Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that affects primarily older individuals. Patients ineligible to receive intensive standard chemotherapy followed by consolidation with/without hematopoietic stem cell transplant have a suboptimal prognosis. In recent years, significant advances have been made in the AML field leading to the development of new anti-leukemic approaches, including lower-intensity therapies specifically developed for patients who are ineligible for intensive chemotherapy. As the available options for this hard-to-manage and historically undertreated patient category are increasing, selecting the best treatment for each patient is crucial and ever more challenging. Accordingly, accurate patient evaluation is required to guide this decision-making process. There is currently no consensus on how to evaluate patients' fitness status, and the available tools that were originally developed for this purpose might not be adequate in the setting of the new treatment options. In this review we describe current management of AML patients unfit for intensive chemotherapy, aiming to highlight current challenges and suggest possible strategies for an accurate therapeutic selection. For this purpose, we will first provide an overview of epidemiology and classification of AML, and then move to current anti-leukemic treatments for unfit patients and the tools used for evaluating patient eligibility for a specific treatment. Finally, we will suggest possible measures to improve the management of AML patients in the era of novel lower-intensity regimens.

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35

Calreticulin (CALR) mutations are detected in around 20% of patients with primary and post-essential thrombocythemia myelofibrosis (MF). Regardless of driver mutations, patients with splenomegaly and symptoms are generally treated with JAK2-inhibitors, most commonly ruxolitinib. Recently, new therapies specifically targeting the CALR mutant clone have entered clinical investigation. To collect information on efficacy and safety of ruxolitinib in CALR-mutated patients, we report a sub-analysis of the "RUX-MF" (NCT06516406) study, comprising 135 CALR-mutated and 786 JAK2-mutated ruxolitinib-treated patients. Compared to JAK2-mutated patients, CALR-mutated patients started ruxolitinib with a more severe disease (higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis) and after a longer median time from diagnosis (2.6 versus 0.7 years, p < 0.001). At 6 months, spleen responses were numerically inferior in CALR-mutated patients, who also had significantly lower rates of symptom responses (56.1% versus 66.7%, p = 0.04).

BACKGROUND:Most cases of non-Hodgkin lymphoma (NHL) can be diagnosed using a combination of fine-needle cytology (FNC) and flow cytometry together with immunoglobulin light chain restriction and/or specific phenotypic profiles. However, 5%-15% of B-cell NHLs lack these specific diagnostic features. In such cases, the diagnosis of NHL may be supported by molecular clonality testing based on the immunoglobulin heavy chain (IGH) assay of clonality by polyacrylamide heteroduplex analysis or by automated capillary electrophoresis via GeneScan analysis. Chip-based microfluidic technology (MT), based on miniaturized parallel capillary electrophoresis structures, is a viable alternative to capillary electrophoresis analysis, being less costly and cumbersome. In this study, we evaluated the performance of MT platform in IGH clonality assessment in a series of lymph node FNC samples.METHODS:Thirty-five consecutive lymph node FNCs were evaluated. In all cases, the first and the second passes were used to prepare a conventional smear and to collect material for flow cytometry analysis; residual material was collected for molecular clonality assessment, and PCR products were analyzed both by MT and GeneScan platforms.RESULTS:Molecular clonality assessment by MT had a sensitivity of 84.2% and a specificity of 76.9%; GeneScan analysis had a sensitivity of 88.8% and a specificity of 92.8%. The overall agreement between the two platforms was 85.7% (30/35).CONCLUSIONS:MT analysis proved to be a viable technique for IGH clonality assessment on FNC samples. Should our data be confirmed in larger studies, the MT procedure may be suitable for routine diagnostic practice, even on cytological samples.

Additional Supporting Information may be found in the online version of this article: Fig S1. Western blot analysis for KAT8 expression and H4K16 acetylation level in three leukemia cell lines. (B) Realtime PCR analysis for KAT8 mRNA expression during U937 cell line PMA-induced differentiation. (C) Vector control (Vec) and shKAT8 cells were incubated with PMA (10 ng/ ml) for 0 and 48 h, and adherent cells were photographed following PBS washing. (D) Real-time PCR analysis for KAT8 knockdown in U937 cell line. (E) Real-time PCR analysis for MN1 mRNA expression in vector control (Vec) and shKAT8 U937 cell line. (F) Vector control (Vec), shKAT8 and and shKAT8 + siMN1 cells lines were incubated with PMA (10 ng/ml) for 0 and 48 h, and adherent cells were photographed following PBS washing. Table SI. Clinical characteristics of the patients with AML.

Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making

The ubiquitin-proteasome system is an attractive target for anticancer drug development in several cancer including Chronic Myeloid Leukemia Ph+ (CML). The Bcr/Abl tyrosine kinase, the hallmark of CML, by multiple signaling/survival pathways downstream, including the ubiquitin-proteasome system, contributes to leukemic transformation Several key proteins that regulate important cellular processes such as proliferation and apoptosis are regulated by proteasome-dependent proteolysis. For these reasons, proteasome inhibitors represent a relatively new class of antineoplastic agents that act by interfering with the catalytic 20S core of the proteasome, thereby preventing the elimination of diverse cellular proteins targeted for degradation, including BCR-ABL. There are several classes of proteasome inhibitors including peptide aldehydes such as MG-132, the dipeptidyl boronic acid bortezomib, etc, with increased interest in the clinical development. Currently, the clinical utility of proteasome inhibitors in leukemia in general, and in CML in particular, remains relatively unexplored In this review we explore the molecular basis for use of this drugs in CML and the preliminary clinical utility of proteasome inhibitors in CML.

Purpose To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy. Methods These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008. Results Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure. Conclusion Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.