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

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

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

Atypical Chronic Myeloid Leukemia: Where Are We Now?

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (&gt;20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (&lt; 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options

A retrospective study of R-DHAP/Ox for early progressing follicular lymphoma

R-DHAP/Ox; autologous transplantation; early disease progression; follicular lymphom

Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists

Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve telomere maintenance, DNA repair, biogenesis of ribosomes, control of proliferation and others. The increased knowledge on the genes involved in MDS pathogenesis and the wider availability of molecular diagnostic assessment have led to an improvement in the detection of IBMFS genetic predisposition in MDS patients. A punctual recognition of these disorders implies a strict surveillance of the patient in order to detect early signs of progression and promptly offer allogeneic hematopoietic stem cell transplantation, which is the only curative treatment. Moreover, identifying an inherited mutation allows the screening and counseling of family members and directs the choice of donors in case of need for transplantation. Here we provide an overview of the most recent data on MDS with genetic predisposition highlighting the main steps of the diagnostic and therapeutic management. In order to highlight the pitfalls of detecting IBMFS in adults, we report the case of a 27-year-old man affected by MDS with an underlying telomeropathy