Comparison of prognostication by IPSS-M, IPSS-R and AIPSS-MDS in the context of limited availability of molecular data in daily clinical practice.

The IPSS-M was developed to revolutionize the prediction of MDS patients' survival by incorporating molecular data. To compensate for lack of access to molecular analyses, the AIPSS-MDS, a supervised machine learning algorithm exclusively based on clinical and cytogenetic data, was developed by the Spanish MDS Group. We used data of the Düsseldorf MDS Registry and included 207 of more than 8500 registry patients whose IPSS-M-requested complete molecular data were known to compare and validate prognostication regarding OS and LFS of the IPSS-M, IPSS-R and AIPSS-MDS.

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.

Response-guided first-line therapy and treatment of relapse in aggressive lymphoma: 10-year follow-up of the PETAL trial.

The PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas) trial investigated whether treatment intensification after 2 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; plus rituximab [R] for CD20 lymphomas) improved survival in aggressive non-Hodgkin lymphoma. A total of 754 patients (87.5%) had a negative and 108 (12.

Clec12a is required for the pathogenesis of NUP98::NSD1 AML.

NUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NUP98::NSD1 positive AML is often associated with adverse outcomes and poor response to conventional treatments. However, limited studies have been done to identify new potential targets to develop better treatment approaches.

XPO1-dependency of DEK::NUP214 leukemia.

The nuclear export protein XPO1 interacts with nucleoporin 214 (NUP214) and has been implicated in the pathogenesis of SET::NUP214 acute myeloid leukemia (AML). We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1.

Bemcentinib as monotherapy and in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy: a phase 1b/2a trial.

Beyond first line, the prognosis of relapsed/refractory (R/R) acute myeloid leukemia (AML) patients is poor with limited treatment options. Bemcentinib is an orally bioavailable, potent, highly selective inhibitor of AXL, a receptor tyrosine kinase associated with poor prognosis, chemotherapy resistance and decreased antitumor immune response. We report bemcentinib monotherapy and bemcentinib+low-dose cytarabine combination therapy arms from the completed BerGenBio-funded open-label Phase 1/2b trial NCT02488408 ( www.

Cell-free DNA for detection and monitoring of extramedullary AML relapse.

Isolated extramedullary manifestations (IEM) of acute myeloid leukemia (AML) are recurrent events, especially following allogeneic hematopoietic cell transplantation (alloHCT). To date, measurable residual disease (MRD) assessment for this difficult-to-treat patient cohort has not been established. In this study, we evaluated highly sensitive next-generation sequencing (NGS) of IEM-AML tumor and compared it with cell-free DNA (cfDNA) from plasma, as well as highly sensitive NGS analysis of bone marrow mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC), in a cohort of 15 IEM-AML patients with 19 IEM-AML episodes.

Late-onset telomere biology disorders in adults: clinical insights and treatment outcomes from a retrospective registry cohort.

Pathogenic germ line variants affecting proper telomere maintenance result in premature telomere shortening and cause telomere biology disorders (TBDs). Although classical dyskeratosis congenita in children is rather well defined, late-onset ("cryptic") TBDs remain underrecognized, resulting in underdiagnosis and inadequate treatment in affected adults. Here, we present a series of adult TBD cases collected through the German TBD reference center between 2014 and 2024.

Fitness assessment in acute myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.

Fitness assessment in patients with acute myeloid leukemia (AML) is critical to deliver the right therapy to the right patient. Although several scoring systems are available to aid in determining fitness, the absence of validation studies has resulted in the lack of universally accepted assessment procedures. This limitation, combined with the increasing availability of novel agents expanding the spectrum of less-intensive options, has introduced additional complexity to the fitness assessment process.

Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with -mutated AML.

This study aimed to evaluate the impact of the myelodysplasia-related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with -mutated ( ) AML. Targeted DNA sequencing of 263 genes was performed in 568 AML patients (median age: 59 years) entered into the prospective AMLSG 09-09 treatment trial. Most commonly co-mutated genes were (49.

A novel prognostic risk model for patients with refractory/relapsed acute myeloid leukemia receiving venetoclax plus hypomethylating agents.

Off-label hypomethylating agents and venetoclax (HMA/VEN) are often used for relapsed and refractory (R/R) AML patients. However, predictors of outcome are elusive. The objective of the current retrospective observational multicenter study of 240 adult patients (median age 68.

Mutation- and MRD-informed treatment decisions for the transplant-eligible AML patient.

Acute myeloid leukemia (AML) is classified by risk groups according to a number of genetic mutations, which may occur alone or in combination with other mutations and chromosomal abnormalities. Prognosis and appropriate therapy can vary significantly based on a patient's genetic risk group, making mutation-informed decisions crucial to successful management. However, the presence of measurable residual disease (MRD) after induction and consolidation therapy, before hematopoietic cell transplant, and during posttransplant monitoring can be even more significant to patient prognosis than their genetic subtype.

Dose-Reduced FLA-IDA in Combination with Venetoclax Is an Effective and Safe Salvage Therapy in Relapsed and Refractory Acute Myeloid Leukemia (R/R AML).

Despite the development of targeted therapies in first-line AML, complete remissions (CR) cannot be achieved in 30-40%, and relapse rates remain high. In R/R AML the intensive treatment regimen of fludarabine, cytarabine, idarubicin combined with venetoclax (FLA-VIDA) showed improved remission rates compared to FLA-IDA. In this retrospective single-center analysis, we investigated the efficacy and safety of dose-reduced FLA-IDA with and without venetoclax to minimize the risk of infectious complications and excessive myelosuppression; Methods: Between 2011 and 2023, 89 R/R AML patients were treated with dose-reduced FLA-IDA (fludarabine 30 mg/m day 1-4, cytarabine 2000 mg/m day 1-4, idarubicin 10 mg/m day 1 + 4).

Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.

The aim of our study was to analyze the potential survival benefit associated with hematopoietic stem cell transplantation (HSCT) according to clinicobiological scores, which incorporate mutation-enhanced international prognostic score system (MIPSS) to facilitate decision-making in this context. One transplant (n = 241) and 1 nontransplant cohort (n = 239) were used to test the hypothesis that patients with primary myelofibrosis with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference.

Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine.

In a randomized phase II trial (AMLSG 14-09, NCT00867672) of elderly, newly diagnosed AML patients, ATRA combined with decitabine (DEC) significantly improved the overall response rate (ORR) and survival also in patients with adverse-risk genetics, without adding toxicity. We performed a post hoc analysis to determine the predictive impact of TP53 status. Despite a nominally higher ORR, the clinically meaningful survival benefit when adding ATRA to DEC was diminished, but not completely negated, in TP53-mutated patients.

Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin.

Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)-based MRD assay (limit of detection 10-4 to 10-5), we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study.

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis.

Relapse Prevention in Acute Myeloid Leukemia: The Role of Immunotherapy with Histamine Dihydrochloride and Low-Dose Interleukin-2.

The treatment and management of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy for subgroups of patients, expanded indications for allogeneic stem cell transplantation (allo-SCT) and surveillance of residual or arising leukemia. However, hematological relapse among patients who have attained complete remission (CR) after the initial courses of chemotherapy remains a significant cause of morbidity and mortality. Here, we review an immunotherapeutic option using histamine dihydrochloride and low-dose interleukin-2 (HDC/LD-IL-2) for remission maintenance in AML.