Allogeneic Hematopoietic Stem Cell Transplantation in patients with Acute Myeloid Leukemia : a personalized approach

The majority of patients with newly diagnosed acute myeloid leukemia (AML) obtain complete hematological remission (CR) after induction chemotherapy, but the incidence of relapse is considerable despite chemotherapeutic consolidation therapy. Currently, post-remission treatment (PRT) for the prevention of relapse may include continued chemotherapy, autologous hematopoietic stem cell transplantation (HSCT), or allogeneic HSCT (alloHSCT). Although alloHSCT is associated with the lowest incidence of relapse, counterbalancing non-relapse mortality (NRM) may compromise overall outcome. The decision to perform an alloHSCT for patients with AML in first CR depends on the assessment of risks and benefits (ie, mortality and relapse risk reduction), which is based on disease features, but also factors related to patient characteristics, transplantation procedures and type of donor. Such a risk versus benefit evaluation of alloHSCT has evolved into a personalized approach for patients with AML in first CR. The studies described in this thesis address the benefits of alloHSCT identifying different AML patient subgroups with improved outcome following alloHSCT. Secondly, the studies in this thesis addressed morbidity and mortality following alloHSCT. Lastly, this thesis discussed the value of alloHSCT as PRT in specific AML subgroups, potential challenges with respect to alloHSCT-related NRM, and statistical considerations analyzing PRT for AML. A personalized transplant decision approach for patients with AML in first CR was presented, which may be applied in daily clinical practice

Allogeneic Hematopoietic Stem Cell Transplantation in patients with Acute Myeloid Leukemia : a personalized approach

The majority of patients with newly diagnosed acute myeloid leukemia (AML) obtain complete hematological remission (CR) after induction chemotherapy, but the incidence of relapse is considerable despite chemotherapeutic consolidation therapy. Currently, post-remission treatment (PRT) for the prevention of relapse may include continued chemotherapy, autologous hematopoietic stem cell transplantation (HSCT), or allogeneic HSCT (alloHSCT). Although alloHSCT is associated with the lowest incidence of relapse, counterbalancing non-relapse mortality (NRM) may compromise overall outcome. The decision to perform an alloHSCT for patients with AML in first CR depends on the assessment of risks and benefits (ie, mortality and relapse risk reduction), which is based on disease features, but also factors related to patient characteristics, transplantation procedures and type of donor. Such a risk versus benefit evaluation of alloHSCT has evolved into a personalized approach for patients with AML in first CR. The studies described in this thesis address the benefits of alloHSCT identifying different AML patient subgroups with improved outcome following alloHSCT. Secondly, the studies in this thesis addressed morbidity and mortality following alloHSCT. Lastly, this thesis discussed the value of alloHSCT as PRT in specific AML subgroups, potential challenges with respect to alloHSCT-related NRM, and statistical considerations analyzing PRT for AML. A personalized transplant decision approach for patients with AML in first CR was presented, which may be applied in daily clinical practice

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting

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.</p

Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups:Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study

PURPOSE:Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.METHODS:We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).RESULTS:The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P =.89), ASXL1 (23% v 29%; P =.37), and SRSF2 (16% v 16%; P =.99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P &lt;.001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P =.31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P =.04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P &lt;.001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P =.001).CONCLUSION:HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.</p

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study

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.</p

Investigating feasibility of 2021 WHO protocol for cervical cancer screening in underscreened populations:PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC)

Abstract Background High-risk human papillomavirus (hrHPV) testing has been recommended by the World Health Organization as the primary screening test in cervical screening programs. The option of self-sampling for this screening method can potentially increase women’s participation. Designing screening programs to implement this method among underscreened populations will require contextualized evidence. Methods PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC) will use a multi-method approach to investigate the feasibility of implementing a cervical cancer screening strategy with hrHPV self-testing as the primary screening test in Bangladesh, India, Slovak Republic and Uganda. The primary outcomes of study include uptake and coverage of the screening program and adherence to follow-up. These outcomes will be evaluated through a pre-post quasi-experimental study design. Secondary objectives of the study include the analysis of client-related factors and health system factors related to cervical cancer screening, a validation study of an artificial intelligence decision support system and an economic evaluation of the screening strategy. Discussion PRESCRIP-TEC aims to provide evidence regarding hrHPV self-testing and the World Health Organization’s recommendations for cervical cancer screening in a variety of settings, targeting vulnerable groups. The main quantitative findings of the project related to the impact on uptake and coverage of screening will be complemented by qualitative analyses of various determinants of successful implementation of screening. The study will also provide decision-makers with insights into economic aspects of implementing hrHPV self-testing, as well as evaluate the feasibility of using artificial intelligence for task-shifting in visual inspection with acetic acid. Trial registration ClinicalTrials.gov, NCT05234112 . Registered 10 February 202

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia

Background: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). Aims: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. Materials and Methods: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. Results: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). Discussion and Conclusion: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting

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.</p