < 0.001). The negative predictive value of a severity grade < 2 at TTE(1) for late tamponade was 100%. Late tamponade incidence was higher after VR surgery than after CABG surgery (11% vs 2%, respectively; p < 0.01), and was higher in patients who had received anticoagulation therapy than in those who had not (8% vs 2%, respectively; p < 0.05). CONCLUSION: Persisting PE is common after postoperative day 15 and is more frequent after undergoing CABG surgery than after undergoing VR surgery. The incidence of late tamponade is usually underestimated, and it increases with the presence of VR, anticoagulation therapy, and/or higher postoperative TTE severity grade. Our data suggest that only patients with a PE severity grade of >/= 2 (< 10% of patients) require TTE follow-up after postoperative day 20.

Comparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers.

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P<10(-4) and intravenously: 15.0+/-2.4 versus 5.1+/-0.6 hr, P<10(-4)). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0-->24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.

[Avoidable hospital drug prescription in the elderly. A review of the literature]. / Iatrogénie médicamenteuse hospitalière évitable et personnes âgées.

Elderly persons are particularly exposed to drug reactions, especially drug interactions subsequent to multiple prescriptions. It is also recognized that the drug risk is the leading hospital risk involving 1 to 10% of all hospitalized patients. An analysis of the avoidable nature of drug reactions leads to consideration of a sequence of 4 events leading to drug exposure: prescription, delivery, administration and compliance. Each event in this sequence corresponds to a distinct person: physician, pharmacist, nurse, patient. This suggests that the prevention of drug reactions in hospitalized elderly persons requires implementation of an "alert-causal attributability-avoidability-prevention" system by the healthcare teams where physicians, pharmacists, and nurses work in close coordination with the patient.