The therapeutic landscape of haematological malignancies has evolved rapidly with the introduction of targeted therapies, immunotherapies, and cell-based and gene-based interventions, leading to improved survival and, in some cases, long-term remission or cure. These advances have exposed limitations in traditional approaches to adverse event assessment and reporting. Building on the 2025 Lancet Haematology Series on adverse event reporting, this Series paper examines how proposed improvements in toxicity reporting can be operationalised and integrated into regulatory decision making across clinical trials and real-world settings. We focus on key challenges and opportunities related to measuring cumulative and long-term toxicity burden, incorporating patient-reported outcomes, improving adverse event reporting quality and efficiency in clinical trials, and leveraging real-world data, registries, and emerging technologies, such as artificial intelligence and natural language processing. We also discuss regulatory perspectives from international agencies, including the European Medicines Agency, the Japanese Pharmaceuticals and Medical Devices Agency, and the Australian Therapeutic Goods Administration.

Clinical trials in Europe must become far more efficient to support the needs of investigators and their patients. The way trials are designed, conducted and regulated should be attuned first and foremost to the needs of patients, to ensure timely and equitable access to safe, effective and innovative treatments.

The management of large B-cell lymphomas (LBCL) has undergone major changes over the last 5 years. These changes reflect the availability of new therapies (immunotherapies, cell therapies, targeted molecules), but also a better compartmentalization of the entities and their specific clinical characteristics. Numerous first-, second- and third-line therapeutic strategies are available, and each practitioner is committed to selecting the treatment that offers the best balance between efficacy and toxicity. Advances in the understanding of LBCL biology, coupled with improvements in diagnostic and monitoring tools and therapeutic approaches, have significantly enhanced patient outcomes in recent years. In this article, we present a set of pragmatic guidelines developed by the LYSA (Lymphoma Study Association) for the management of LBCL. These guidelines address key aspects of diagnosis, staging, response evaluation, and treatment, integrating the latest evidence from clinical trials, expert consensus, and real-world practice. They aim to provide clinicians with a clear, practical framework to optimize care for patients with LBCL, ensuring that the best available evidence is translated into clinical practice.

