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Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis.

ABSTRACT: The term systemic mastocytosis (SM) encompasses a group of hematopoietic malignancies characterized by excessive proliferation of neoplastic mast cells that accumulate in the bone marrow and visceral organs. Most patients with SM, particularly those who present with aggressive clinical courses, carry somatic mutations of the v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) gene. KIT mutations are considered central events in the pathogenesis of SM and serve as diagnostic markers and putative therapeutic targets. The heterogeneity in the clinical course of patients with SM and recent advances in the genetic and immunophenotypic characterization of neoplastic mast cells may help to improve current diagnostic, taxonomic, and therapeutic approaches in SM.

SUBMITTER: Quintas-Cardama A

PROVIDER: S-EPMC4839285 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis.

Quintás-Cardama Alfonso A Jain Nitin N Verstovsek Srdan S

Cancer 20110620 24

The term systemic mastocytosis (SM) encompasses a group of hematopoietic malignancies characterized by excessive proliferation of neoplastic mast cells that accumulate in the bone marrow and visceral organs. Most patients with SM, particularly those who present with aggressive clinical courses, carry somatic mutations of the v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) gene. KIT mutations are considered central events in the pathogenesis of SM and serve as diagnostic marke ...[more]

PMID: 21692073

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Project description:Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred. The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual. The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se. Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is widely used for the treatment, but evidence-based information about its real benefi ts and short- and long-term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.

Project description:Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by eosinophil-rich granulomatous inflammation and necrotizing vasculitis, pre-dominantly affecting small-to-medium-sized vessels. It is categorized as a primary antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) but also shares features of hypereosinophilic syndrome (HES); therefore, both vessel inflammation and eosinophilic infiltration are suggested to cause organ damage. This dual nature of the disease causes variable clinical presentation. As a result, careful differentiation from mimicking conditions is needed, especially from HES, given the overlapping clinical, radiologic, and histologic features, and biomarker profile. EGPA also remains a diagnostic challenge, in part because of asthma, which may pre-dominate for years, and often requires chronic corticosteroids (CS), which can mask other disease features. The pathogenesis is still not fully understood, however, the interaction between eosinophils and lymphocytes B and T seems to play an important role. Furthermore, the role of ANCA is not clear, and only up to 40% of patients are ANCA-positive. Moreover, two ANCA-dependent clinically and genetically distinct subgroups have been identified. However, a gold standard test for establishing a diagnosis is not available. In practice, the disease is mainly diagnosed based on the clinical symptoms and results of non-invasive tests. The unmet needs include uniform diagnostic criteria and biomarkers to help distinguish EGPA from HESs. Despite its rarity, notable progress has been made in understanding the disease and in its management. A better understanding of the pathophysiology has provided new insights into the pathogenesis and therapeutic targets, which are reflected in novel biological agents. However, there remains an ongoing reliance on corticosteroid therapy. Therefore, there is a significant need for more effective and better-tolerated steroid-sparing treatment schemes.

Project description:In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Approval was based on results from CPKC412D2201, a single-arm trial of midostaurin (100 mg orally twice daily) in previously treated or untreated patients. For the patients with ASM and SM-AHN, efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria with six cycles of midostaurin. There were no CRs reported; ICR was achieved by 6 of 16 patients (38%; 95% confidence interval [CI]: 15%-65%) with ASM and by 9 of 57 patients (16%; 95% CI: 7%-28%) with SM-AHN. Within the follow-up period, the median duration of response was not reached for the patients with ASM (range, 12.1+ to 36.8+ months) or with SM-AHN (range, 6.6+ to 52.1+ months). For the patients with MCL, efficacy was established on the basis of confirmed CR using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis criteria. Of 21 patients with MCL, 1 (5%) achieved a CR. Of 142 patients with SM evaluated for safety, 56% had dose modifications for toxicity, and 21% discontinued treatment due to a toxicity. Over 50% reported nausea, vomiting, or diarrhea, and ≥30% reported edema, musculoskeletal pain, fatigue, abdominal pain, or upper respiratory tract infection. New or worsening grade ≥3 lymphopenia, anemia, thrombocytopenia, or neutropenia developed in ≥20%. Although midostaurin is an active drug for treatment of advanced SM, it is not clear that the optimal dose has been identified. IMPLICATIONS FOR PRACTICE: Midostaurin is the only U.S. Food and Drug Administration-approved therapy for patients with systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and is the only therapy approved for patients with aggressive systemic mastocytosis regardless of KIT D816V mutation status. Based on response rate and duration, midostaurin has meaningful clinical activity in these rare, life-threatening diseases.

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Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis.

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Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis.

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