Annamaria Brioli

All-trans retinoic acid (ATRA), a bioactive vitamin A derivative, regulates cellular differentiation by activating retinoic acid receptors (RARs). While ATRA has revolutionised acute promyelocytic leukaemia (APL) treatment, its efficacy in non-APL acute myeloid leukaemia (AML) remains limited due to intrinsic resistance mechanisms, including aberrant epigenetic states and signalling pathways. This review summarises recent mechanistic and translational advances in ATRA-based combination therapies that target differentiation blockade. We focus on the interplay between retinoic acid signalling, chromatin regulation, cell cycle control, and apoptosis, with a particular emphasis on AML. Epigenetic regulators, including the lysine-specific demethylase LSD1 (KDM1A) and the acetyltransferase GCN5 (KAT2A), together with dysregulated cell cycle control and oncogenic signalling, including Fms-like tyrosine kinase 3 (FLT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), sustain proliferation and block differentiation. Targeting these pathways with specific inhibitors synergises with ATRA to restore myeloid maturation, induce cell cycle arrest, and promote apoptosis. Future studies should identify predictive biomarkers for patient stratification to translate these synergistic concepts into clinical benefit.

Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.

Multiple myeloma (MM) resistant to CD38 antibodies, two immunomodulatory drugs (IMiDs), two proteasome inhibitors (PIs), and both BCMA- and GPRC5D-directed immunotherapies defines hepta-refractory MM, a novel end-stage entity. In a multi-center cohort of 37 patients, median overall survival was 12.8 months, with progression-free survival across salvage therapy lines of only 2.7–3.7 months. Whole genome sequencing (WGS) revealed frequent biallelic tumor suppressor gene events, particularly TP53 , consistent with proliferative, apoptosis-resistant disease. Genomic alterations linked to IMiD, BCMA, GPRC5D, and CD38 resistance occurred in 71%, 41%, 35%, and 12% of patients, respectively. Almost one-third of patients showed concurrent loss of BCMA ( TNFRSF17 ) and GPRC5D. Sequential WGS demonstrated branching evolutionary trajectories with multiple distinct TNFRSF17 and GPRC5D variants arising within individual patients, pointing to a hidden reservoir of persistent clones with ongoing mutational processes even after deep remissions. Immunohistochemistry (IHC) confirmed loss of BCMA expression caused by biallelic TNFRSF17 genomic events but also revealed loss of expression attributable to other mechanisms. Importantly, BCMA status predicted benefit from BCMA re-treatment. Hepta-refractory MM is marked by profound genomic complexity, antigen loss, and poor outcomes, highlighting the need for novel therapies and broader diagnostics such as integrated genomic and IHC testing for this ultra-refractory population.

Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.

Multiple myeloma (MM) the second most frequent hematological malignancy is typically preceded by asymptomatic precursor stages. Genetic alterations alone do not fully explain disease progression, as many are already present in pre-malignant stages, highlighting the critical role of the bone marrow microenvironment (BMME) in supporting malignant transformation, disease progression, and therapy resistance. BMME provide survival cues, mediate adhesion-dependent drug resistance, and orchestrate cytokine networks that protect MM cells from therapeutic stress. Despite the advances made in the past two decades, MM is, in most cases, still an incurable disease. The rising use of T cell redirecting therapy (CAR-T cells and bispecific antibodies) has increased awareness on the importance of the immune microenvironment. In this paper we will review the role of the different components of the BMME putting them in the context of novel therapy, with a special focus on T-cell redirecting therapies, with a glance at future perspectives and developments.

Introduction: Pneumonia is a common and serious complication during high-risk neutropenia in patients with cancer. Even though sex differences were described in patients with infectious diseases or cancer in general, sex-specific analyses for pneumonia are lacking. This exploratory study aimed to compare epidemiology and outcome of pneumonia between men and women in this high-risk cohort. Methods: Patient data were harmonized from four primary databases collected by our research group at two tertiary care centers in Germany. High-risk neutropenia was either defined by duration of neutropenia or assumed for autologous or allogeneic hematopoietic stem cell transplantation. All patients who developed pneumonia associated with febrile neutropenia were stratified by sex, and their characteristics during the first observed pneumonia case were compared. Additionally, all identified causative pathogens were stratified by sex and described. Results: In total, 906 patients contributed 1,511 cases of high-risk neutropenia. Pneumonia occurred in 110/689 (16.0%) of cases in women and 132/822 (16.1%) of cases in men. Patient characteristics such as age, underlying disease, and risk factors like duration of neutropenia did not show significant differences. Intensive care unit treatment was needed by 15/97 (15.5%) women and 22/104 (21.2%) men, and the inhospital mortality was 5/98 (5.1%) in women and 12/113 (10.6%) in men, but this result did not reach statistical significance. Seventy-three causative pathogens were identified. Among them, Gram-positive pathogens were identified in three times as often in women (13/36 [36.1%]) than in men (5/37 [13.5%]; p < 0.001, q = 0.002). In contrast, fungi were identified twice as often in men (13/37 [35.1%]) than in women (7/36 [19.4%]; p < 0.001, q = 0.002). Conclusion: Our exploratory study suggests that while pneumonia rates are similar in women and men, pathogen patterns differ and outcomes may be different. These findings should be verified prospectively and in larger cohorts.