Introduction: TRANSFORM (NCT03575351) is a multinational, phase 3 study that compared efficacy and safety of liso-cel versus SOC, including overall survival (OS) as a key secondary endpoint, as a 2L treatment for patients (pt) with relapsed/refractory (R/R) large B-cell lymphoma who were eligible for transplant. The study design permitted pts treated with 2L SOC to receive liso-cel as third line (3L) treatment if protocol-defined conditions were met and requested by investigators. The intention-to-treat (ITT) analysis of OS for liso-cel versus SOC in TRANSFORM addressed a specific research question that did not account for treatment switching. Additionally, as real-world use of chimeric antigen receptor (CAR) T cell therapies in 3L may be less common compared with TRANSFORM, the ITT analysis may provide a conservative estimate of the treatment effect for liso-cel versus SOC on OS. Here, we conducted a complementary analysis of OS to adjust for crossover and estimate the relative effect of liso-cel versus SOC in the absence of 3L CAR T cell therapy. Methods: An external control arm based on external data from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) phase 3 study (NCT00137995) was created using the inverse probability of treatment weighting (IPTW) method. CORAL provided relatively mature survival data and reflects OS in the absence of CAR T cell therapies, which were not available at the time CORAL was conducted. After aligning inclusion/exclusion criteria of the 2 studies, 258 pts from CORAL were retained. To control for confounding, the 2L SOC cohort from CORAL was weighted to match the baseline distributions of prognostic factors and treatment effect modifiers of the liso-cel population in TRANSFORM. Relative efficacy was estimated by fitting a weighted Cox regression model to survival data for the external SOC arm from CORAL and the liso-cel arm from TRANSFORM. Results: After population adjustment via IPTW, the effective sample size (ESS) for SOC (CORAL) was 43.6% of the unadjusted sample size. The IPTW approach generally reduced imbalances in baseline characteristics between the 2 populations. The adjusted hazard ratio (HR; 95% CI) for liso-cel versus SOC was 0.50 (0.32–0.78), indicating that liso-cel was associated with a survival benefit in comparison with SOC in the absence of treatment switching (Table). Conclusions: These analyses demonstrated that liso-cel is associated with prolonged OS in comparison with SOC under a scenario of no 3L CAR T cell therapy, and the consideration of external data is a suitable alternative to existing statistical methods to adjust for treatment switching. The research was funded by: This study was funded by Bristol Myers Squibb. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Emily Burke, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. F. Morschhauser Consultant or advisory role: Roche, Gilead, Abbvie Other remuneration: Membership on an entity's Board of Directors or advisory committees: Roche, Gilead, Novartis, BMS, Abbvie, Genmab, Miltenyi, Allogene therapeutics, AstraZeneca, Janssen H. Ghesquieres Consultant or advisory role: Gilead Sciences, Roche Honoraria: Gilead Sciences, Roche, Takeda Educational grants: Abbvie M. Kamdar Consultant or advisory role: AstraZeneca, Adaptive Biotechnologies, Abbvie, BeiGene, ADC Therapeutics, Syncopation Life Sciences, Bristol-Myers Squibb, Genetech/Roche Research funding: Novartis Other remuneration: Speakers' Bureau: Seattle Genetics F. F. Liu Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb C. Chandler Employment or leadership position: Conor Chandler is employed by Evidera, an independent research company that provides consulting services to life science companies; in his salaried position, he works with a variety of companies and is precluded from receiving payments or honoraria directly from these organizations for services rendered. Evidera received payment from Bristol Myers Squibb for the conduct of this study. A. Crotta Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. L. Klijn Employment or leadership position: Bristol Myers Squibb Consultant or advisory role: Bayer, Bristol Myers Squibb, Kite, Janssen - Payments made to OPEN Health Stock ownership: Bristol Myers Squibb A. Elsada Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb A. Previtali Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb I. Proskorovsky Employment or leadership position: Full-time employee of Evidera, which received funding from Bristol Myers Squibb to conduct this research. N. Schmitz Honoraria: Allogene Educational grants: Allogene, Miltenyi Other remuneration: Grants from Janssen, AstraZeneca, Abbvie J. S. Abramson Consultant or advisory role: Celgene, Novartis, Abbvie, Kite, Genetech, EMD Serono, MorphoSys, Alimera Sciences, Karyopharm Therapeutics, Bristol-Myers Squibb, C4 Therapeutics, BeiGene, AstraZeneca, Incyte, Bluebird Bio, Kymera, Epizyme, Genmab, MustangBio, Ono Pharmaceutical, Century Therapeutics, Lilly, Caribou Biosciences, Janssen, Takeda Honoraria: Regeneron, AstraZeneca, Janssen, Bristol-Myers Squibb Research funding: Seattle Genetics, AI Therapeutics, Bristol-Myers Squibb/Celgene

Treatment of relapsed/refractory diffuse large B-cell lymphoma remains a challenge with the advent of chimaeric antigen receptor CAR-T cell treatment. Whether or not eligibility criteria should replace the standard autologous transplantation is debated. By using PET-derived parameters, the report of Cherng and colleagues suggests that patients with positive residual mass can have a five-year survival of 54% with standard treatment.

The SCHOLAR-1 international retrospective study highlighted poor clinical outcomes and survival among patients with refractory large B-cell lymphoma (LBCL) treated with conventional chemotherapy. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated durable responses in patients with refractory LBCL in the pivotal phase 1/2 ZUMA-1 study (NCT02348216). Here, we compared SCHOLAR-1 with the 2-year outcomes of ZUMA-1. Prior to comparison of clinical outcomes, propensity scoring (based on a broad set of prognostic covariates) was used to create balance between ZUMA-1 and SCHOLAR-1 patients. In the pivotal phase 2 portion of ZUMA-1, 101 patients received axi-cel and were evaluable for response and survival. In SCHOLAR-1, 434 and 424 patients were evaluable for response and survival, respectively. ZUMA-1 patients were more heavily pretreated than were SCHOLAR-1 patients. The median follow-up was 27.1 months in ZUMA-1. The objective response rate (ORR) and complete response rate were 83% and 54% in ZUMA-1 vs 34% and 12% in SCHOLAR-1, respectively. The 2-year survival rate was 54% in ZUMA-1 and 20% in SCHOLAR-1, and a 73% reduction in the risk of death was observed in ZUMA-1 vs SCHOLAR-1. These results were consistent with those of an additional standardization analysis in which strata were limited to 2 prognostic factors (refractory categorization and presence/absence of stem cell transplant after refractoriness to chemotherapy) to conserve sample size. Despite the limitations of a nonrandomized analysis, these results indicate that axi-cel produces durable responses and a substantial survival benefit vs non-CAR T-cell salvage regimens for patients with refractory LBCL.

