0000000000115938
AUTHOR
Uwe Platzbecker
Validation of response assessment according to international consortium for MDS/MPN criteria in chronic myelomonocytic leukemia treated with hypomethylating agents
Validation of response assessment according to international consortium for MDS/MPN criteria in chronic myelomonocytic leukemia treated with hypomethylating agents
Infectious complications in patients with myelodysplastic syndromes: A review of the literature with emphasis on patients treated with 5-azacitidine.
Myelodysplastic Syndromes are oligo-clonal stem cell disorders that are associated with cytopenias in the peripheral blood. Major causes for morbidity and mortality in myelodysplastic syndromes (MDS) patients are infections mostly due to bacteria or fungi. Beside leucopenia per se in affected patients, function of white blood cells particularly that of neutrophils seems to be impaired. Here we summarize the available data on infections in MDS patients in general and particularly those treated with 5-azacitidine.
Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results from Phase 2 PACE-MDS Study
Abstract Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid respo…
Luspatercept Response in ESA-NaïVe/RS+ Patients and RS- Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS)
Abstract Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfus…
Biomarkers of Ineffective Erythropoiesis Predict Response to Luspatercept in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Final Results from the Phase 2 PACE-MDS Study
Abstract Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting ineffective erythropoiesis. Aims: This completed, 3-month, phase 2, multicenter, open-label study evaluated the effects of luspatercept on anemia in patients with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased hemoglobin (Hb) in low transfusion burden (LTB) pa…
Real-World Experience of CPX-351 As First-Line Treatment in 188 Patients with Acute Myeloid Leukemia
Abstract Background In a recent phase-III trial CPX-351 (Jazz Pharmaceuticals, Palo Alto, CA), a liposomal encapsulation of cytarabine and daunorubicin, has shown higher remission rates and longer overall survival (OS) in patients aged 60 to 75 years with AML with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML) in comparison to conventional 7+3 regimen. Based on this CPX-351 has been approved in the USA 2017 and in Europe 2018 for adult patients with newly-diagnosed AML-MRC or t-AML. Still, several issues such as age (<60 years), measurable residual disease (MRD), molecular subgroups and outcome after allo-HCT were not addressed in the phase-III trial. Aiming …
Clinical Presentation of Patients with Adult Late-Onset Telomere Biology Disorders - Results from the Aachen Telomeropathy Registry
Abstract Introduction: Telomere biology disorders (TBD) are caused by mutations affecting proper telomere maintenance resulting in premature telomere shortening. Telomere length (TL) assessment is currently being used for screening and diagnosis of TBD of which Dyskeratosis congenita (DKC) is the most prominent TBD subtype typically found in children and adolescents. In adults, TBDs are characterized by a broad spectrum of more "cryptic" diverging mono- or oligosymptomatic clinical manifestations such as bone marrow failure (BMF), hepatopathy or interstitial lung disease (ILD). However, despite growing general clinical awareness and exertion of improved TL screening strategies, insufficient…
MDS-191: Long-Term Efficacy and Safety of Luspatercept in Lower-Risk Myelodysplastic Syndromes (MDS): Phase 2 PACE-MDS Study
Background: Luspatercept, a first-in-class erythroid maturation agent, has been investigated in patients with LR-MDS and ring sideroblasts (RS) (MEDALIST; Fenaux and Platzbecker NEJM 2020) and in an ongoing Phase 3 trial regardless of RS status (COMMANDS, NCT03682536 ). The previously reported Phase 2 trial of luspatercept (Platzbecker Lanc Onc 2017) includes subtypes of LR-MDS with and without RS, regardless of prior ESA exposure, and various EPO levels. Aims: Evaluate the long-term safety and efficacy of luspatercept in LR-MDS. Methods: Patients were IPSS low/int-1, age ≥ 18 years, Hgb NCT01749514 ; NCT02268383 ). Results: As of 13July2019, 115 patients were enrolled, of whom 108 were tre…
Feasibility of an exercise programme in elderly patients undergoing allogeneic stem cell transplantation - a pilot study
It has been demonstrated that physical exercise benefits younger patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). We designed a prospective pilot study investigating whether elderly patients (>60 years) would also be able to participate in such a programme. It consisted of physiotherapist-supervised alternating endurance and resistance workouts on 6 of 7 days a week. Sixteen consecutive patients undergoing allo-HSCT were enrolled into the study. The median age was 64.5 years. Twelve patients participated in the programme until the time of discharge (75%) from the transplant unit. Therefore, the predefined criteria regarding feasibility were met. The reaso…
Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet
Abstract Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the …
53 LUSPATERCEPT INCREASES HEMOGLOBIN AND REDUCES TRANSFUSION BURDEN IN PATIENTS WITH LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS FROM A PHASE 2 STUDY
Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-s superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-st…
Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Extension Study
Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting the ineffective erythropoiesis. Aims: This is an ongoing, phase 2, multicenter, open-label, 24-month extension study (following a 3-month base study) to evaluate the longer-term effects of luspatercept on anemia in patients (pts) with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response…
Erythropoietic cellular analyses in luspatercept-treated lower-risk myelodysplastic syndromes (MDS): Phase 2 PACE-MDS study.
