PURPOSE: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML).PATIENTS AND METHODS: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m²/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression.RESULTS: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 10⁹/L and 31.2 × 10⁹/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System–mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04).CONCLUSION: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407 ).

Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies.

Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34⁺ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34⁺ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8⁺ and FOXP3⁺ T cells and only single MUM1p⁺ B/plasma cells were detected in an area of ≤10 μm to CD34⁺ HSPC. Conclusions: CD8⁺ and FOXP3⁺ T cells are regularly seen in the 10 μm area around CD34⁺ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34⁺ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.

In adult ALL, 5-10% of patients show KMT2A translocations (KMT2A rearrangements) with only a few secondary alterations, implicating it as a leukemia-initiating factor [1, 2]. Approximately 95% of all fusions in adult ALL are KMT2A::AFF1 or KMT2A::MLLT1 [3]. KMT2A-rearranged adult ALL patients are generally considered high-risk and are treated with intensified therapy, including allogeneic hematopoietic stem cell transplantation (SCT) [4]. Current ALL treatment protocols are often guided by measurable residual disease (MRD)-based risk stratification [4-8], however, limited data are available regarding the prognostic value of MRD in adult ALL with KMT2A rearrangement. In infant KMT2Arearranged ALL, more reliable MRD data were obtained using the individual KMT2A breakpoints as molecular MRD target as compared to IG/TR [6, 9-11], but no such comparisons have been made in adult ALL. We evaluated the impact of MRD on diseasefree survival (DFS) and overall survival (OS) in a cohort of 156 KMT2A-rearranged adult patients and compared IG/TR-and KMT2A-based MRD levels in 46 patients. In total, 769 bone marrow and/or peripheral blood samples from 193 adult ALL patients with KMT2A rearrangement (175 KMT2A::AFF1, 13 KMT2A::MLLT1, 1 KMT2A::MLLT3, 4 KMT2A+ unspecified) obtained between 2001 and 2021 were available for longitudinal MRD measurements. All patients were treated according to different protocols of the German Multicenter ALL (GMALL) study group and gave their informed consent to further scientific investigations on residual material. Patients with KMT2A::AFF1 aged up to 55 years were assigned to the high-risk group and were candidates for SCT in first CR after consolidation I. Immunophenotyping and MRD measurement with real-time PCR based on KMT2A fusion genes