On 5 November 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase 3 multicenter randomized trials. The first trial (007) randomly allocated acalabrutinib vs. AcalaObi vs. chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee (IRC), was superior for both the AcalaObi (hazard ratio [HR] 0.1; 95% confidence interval [CI] 0.06-0.17) and acalabrutinib (HR 0.2; 95% CI 0.13-0.3) arms compared to the ChlObi arm. The second trial (309) randomly allocated acalabrutinib vs. rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial the PFS was significantly longer in the acalabrutinib arm (HR 0.31; 95% CI 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea and infections. The scientific review concluded that the benefit/risk ratio of acalabrutinib was positive for both indications. The aim of this manuscript was to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before, or for those who have received therapy, but the disease did not respond or relapsed afterwards. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared to standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.

Tafasitamab is a humanized monoclonal antibody that binds to the CD19 antigen, which is expressed in tumor cells from patients with diffuse large B-cell lymphoma (DLBCL). On June 24, 2021, a positive opinion for a conditional marketing authorization was issued by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) for tafasitamab, in combination with lenalidomide, for the treatment of adult patients with relapsed or refractory DLBCL who are ineligible for autologous stem cell transplantation. Tafasitamab was evaluated in the phase 2 single-arm, multicenter, open-label L-MIND clinical trial. The primary endpoint of this trial was objective response rate (ORR). The best ORR, achieved at any time during the study, was 56.8% (95% confidence interval: 45.3%–67.8%), and the median duration of response was 34.6 months (95% confidence interval: 26.1–not reached). The most frequently reported adverse events by system organ class were infections and infestations (72.8%; grade ≥3: 29.6%), blood and lymphatic system disorders (65.4%; grade ≥3: 56.8%), gastrointestinal disorders (64.2%; grade ≥3: 2.5%), and general disorders and administration site conditions (58.0%; grade ≥3: 8.6%). The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the CHMP.

Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta superfamily, resulting in erythroid maturation and differentiation. On June 25, 2020, a marketing authorization valid through the European Union (EU) was issued for luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, or those with transfusion-dependent beta thalassemia (BT). Luspatercept was evaluated in 2 separate phase 3, double-blind, placebo-controlled multicentre trials. The primary endpoints of these trials were the percentage of patients achieving transfusion independence over ≥8 weeks or longer for patients with MDS, and the percentage of patients achieving a ≥33% reduction in transfusion burden from baseline to week 13–24 for patients with BT. In the MDS trial, the percentage of responders was 37.91% versus 13.16%, P < 0.0001, for patients receiving luspatercept versus placebo, respectively. In the BT trial, the percentage of responders was 21.4% versus 4.5% ( P < 0.0001) for luspatercept versus placebo, respectively. Treatment with luspatercept led to similar incidences of adverse events (AEs), but higher incidences of grade ≥3 AEs and serious AEs compared to placebo. The most frequently reported treatment-emergent AEs (≥15%) in the pooled luspatercept group were headache; back pain, bone pain, and arthralgia; diarrhea; fatigue; pyrexia; and cough. The aim of this article is to summarize the scientific review of the application, which led to the regulatory approval in the EU.

On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE-CL-007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06-0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13-0.3) arms compared with the ChlObi arm. The second trial (ACE-CL-309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit-risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.

Crizanlizumab is a monoclonal antibody that binds to P-selectin. On October 28, 2020, a conditional marketing authorization valid through the European Union (EU) was issued for crizanlizumab for the prevention of recurrent vaso-occlusive crises (VOCs) in patients with sickle cell disease aged 16 years or older. Crizanlizumab was evaluated in a phase 2, double-blind, placebo-controlled randomized multicenter trial comparing high-dose (5 mg/kg) crizanlizumab, low-dose (2.5 mg/kg) crizanlizumab and placebo in patients with a history of 2–10 VOCs in the previous year. Patients who were receiving concomitant hydroxycarbamide (HC) as well as those not receiving HC were included in the study. The primary endpoint of the trial was the annual rate of sickle cell-related pain crises as adjudicated by a central review committee. High-dose crizanlizumab led to a 45.3% lower median annual rate of sickle cell-related pain crises compared to placebo ( P = 0.010), with no statistically significant difference for the low dose. Treatment with high-dose crizanlizumab led to similar incidences of adverse events (AEs), grade 3 AEs, and serious AEs compared to placebo. Most frequently observed AEs that occurred more often in the crizanlizumab arm compared to placebo were infusion related reactions (34.8% versus 21%), arthralgia (18.2% versus 8.1%), diarrhea (10.6% versus 3.2%), and nausea (18.2% versus 11.3%). The aim of this article is to summarize the scientific review of the application leading to regulatory approval in the EU.

