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17 pages, 2487 KiB

Open AccessArticle

Poor Applicability of Currently Available Prognostic Scoring Systems for Prediction of Outcome in KIT D816V-Negative Advanced Systemic Mastocytosis

by Nicole Naumann, Martina Rudelius, Johannes Lübke, Deborah Christen, Jakob Bresser, Karl Sotlar, Georgia Metzgeroth, Alice Fabarius, Wolf-Karsten Hofmann, Jens Panse, Hans-Peter Horny, Nicholas C. P. Cross, Andreas Reiter and Juliana Schwaab

Cancers 2024, 16(3), 593; https://doi.org/10.3390/cancers16030593 - 30 Jan 2024

Cited by 3 | Viewed by 1948

Abstract

Within our nationwide registry, we identified a KIT D816V mutation (KIT D816V^pos.) in 280/299 (94%) patients with advanced systemic mastocytosis (AdvSM). Age, cytopenias and the presence of additional somatic mutations confer inferior overall survival (OS). However, little is known about the characteristics of KIT D816V-negative (D816V^neg.) AdvSM. In 19 D816V^neg. patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a) KIT D816H- or Y-positive SM (KIT D816H/Y^pos., n = 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative KIT sequencing (KIT^neg. MCL, n = 7) and (c) KIT^neg. SM with associated hematologic neoplasm (KIT^neg. SM-AHN, n = 5). Although >70% of patients in the two MCL cohorts (KIT D816H/Y^pos. and KIT^neg.) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a KIT D816V^pos. MCL control cohort (n = 29; 1.7 vs. 0.9 vs. 2.6 years; p < 0.04). The KIT^neg. SM-AHN phenotype was dominated by the heterogeneous AHN (low mast cell burden, presence of additional mutations) with a better median OS of 4.5 years. We conclude that (i) in MCL, negativity for D816V is a relevant prognostic factor and (ii) PSS fail to correctly classify D816V^neg. patients. Full article

(This article belongs to the Special Issue New Insights of Hematology in Cancer)

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13 pages, 1766 KiB

Open AccessReview

Recent Advances in the Therapeutic Management of Advanced Systemic Mastocytosis

by Scott Veitch and Deepti H. Radia

Diagnostics 2024, 14(1), 80; https://doi.org/10.3390/diagnostics14010080 - 29 Dec 2023

Cited by 2 | Viewed by 2903

Abstract

Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function KIT D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease. Full article

(This article belongs to the Special Issue Current Challenges in Diagnosis and Management of Mast Cell Disorders)

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14 pages, 1169 KiB

Open AccessReview

Antibody-Based and Cell Therapies for Advanced Mastocytosis: Established and Novel Concepts

by Peter Valent, Cem Akin, Michel Arock, Karoline V. Gleixner, Hildegard Greinix, Olivier Hermine, Hans-Peter Horny, Daniel Ivanov, Alberto Orfao, Werner Rabitsch, Andreas Reiter, Axel Schulenburg, Karl Sotlar, Wolfgang R. Sperr and Celalettin Ustun

Int. J. Mol. Sci. 2023, 24(20), 15125; https://doi.org/10.3390/ijms242015125 - 12 Oct 2023

Cited by 2 | Viewed by 3067

Abstract

Advanced systemic mastocytosis (SM) is a heterogeneous group of myeloid neoplasms characterized by an uncontrolled expansion of mast cells (MC) in one or more internal organs, SM-induced tissue damage, and poor prognosis. Advanced SM can be categorized into aggressive SM (ASM), MC leukemia (MCL), and SM with an associated hematologic neoplasm (SM–AHN). In a vast majority of all patients, neoplastic cells display a KIT mutation, mostly D816V and rarely other KIT variants. Additional mutations in other target genes, such as SRSF2, ASXL1, or RUNX1, may also be identified, especially when an AHN is present. During the past 10 years, improved treatment approaches have led to a better quality of life and survival in patients with advanced SM. However, despite the availability of novel potent inhibitors of KIT D816V, not all patients enter remission and others relapse, often with a multi-mutated and sometimes KIT D816V-negative disease exhibiting multi-drug resistance. For these patients, (poly)chemotherapy, antibody-based therapies, and allogeneic hematopoietic stem cell transplantation may be viable treatment alternatives. In this article, we discuss treatment options for patients with drug-resistant advanced SM, including novel KIT-targeting drugs, antibody-based drugs, and stem cell-eradicating therapies. Full article

(This article belongs to the Special Issue Pathogenesis and Management of Mastocytosis)

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17 pages, 15935 KiB

Open AccessReview

Mast Cell Leukemia: An Update with a Practical Review

by Magda Zanelli, Martina Quintini, Salvatore Magnasco, Lara Aprile, Andrea Palicelli, Maurizio Zizzo, Francesca Sanguedolce, Stefano Ricci, Saverio Pancetti, Valeria Zuccalà, Veronica Martino, Giuseppe Broggi, Rosario Caltabiano, Alberto Cavazza, Paola Parente, Cristina Mecucci, Giovanni Martino and Stefano Ascani

Cancers 2023, 15(6), 1664; https://doi.org/10.3390/cancers15061664 - 8 Mar 2023

Cited by 12 | Viewed by 4009

Abstract

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included. Full article

(This article belongs to the Special Issue Advances in Lymphoma, Plasma Cell Myeloma, and Leukemia Diagnostics)

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20 pages, 2329 KiB

Open AccessReview

Precision Medicine in Systemic Mastocytosis

by Maura Nicolosi, Andrea Patriarca, Annalisa Andorno, Abdurraouf Mokhtar Mahmoud, Alessandra Gennari, Renzo Boldorini, Gianluca Gaidano and Elena Crisà

Medicina 2021, 57(11), 1135; https://doi.org/10.3390/medicina57111135 - 20 Oct 2021

Cited by 7 | Viewed by 3870

Abstract

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. Full article

(This article belongs to the Special Issue Myeloproliferative Diseases: From Diagnosis to Treatment Approach, through the Molecular Landscape)

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19 pages, 1632 KiB

Open AccessArticle

Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis

by Noelia Dasilva-Freire, Andrea Mayado, Cristina Teodosio, María Jara-Acevedo, Iván Álvarez-Twose, Almudena Matito, Laura Sánchez-Muñoz, Carolina Caldas, Ana Henriques, Javier I. Muñoz-González, Andrés C. García-Montero, J. Ignacio Sánchez-Gallego, Luis Escribano and Alberto Orfao

Int. J. Mol. Sci. 2019, 20(3), 552; https://doi.org/10.3390/ijms20030552 - 28 Jan 2019

Cited by 11 | Viewed by 5298

Abstract

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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