0000000000205016
AUTHOR
Ulrich Germing
The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large International Patient Cohort
Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients tr…
Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents
Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 6…
Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7
Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequen…
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…
Outcome of Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-T) In a Large Cohort of Patients
Abstract Abstract 4113 Introduction: Most of the data related to RARS-T, a rare disorder, involve small cohorts of patients. We aimed to analyze more patients also considering a variety of myelodysplastic or myeloproliferative disorders. Objective: To compare a large cohort of patients with RARS-T to refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and multilineage dysplasia (RARS-MD) or essential thrombocythemia (ET) at the time of diagnosis and during disease evolution, in terms of survival and complications. Materials: Data of a European multi-center study was used including 199 cases of RARS-T 173 cases of RARS, 102 cases of RARS-MD and 431 c…
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 …
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…
An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults
Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future…
Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort.
Although hypomethylating agents (HMAs) are frequently used in the frontline treatment of older acute myeloid leukemia (AML) patients, little is known about their effectiveness in relapsed or primary treatment–refractory (RR)-AML. Using an international multicenter retrospective database, we studied the effectiveness of HMAs in RR-AML and evaluated for predictors of response and overall survival (OS). A total of 655 patients from 12 centers received azacitidine (57%) or decitabine (43%), including 290 refractory (44%) and 365 relapsed (56%) patients. Median age at diagnosis was 65 years. Best response to HMAs was complete remission (CR; 11%) or CR with incomplete count recovery (CRi; 5.3%). …
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…
Clinical Features And Course Of Refractory Anemia With Ring Sideroblasts Associated With Marked Thrombocytosis
Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis…
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.
Clinical Impact of GATA2 Mutations in Acute Myeloid Leukemia Patients Harboring CEBPA Mutations: A Study of the AML Study Group (AMLSG)
Abstract Background Based on their association with certain biological and clinical features as well as their prognostic significance, mutations in the CCAAT/enhancer-binding protein-alpha (CEBPA) gene have been included as a provisional entity into the 2008 World Health Organization (WHO) classification of myeloid neoplasms. CEBPA mutations (CEBPAmut) are mainly found in acute myeloid leukemia (AML) with normal cytogenetics, and approximately 60% of the mutated patients (pts) carry biallelic mutations. Several studies showed that in particular pts with double mutant CEBPA (CEBPAdm) have a favorable outcome compared to all others. Recently, mutations in the transcription factor GATA2 were i…
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…
Minimal Residual Disease (MRD) Monitoring in NPM1 Mutated Acute Myeloid Leukemia (AML): Impact of Concurrent FLT3-ITD and DNMT3A Mutations on MRD Kinetics and Clinical Outcome
Abstract Introduction In a recent update on MRD monitoring in 407 NPM1 mutated (NPM1mut) AML patients (pts) we could confirm the results from our previous study showing that achievement of RQ-PCR negativity after double induction (DI), after completion of therapy (CT) as well as during the follow-up period (FUP) is significantly associated with a lower cumulative incidence of relapse (CIR) and superior overall survival (OS) [Döhner K, Annals of Hematol; 2013;Suppl.1,92:S39]. In addition, in pts with concurrent FLT3-ITD (FLT3-ITDmut) or DNMT3A (DNMT3Amut) mutations, we also showed that the median NPM1mut transcript levels after each treatment cycle were significantly higher. Aim To evaluate …
Prognostic Impact of Mutant to Wild-Type Ratio and Insertion Site in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication
Abstract Abstract 785 Background: FLT3 internal tandem duplications (FLT3-ITD) occur in about 25% of acute myeloid leukemia (AML), are associated with cooperating gene mutations (NPM1, DNMT3A), and confer an adverse prognosis. Several studies have indicated that the unfavorable impact of FLT3-ITD is influenced by a number of factors, such as the mutant to wild-type ratio (allelic ratio), insertion site of FLT3-ITD in the beta1 sheet of the tyrosine kinase domain 1, and the molecular background of cooperating mutations. Aims: To evaluate the relative impact of FLT3-ITD allelic ratio and insertion site, as well as cooperating genetic lesions on prognosis and treatment decision making in a lar…
Performance of the Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) score in predicting survival benefit with hypomethylating agent use in patients with relapsed or refractory acute myeloid leukemia
Patients with primary refractory or relapsed-acute myeloid leukemia (RR-AML), particularly older adults, have dismal outcomes and limited therapy options [1]. Given the tolerability of hypomethylat...
Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group.
Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group