Isatuximab is a monoclonal antibody that binds to the human CD38 antigen. On 30 May 2020, a marketing authorization valid through the European Union (EU) was issued for isatuximab in combination with pomalidomide and dexamethasone (IsaPd) for the treatment of adult patients with relapsed and refractory (RR) multiple myeloma (MM). The recommended dose of isatuximab was 10 mg/kg, administered IV weekly at cycle 1 and then biweekly in subsequent 28-day cycles. Isatuximab was evaluated in a phase 3, open label, multicenter randomized trial that randomly allocated IsaPd vs. pomalidomide plus dexamethasone (Pd) to adult patients with RR MM. The primary endpoint of the trial was progression-free survival (PFS), as assessed by an independent review committee (IRC), which was superior for the IsaPd arm (hazard ratio [HR] 0.596; 95% confidence interval [CI] 0.436-0.814, p=0.001) compared to the Pd arm. Treatment with IsaPd led to higher incidences of treatment-related adverse events (AEs), grade ≥3 AEs and serious AEs compared to Pd treatment. Most frequently observed AEs that occurred more often in the IsaPd arm were infusion related reactions, infections, respiratory AEs, neutropenia (including neutropenic complications), and thrombocytopenia. The aim of this manuscript is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Isatuximab was approved in the European Union, in combination with pomalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have already received therapy, but the disease did not respond or relapsed afterwards. The addition of isatuximab resulted in a clinically meaningful and significant prolongation of the time from treatment initiation to further disease relapse or patient's death. The safety profile was considered acceptable and the benefit-risk ratio was determined to be positive.

AbstractOn June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable.The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3-zeta signaling domain. The transduced anti-CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19-expressing cells.The benefits of Yescarta as studied in ZUMA-1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%–75%) at a median follow-up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue.

