Assessing prognosis of chronic lymphocytic leukemia using biomarkers and genetics

Chronic lymphocytic leukemia (CLL) is a clinically and genetically heterogenous disease. Genomic studies have deciphered the pathogenesis of CLL and has allowed the identification of prognostic and..

Precision Medicine in Systemic Mastocytosis

Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice

Targeting p53 in chronic lymphocytic leukemia.

Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring.The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options forThe key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, howeve

Stiffer Spleen Predicts Higher Bone Marrow Fibrosis and Higher JAK2 Allele Burden in Patients With Myeloproliferative Neoplasms

A total of 63 myeloproliferative neoplasms [MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF)] underwent spleen stiffness (SS) measurement by vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (p=0.035), with hemoglobin level <10 g/dl (p=0.014) and with white blood cells 6510,000/ml (p=0.008). Median SS was significantly higher in MF patients compared to ET and PV (p=0.015). SS also correlated with higher JAK2 variant allele frequency (p=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN

A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation

Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated regions are named "variable chromatin modules" (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect a VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a large change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology

Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Simple Summary Richter Syndrome is the development of an aggressive lymphoma in patients affected by chronic lymphocytic leukemia, the most common leukemia in adults. This transformation occurs in 1-10% of chronic lymphocytic leukemia patients and represents an unmet clinical need due to its refractory behavior towards conventional therapies. Recently, the pathogenesis of Richter Syndrome has been shown to be partly related to dysfunction of the immune system, and several immune alterations have been found in patients affected by this disease. Hence, the lack of effective therapies may be overcome through immunotherapy, a type of treatment that improves the immune system response against cancer cells. Several immunotherapeutic approaches have been developed and are currently under investigation, including the use of naked monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor-T cells. Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells

New Frontiers in Monoclonal Antibodies for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Simple Summary Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) have a refractory or relapsed (R/R) disease. In this setting, prognosis is poor, particularly for patients not eligible for autologous stem-cell transplantation or CAR-T-cell therapy, thus representing an unmet need in the field of hematological malignancies. Currently, the optimal treatment approach for these patients remains controversial. Over the last few decades, monoclonal antibodies (mAbs) have dramatically changed the therapeutic landscape for cancer patients. The aim of our review is focused on novel and emerging therapeutic strategies based on different types of mAbs, including monospecific and bispecific mAbs as well as antibody-drug conjugates and immune checkpoint inhibitors, in the challenging setting of R/R DLBCL.Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Approximately 60% of patients are cured with R-CHOP as a frontline treatment, while the remaining patients experience primary refractory or relapsed disease (R/R). The prognosis for R/R DLBCL patients who are neither eligible for autologous stem-cell transplantations nor CAR-T-cell treatment is poor, representing an important unmet need. Monoclonal antibodies (mAbs) have dramatically improved therapeutic options in anti-cancer strategies, offering new opportunities to overcome chemo-refractoriness in this challenging disease, even in cases of primary non-responder DLBCL. Several novel mAbs, characterized by different mechanisms of action and targets, are now available for R/R DLBCL. Unbound mAbs induce an immune response against cancer cells, triggering different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), activation of antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) and radioimmunotherapy (RIT), respectively, deliver a cytotoxic payload or a beta-emitter radionuclide to the targeted cells and nearby bystanders. Bispecific T-cell engagers (BiTes) and immune checkpoint inhibitors (ICIs) redirect and enhance the immune response against tumor cells. Here, we review therapeutic strategies based on monoclonal antibodies for R/R DLBCL

New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent an unmet clinical need whose prognosis is still dismal. Alterations of immune response play a prominent role in AML/MDS pathogenesis, revealing novel options for immunotherapy. Among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 (TLR2) are major targets. Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death. Several other surface molecules, namely CD33, CD123, CD45, and CD70, can be targeted with monoclonal antibodies (mAbs) that exert different mechanisms of action and include naked and conjugated antibodies, bispecific T-cell engagers, trispecific killer engagers, and fusion proteins linked to toxins. These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment

Prognostic value of clonal evolution identified by sequential FISH in untreated chronic lymphocytic leukaemia

Aim: The aim of the current study was to evaluate the potential clinical impact of clonal evolution detected by fluorescence in situ hybridization (FISH) in untreated chronic lymphocytic leukaemia (CLL) patients managed with a watch -and -wait strategy. Methods: We performed both overall survival (OS) and time to first treatment (TTFT) analysis. For the first one, we exploited a real -life cohort of 123 consecutive CLL patients followed at our institution, for which at least a second FISH evaluation during watch and wait was available. For TTFT analysis, we considered only patients treated after the second FISH sample (n = 69). Results: Considering the original cohort, patients who acquired a FISH abnormality displayed a worse outcome with a median OS of 91.9 months compared to 147.3 months for patients who did not acquire any FISH abnormalities (P = 0.007). Unmutated immunoglobulin heavy chain gene (IGHV) genes were associated with a higher probability of acquiring a FISH abnormality (P = 0.04). Turning to TTFT analysis, patients who gained at least one FISH abnormality (n = 7, 10%) were characterised by an earlier treatment requirement with a median TTFT of 1.1 months, compared to 2.7 months in patients who did not acquire any FISH abnormalities (n = 62, 90%) (P = 0.025). Conclusions: The dynamic acquisition of karyotypic abnormalities by FISH predicts poor outcomes and early treatment requirement in CLL patients. Our results suggest that FISH analysis could be integrated with other clinical and biological features to obtain dynamic scores that are able to predict outcomes at different phases of disease history