Search

Purpose: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. Methods: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the “Stichting Hemato-Oncologie voor Volwassenen Nederland” (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents’ willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). Results: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. Conclusion: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.

Contains fulltext : 306339.pdf (Publisher’s version ) (Open Access)

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95% CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.

Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisi

In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.

Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation included 479 patients with idiopathic SAA who underwent allo-HSCT in two conventional situations: i) upfront allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GvHD, extensive chronic GvHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (hazard ratio [HR]=4.08; 95% confidence interval [CI]: 1.41-11.83; P=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR=1.04; 95% CI: 1.02-1.06; P<0.001), acute GvHD (HR=1.03; 95% CI: 1.00-1.07; P=0.041), and chronic GvHD (HR=1.04; 95% CI: 1.01-1.08; P=0.032) as the cause of GRFS failure. GRFS after upfront MRD allo-HSCT was very good, notably with early allo-HSCT, confirming that younger patients with an MRD should be transplanted immediately. GRFS was worse in cases of salvage allo-HSCT, most notably in older patients, questioning the utility of allo-HSCT earlier in the disease course.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV+ Hodgkin (EBV+HL) or non-Hodgkin lymphomas (EBV+nHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBV+HL and EBV+nHL. Therefore, we recruited a study cohort of 63 EBV+HL and EBV+nHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV+ lymphoma patients exclusively the high-affine LMP-1 GGDPHLPTL peptide variant-encoding EBV-strains reactivate. In EBV+HL and EBV+nHL patients, the high-expressing HLA-E*0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 GGDPHLPTL and HLA-E*0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the in vitro spread of EBV-infected tumor cells. In addition, EBV+HL and EBV+nHL patients, showed impaired pro-inflammatory NKG2C+ NK cell responses, which accelerated the in vitro EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2A+NKG2C+ NK cells. Thus, the HLA-E/LMP-1/NKG2A pathway and individual NKG2C+ NK cell responses are associated with the

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.