The increasing administrative burden associated with conducting clinical trials is a threat to patient safety, independent academic clinical research, and access to affordable innovation. While the Clinical Trials Regulation1—adopted by the European Parliament in 2014 to replace the Clinical Trials Directive2 (from 2001) and finally expected to become applicable in the course of 2020—will go some way in addressing bureaucracy overload, more action is needed. This article discusses the issues resulting from the exponential growth of regulatory and administrative requirements for the conduct of clinical studies and the impact this is having on researchers and patients. It also describes how the European Hematology Association (EHA) is coordinating a series of activities to advance potential solutions for these issues. Issues of safety reporting Nothing is more important than the safety of our patients in clinical trials and there is a need to communicate new and important safety data to investigators. However, researchers now receive a significant amount of information on (1) side effects that are already well known, (2) side effects alleged to be treatment-related that are not, or (3) suspected unexpected serious adverse reactions (SUSARs) that are revealed to be neither unexpected nor serious.3 This large and uncontrolled volume of information is now diluting and masking the truly important SUSAR reports, thereby compromising patient safety. It is evident that this issue is due, in part, to the overinterpretation of regulations by Contract Research Organizations (CROs),4,5 which require even minor events to be documented and reported to fulfill the frequent audits and inspections to which they are subjected.6 A simplified and less ambiguous formulation of the laws would help to prevent the overinterpretation of legislation. However, it is important to stress that physicians should not be encouraged to under-report serious adverse events (SAEs), as seemingly minor events could be significant if they occur in large numbers of patients. Another issue with regard to safety reporting during clinical trials is that reported adverse events (AEs) tend to reflect investigators’ impressions of these events rather than actual patient experience.7,8 The methods currently used for detecting AEs in clinical trials are recognized as having limitations.9 It has been suggested that direct reporting of AEs by patients, as opposed to relying on data recorded by clinicians or trial practitioners, could be a better approach that would both improve the quality of safety information and allow the earlier detection of SAEs.10,11 We envision the introduction of simplified risk adapted reports, integrating data from electronic medical records. We strongly recommend that regulators involve the key stakeholders—clinical researchers and patients—in the drafting of guidance documents for safety reporting. It is promising that the latest revision of the questions and answers document on Clinical Trials Regulation by the Directorate-General for Health and Food Safety of the European Commission now includes a separate chapter on safety reporting.12 Furthermore, the US Food and Drug Administration (FDA) is currently revising its guidelines for safety reporting13 and has recently issued a related questions and answers document.14 Informed consent forms Several issues have been identified with the current informed consent process for participation in clinical trials. Informed consent forms (ICFs) are often too complicated for trial participants to understand, use complex scientific terminology, and demonstrate poor readability.15 In addition, they are often too long and cannot easily be translated into multiple languages.16 As a result, many participants, especially those from less developed countries, may not understand the clinical trial despite having signed the ICF.15 In the USA, it is required to include a key information section summarizing the ICF, but patients are still expected to read the complete form.17 We suggest that the key information page in an ICF be considered sufficient and only this page should be mandatory, with further details available for those who are interested. We also feel that ICFs should be critically reviewed by patient representatives and that their opinions should carry more weight than the opinions of lawyers, given that the document is aimed at patients. Another issue is that re-consent is often required during the course of a clinical trial due to ICF amendments, but this can cause confusion and anxiety among some participants.18 It has been suggested that the re-signing of consent forms should only be necessary for ethical reasons, such as to protect participants from harm in the event of new findings about AEs, to maintain participant autonomy, or in the case of legally defective ICFs. Additionally, research review committees such as institutional review boards should oversee the re-consent process to ensure that participants are not contacted unnecessarily.18 As a starting point to simplify ICFs, EHA is developing a European ICF template through discussion with multiple stakeholders, including patient representatives. Another solution to the issue could be to make clinical trial documents publicly available to enable patients and other interested stakeholders to provide input into the ICFs. Alternatively, ICFs could be developed through procedures used for the drafting of other patient-focused documents, such as package leaflets. The latter must strictly adhere to the European Medicines Agency (EMA) Quality Review of Documents template and official glossaries,19 and their readability is validated and continuously reviewed.20 Regulatory challenges The administrative demands associated with current regulatory processes for the conduct of clinical trials are time consuming, at times clinically irrelevant, and partly responsible for the rising costs of developing new drugs.3 CROs are necessary to manage this increasing amount of administration, but their personnel are not always experts in the area under investigation. Consequently, researchers often receive numerous queries from CROs that are unimportant yet involve an inordinate amount of paperwork.3 By law, clinical trial sponsors are ultimately responsible for the conduct of their clinical trials and, therefore, retain responsibility for the management of any contractor, including associated bureaucracy and any impact it may have. As a practical solution, regulators could set a framework for the conduct of CROs to prevent bureaucracy from spiraling out of control. If left uncontrolled, bureaucracy and the increasing costs of conducting clinical trials could lead to the disappearance of independent academic clinical researchers, particularly new researchers who may not have a supportive infrastructure to cope with these ever increasing administrative demands.3 Another channel for addressing these two interrelated issues—overinterpretation/over-reporting and an imbalanced relationship between CROs, sponsors and investigators—is the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH, which brings together regulatory authorities and the pharmaceutical industry, has released the E8 revised guideline on General Considerations for Clinical Trials for public consultation21 and is also revising guideline E6 on Good Clinical Practice.22 We are heartened to see that multiple stakeholders including healthcare providers, academia, and patient organizations, are being invited to participate in workshops organized as part of the revision process. Role of EHA EHA is identifying specific issues23 and is facilitating discussions between clinical researchers, regulators, and other relevant stakeholders to address the issues resulting from the increasing administrative burden associated with conducting clinical trials. As a first step, a workshop was held at the EHA Executive Office in The Hague on June 27, 2019, to discuss bureaucratic obstacles in clinical research.24 This workshop was attended by different stakeholders involved in the legislation and conduct of clinical trials, including clinical researchers, the European Commission, EMA, FDA, and patient organizations. As a follow-up to this meeting, EHA is actively participating in revisions of the ICH E8 and E6 guidelines and has provided input to the European Commission on the latest revision of the Clinical Trials Regulation questions and answers document.12 EHA is also aligning with key stakeholders, including the Biomedical Alliance in Europe, to develop specific actions. These include the creation of a ‘conduct of clinical research’ roadmap and a consensus opinion document on ICFs (for sharing with the European Commission). In addition, EHA is engaging with clinical researchers and patients outside of the hematology community to encourage cross-disciplinary debate of the current challenges associated with the conduct of clinical research. Call for action We call on regulators to ensure structural involvement of patients and clinical researchers in the formulation of informed consent forms and guidance documents for safety reporting and other aspects of clinical studies. Regulators should also set a framework for the conduct of CROs to prevent bureaucracy from spiraling out of control. Clearly, bureaucracy in clinical research is a challenge faced not only by hematologists and their patients. EHA therefore calls on medical societies and patient organizations across disciplines to work together to develop a ‘roadmap towards patient-centric, bureaucracy-light clinical research’ in close dialogue with industry, policymakers, and regulators. Collectively, we must ensure that the interests of patients and clinicians are placed back at the center of the design and implementation of clinical trials.