7018Background: Luspatercept (ACE-536) is a TGF-β family ligand trap promoting late-stage erythroid (E) differentiation and increases in hemoglobin. Endpoints of the ongoing, phase 2, open-label st...
Validation of the revised international prognostic scoring system (IPSS-R) in patients with myelodysplastic syndrome: a multicenter study.
The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy (n=214) or allogeneic transplantation (n=167). We could demonstrate a clear distinction of the IPSS-R risk categories with regard to survival and risk of AML evolution in all patient cohorts. When comparing IPSS-R, IPSS, WHO prognostic scoring system (WPSS) and Duesseldorf score, the best results regarding the ability to predict survival were obtained by the IPSS-R.
Evaluation of six different types of sequential conditioning regimens for allogeneic stem cell transplantation in relapsed/refractory acute myelogenous leukemia – a study of the Acute Leukemia Working Party of the EBMT
The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences…
The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression w…
Real Life Experience with ATRA-Arsenic Trioxide Based Regimen in Acute Promyelocytic Leukemia - Updated Results of the Prospective German Intergroup Napoleon Registry
Abstract Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany …
Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study
Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leuk…
Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival
Abstract Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 ce…
Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts
Summary The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be general…
Improved Outcome with ATRA-Arsenic Trioxide Compared to ATRA-Chemotherapy in Non-High Risk Acute Promyelocytic Leukemia - Updated Results of the Italian-German APL0406 Trial on the Extended Final Series
Abstract Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013. Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed…
Prior Treatment with Alemtuzumab Interferes with T-Cell Engraftment After Allogeneic Stem Cell Transplantation in Patients with Chronic Lymphocytic Leukemia.
Abstract Abstract 3351 Poster Board III-239 Objectives: The majority of patients with chronic lymphocytic leukemia (CLL) who receive allogeneic hematopoietic cell transplantation (HCT) have fludarabine-refractory disease. The most active single agent in this disease stage is alemtuzumab. Alemtuzumab has a long half-life and induces profound T-cell depletion (TCD). Since TCD may mitigate graft-versus leukemia effects we evaluated „pre-conditioning“ with alemtuzumab followed by a washout period in order to minimize in vivo T-cell depletion of the graft in a phase II study (NCT 00337519). Methods: Patients received cytoreductive treatment with 3 × 30 mg alemtuzumab weekly prior to HCT. The sch…
Donor Genetic Determinant of Thymopoiesis rs2204985 Impacts Clinical Outcome after Single HLA Mismatched HSCT
Abstract Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT. Methods: The study included 2,…
Pevonedistat (PEV) + Azacitidine (AZA) Versus AZA Alone As First-Line Treatment for Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) with 20-30% Marrow Blasts: The Randomized Phase 3 PANTHER Trial (NCT03268954)
Abstract Background: Older patients with higher-risk MDS/CMML or AML with 20-30% marrow blasts typically receive single-agent hypomethylating agent (HMA) therapy. Median response duration and survival for these patients is poor, and many patients with MDS transform to secondary AML, which is associated with a particularly dismal prognosis. Novel HMA-based combination therapies that improve survival, delay transformation to AML, and increase depth and duration of response vs single-agent HMA therapy without additional toxicity or myelosuppression are needed. In a randomized, proof-of-concept phase 2 study PEV - a first-in-class, selective inhibitor of NEDD8-activating enzyme - in combination…
Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry
Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non-transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo-HCT in 556 MF patients aged > 65years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients > 65years managed with allo-HCT (n=556) or conventional drug treatment (n=176). The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow-up of 3.4years, the estimated 5-year survival rate, non-relapse mor…