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Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis and increased apoptosis in the bone marrow, which cause peripheral cytopenia. Mitochondria are key regulators of apoptosis and a site of iron accumulation that favors reactive oxygen species (ROS) production with detrimental effects on cell survival. Although the energy metabolism could represent an attractive therapeutic target, it was poorly investigated in MDS. The purpose of the study was to analyze how the presence of myelodysplastic hematopoiesis, iron overload and chelation impact on mitochondrial metabolism. We compared energy balance, OxPhos activity and efficiency, lactic dehydrogenase activity and lipid peroxidation in mononuclear cells (MNCs), isolated from 38 MDS patients and 79 healthy controls. Our data show that ATP/AMP ratio is reduced during aging and even more in MDS due to a decreased OxPhos activity associated with an increment of lipid peroxidation. Moreover, the lactate fermentation enhancement was observed in MDS and elderly subjects, probably as an attempt to restore the energy balance. The biochemical alterations of MNCs from MDS patients have been partially restored by the in vitro iron chelation, while only slight effects were observed in the age-matched control samples. By contrast, the addition of iron chelators on MNCs from young healthy subjects determined a decrement in the OxPhos efficiency and an increment of lactate fermentation and lipid peroxidation. In summary, MDS-MNCs display an altered energy metabolism associated with increased oxidative stress, due to iron accumulation. This condition could be partially restored by iron chelation.

Association between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor. Association between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.

Abstract The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2 V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2 V617F cells. Accordingly, proliferation and clonogenic potential of JAK2 V617F -driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2 V617F MPN cells and improve MPN patient care. Not available.

Background: Acute myeloid leukemia is a heterogeneous hematological disease, characterized by karyotypic and molecular alterations. Mutations in IDH2 have a role in diagnosis and as a minimal residue disease marker. Often the variant allele frequency during follow up is less than 20%, which represents the limit of detection of Sanger sequencing. Therefore, the development of sensitive methodologies to identify IDH2 mutations might help to monitor patients’ response to therapy. We compared three different methods to identify and monitor IDH2 mutations in patients’ specimens. Methods: Performances of PNA-PCR clamping, droplet digital PCR and Sanger for IDH2 status identification were evaluated and compared in 96 DNA patients’ specimens. Results: In contrast with Sanger sequencing, our results highlighted the concordance between PNA clamping and digital PCR. Furthermore, PNA-PCR clamping was able to detect more mutated DNA with respect to Sanger sequencing that showed several false negatives independently from the allelic frequency. Conclusions: We found that PNA-PCR clamping and digital PCR identified IDH2 mutations in DNA samples with comparable results in a percentage significantly higher compared to Sanger sequencing. PNA-PCR clamping can be used even in laboratories not equipped for sophisticated analyses, decreasing cost and time for IDH2 characterization.

Bone marrow granulomatosis is not a common finding and remains a diagnostic challenge. Here below we report two bizarre but not so rare cases of bone marrow granulomatosis: bone marrow involvement by Mycobacterium avium-intracellulare and reaction to intravesical administration of Bacillus Calmette-Guérin for non-muscle-invasive bladder cancer; two distinct culprits suggesting the wide range of possible causative factors of this histopathological pattern. In the discussion we provide a brief overview of causes and suggestions for a diagnostic approach.

New techniques are on the horizon for the detection of small leukemic clones in both, acute leukemias and myeloproliferative disorders. A promising approach is based on digital polymerase chain reaction (PCR). Digital PCR (dPCR) is a breakthrough technology designed to provide absolute nucleic acid quantification. It is particularly useful to detect a low amount of target and therefore it represents an alternative method for detecting measurable residual disease (MRD). The main advantages are the high precision, the very reliable quantification, the absolute quantification without the need for a standard curve, and the excellent reproducibility. Nowadays the main disadvantages of this strategy are the costs that are still higher than standard qPCR, the lack of standardized methods, and the limited number of laboratories that are equipped with instruments for dPCR. Several studies describing the possibility and advantages of using digital PCR for the detection of specific leukemic transcripts or mutations have already been published. In this review we summarize the available data on the use of dPCR in acute myeloid leukemia and myeloproliferative disorders.

Acute myeloid leukemia (AML) is a complex hematologic malignancy with high morbidity and mortality. Nucleophosmin 1 (NPM1) mutations occur in approximately 30% of AML cases, and NPM1-mutated AML is classified as a distinct entity. NPM1-mutated AML patients without additional genetic abnormalities have a favorable prognosis. Despite this, 30–50% of them experience relapse. This study aimed to investigate the potential of total RNAseq in improving the characterization of NPM1-mutated AML patients. We explored genetic variations independently of myeloid stratification, revealing a complex molecular scenario. We showed that total RNAseq enables the uncovering of different genetic alterations and clonal subtypes, allowing for a comprehensive evaluation of the real expression of exome transcripts in leukemic clones and the identification of aberrant fusion transcripts. This characterization may enhance understanding and guide improved treatment strategies for NPM1mut AML patients, contributing to better outcomes. Our findings underscore the complexity of NPM1-mutated AML, supporting the incorporation of advanced technologies for precise risk stratification and personalized therapeutic strategies. The study provides a foundation for future investigations into the clinical implications of identified genetic variations and highlights the importance of evolving diagnostic approaches in leukemia management.

Here, we report real-world evidence on the safety and efficacy of nilotinib as a first-line treatment in elderly patients with chronic phase CML, treated in 18 Italian centers. Sixty patients aged > 65 years (median age 72 years (65–84)) were reported: 13 patients were older than 75 years. Comorbidities were recorded at baseline in 56/60 patients. At 3 months of treatment, all patients obtained complete hematological response (CHR), 43 (71.6%) an early molecular response (EMR), while 47 (78%) reached a complete cytogenetic response (CCyR). At last follow-up, 63.4% of patients still had a deep molecular response (MR4 or better), 21.6% reached MR3 as best response and 11.6% persisted without MR. Most patients (85%) started the treatment at the standard dose (300 mg BID), maintained at 3 months in 80% of patients and at 6 months in 89% of them. At the last median follow-up of 46.3 months, 15 patients discontinued definitively the treatment (8 due to side effects, 4 died for unrelated CML causes, 1 for failure, 2 were lost to follow-up). One patient entered in treatment-free remission. As to safety, 6 patients (10%) experienced cardiovascular events after a median time of 20.9 months from the start. Our data showed that nilotinib could be, as first-line treatment, effective and relatively safe even in elderly CML patients. In this setting, more data in the long term are needed about possible dose reduction to improve the tolerability, while maintaining the optimal molecular response.

Background: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM). Methods: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors. Results: One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44–85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib, n = 6), BCL2 inhibitor (venetoclax, n = 9), or FGFR3 inhibitor (erdafitinib, n = 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group (p = 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51–1.78; p = 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46–2.12; p = 0.98), respectively, in MO and no-MO patients. Conclusion: Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.