Transformed mycosis fungoides (tMF) is a rare variant of MF with an aggressive course. In this study, we describe the patient characteristics, treatments, and outcomes of 17 patients with tMF in COMPLETE: a multicenter, prospective US cohort study of peripheral T-cell lymphoma. Responses were observed with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes. Introduction: We examined patient characteristics, treatments, and outcomes of patients with transformed mycosis fungoides (tMF) from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the United States. Methods: Patients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified patients with tMF with completed baseline, treatment, and follow-up records. Median survival was assessed using Kaplan-Meier methodology. Results: Of the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase, and 9 had lymph node involvement. Approximately one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate, and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and 2-year survival rates were 56% and 44%, respectively. Conclusions: tMF often expresses CD30 and presents with lymph node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes.

Autologous stem cell transplantation (ASCT) is a well-established approach to treatment of patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) recommended by both the European Society for Medical Oncology and the National Comprehensive Cancer Network based on the results from randomized controlled studies. However, a considerable number of patients who receive ASCT will progress/relapse and display suboptimal post-transplant outcomes. Over recent years, a number of different strategies have been assessed to improve post-ASCT outcomes and augment HL cure rates. These include use of pre- and post-ASCT salvage therapies and post-ASCT consolidative therapy, with the greatest benefits demonstrated by targeted therapies, such as brentuximab vedotin. However, adoption of these new approaches has been inconsistent across different centers and regions. In this article, we provide a European perspective on the available treatment options and likely future developments in the salvage and consolidation settings, with the aim to improve management of patients with HL who have a high risk of post-ASCT failure. CONCLUSIONS: We conclude that early intervention with post-ASCT consolidation improves outcomes in patients with R/R HL who require ASCT. Future approvals of targeted agents are expected to further improve outcomes and provide additional treatment options in the coming age of personalized medicine.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. Implications for Practice Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

On October 24, 2019, a marketing authorization valid through the European Union (EU) was issued for gilteritinib monotherapy for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication (ITD), FLT3 D835Y, and FLT3 ITD D835Y, and it induced apoptosis in leukemic cells expressing FLT3 ITD. The recommended starting dose of gilteritinib is 120 mg (three 40 mg tablets) once daily. Gilteritinib was evaluated in one, phase III, open-label, multicenter, randomized study of gilteritinib (n = 247, gilteritinib arm) versus salvage chemotherapy (n = 124, salvage chemotherapy arm) in patients with relapsed or refractory AML with FLT3 mutation. Overall survival (OS) was statistically significantly different between the two groups with a median OS of 9.3 months in the gilteritinib arm compared with 5.6 months for salvage chemotherapy (hazard ratio, 0.637; 95% confidence interval, 0.490-0.830; p = .0004 one-sided log-rank test). The most common adverse reactions with gilteritinib treatment were blood creatine phosphokinase increase, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, diarrhea, fatigue, nausea, constipation, cough, peripheral edema, dyspnea, dizziness, hypotension, pain in extremity, asthenia, arthralgia, and myalgia. The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Xospata was approved in the European Union as monotherapy for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib resulted in a clinically meaningful and statistically significant improvement of overall survival compared with salvage chemotherapy. At the time of the marketing authorization of gilteritinib, there were no approved standard therapies specifically for adult patients diagnosed with relapsed or refractory AML with FLT3 mutation. In terms of safety, the overall accepted safety profile was considered manageable.