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

Quintás‐Cardama, Alfonso; Jain, Nitin; Verstovšek, Srđan

doi:10.1002/cncr.26256

Cited by 25 publications

(23 citation statements)

References 92 publications

(138 reference statements)

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“…9 KIT mutations that induce ligand independent phosphorylation of the SCF receptor and consequently lead to constitutive activation seem to play a critical role in the pathogenesis of SM by inducing autonomous MC growth. As such, these mutations may be potential diagnostic markers and therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

Fernandes¹,

Teixeira

Freitas

et al. 2014

An. Bras. Dermatol.

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BACKGROUNDMastocytosis is a clonal disorder characterized by the accumulation of abnormal mast cells in the skin and/or in extracutaneous organs. OBJECTIVESTo present all cases of mastocytosis seen in the Porto Hospital Center and evaluate the performance of World Health Organization diagnostic criteria for systemic disease. METHODSThe cases of twenty-four adult patients with mastocytosis were reviewed. Their clinical and laboratorial characteristics were assessed, and the properties of the criteria used to diagnose systemic mastocytosis were evaluated. RESULTSThe age of disease onset ranged from 2 to 75 years. Twenty-three patients had cutaneous involvement and 75% were referred by dermatologists. Urticaria pigmentosa was the most common manifestation of the disease. One patient with severe systemic mast cell mediator-related symptoms showed the activating V560G KIT mutation. The bone marrow was examined in 79% of patients, and mast cell immunophenotyping was performed in 67% of the participants. Systemic disease was detected in 84% of cases, and 81% of the sample had elevated serum tryptase levels. All the diagnostic criteria for systemic mastocytosis had high specificity and positive predictive value. Bone marrow biopsy had the lowest sensitivity, negative predictive value and efficiency, while the highest such values were observed for mast cell immunophenotyping. Patients were treated with regimens including antihistamines, sodium cromoglycate, alpha-interferon, hydroxyurea and phototherapy. CONCLUSIONSCutaneous involvement is often seen in adult mastocytosis patients, with most individuals presenting with indolent systemic disease. Although serum tryptase levels are a good indicator of mast cell burden, bone marrow biopsy should also be performed in patients with normal serum tryptase, with flow cytometry being the most adequate method to diagnose systemic disease.

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Section: Introductionmentioning

confidence: 99%

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

Fernandes¹,

Teixeira

Freitas

et al. 2014

An. Bras. Dermatol.

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“…For instance, an aberrant immunophenotype and atypical mast cell morphology are almost universally present in SM, but they are only considered minor criteria. In addition, a persistently elevated serum tryptase level (≥ 20 ng/mL), which is a minor diagnostic criterion, is present in only 85% of patients, its diagnostic specificity is limited by the presence of high tryptase levels in other myeloid malignancies or in severe allergic reactions [10], its reliability is very poor in patients with SM-AHNMD, and the cut-off of 20 ng/mL has been established based on retrospective studies involving a limited number of patients [11]. Once a diagnosis of SM is made, patients with this malignancy are further categorized according to the presence of “B- and C-findings,” which are surrogates of disease burden and aggressiveness, respectively.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow mast cell burden and serum tryptase level as markers of response in patients with systemic mastocytosis

Quintás‐Cardama

Sever

Cortes

et al. 2013

Leukemia & Lymphoma

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Two important response criteria in systemic mastocytosis (SM) are the elimination or reduction in percentage of bone marrow mast cells (MCs) and the reduction of serum tryptase levels. We investigated the accuracy of a single time point reduction of bone marrow MCs and serum tryptase level as response criteria in 50 patients with SM with available serial assessments. Bone marrow MC percentage varied significantly, with an average coefficient of variation (CV) of 65% (range, 6–173%) and 44% of patients having a CV higher than the average. The average CV for serum tryptase level was 19% (range, 0–96%), with 36% of patients having a CV higher than average. These wide variations in bone marrow MC burden and serum tryptase level were independent of the administration of SM-directed therapy, type of therapy or disease subtype. Furthermore, the achievement of a single time point therapy-induced bone marrow complete response (no histological evidence of malignant bone marrow MCs) did not correlate with tryptase level or symptomatic improvement. In conclusion, the value of single measurements of bone marrow MC percentage and serum tryptase level as response criteria in SM is not supported by clinical data. Incorporation of an assessment of the degree in reduction of MCs and tryptase, and assessment of response durability, would make response criteria more clinically meaningful.

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“…There is no cure for sm, and earlier treatment strategies using interferon alfa and cladribine have not yielded durable responses 3,14,16 , prompting investigation of tyrosine kinase inhibitors targeting the Kit receptor. Imatinib mesylate has demonstrated in vitro inhibition of proliferation of mast cells with wildtype KIT 15 .…”

Section: Discussionmentioning

confidence: 99%

“…Other tyrosine kinase inhibitors have been evaluated in sm, including dasatinib and nilotinib, with overall response rates of 33% and less than 20% respectively, in patients with the D816V mutation 3,14,21 . Midostaurin, a multi-kinase inhibitor, and masitinib mesilate, a new tyrosine kinase inhibitor, have recently shown benefit in both sm and cm 3,14,22,23 .…”

Section: Discussionmentioning

confidence: 99%

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Symptomatic Response to Imatinib Mesylate in Cutaneous Mastocytosis Associated with Chronic Myelomonocytic Leukemia

et al. 2013

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1 major and 1 minor, or 3 minor World Health Organization diagnostic criteria, which are listed in Table ii 4 . Although cutaneous and systemic involvement can occur together in adults, children rarely experience systemic manifestations and often have self-limiting disease [5][6][7] . The treatment of sm in adults remains a challenge, in part because of its chronicity and heterogeneity. CASE DESCRIPTIONA 67-year-old white woman presented with progressive and debilitating pruritus of 5 years' duration.Her symptoms had begun with intermittent pruritus of her arms, which then progressed to involve unexposed areas. The condition was unresponsive to treatment with histamine antagonists and ultraviolet B phototherapy. Two years later, she was noted to have peripheral blood monocytosis. Bone marrow (bm) examination demonstrated hypercellularity, dysplastic erythroid precursors and megakaryocytes, and increased monocyte precursors (Figure 1), but no increase in blasts. Blood and marrow findings were diagnostic of chronic myelomonocytic leukemia (cmml) 1. Mast cell numbers and morphology were normal.When the patient presented to our tertiary care centre, her pruritus had become constant and involved her entire body. She was unable to sleep unless medicated with sedatives. She was struggling to work and was having suicidal thoughts. Hot showers exacerbated her pruritus, but symptoms persisted even with avoidance of triggers. She noted a chronic truncal rash and erythematous patches on her arms. She denied flushing, wheezing, and diarrhea. Her medical history was otherwise unremarkable.Physical examination revealed a fine maculopapular rash with tan lesions over the patient's anterior trunk, concentrated near the umbilicus and under the breasts, and erythematous plaques on the left arm. She did not have dermatographia.White blood cell count was 6.8×10 3 /μL, with 19% monocytes and 1% eosinophils. Hemoglobin ABSTRACTMastocytosis is an uncommon disorder defined by increased and abnormal mast cells in one or more tissues. Cutaneous mastocytosis (cm) is limited to the skin, with varying degrees of rash, pruritus, and disfigurement. Systemic mastocytosis (sm) typically involves the bone marrow, sometimes in association with other bone marrow disorders, including chronic myelomonocytic leukemia (cmml). Mastocytosis has been associated with somatic mutations in the gene encoding the tyrosine kinase Kit, leading to identification of Kit as a therapeutic target. The Kit inhibitor imatinib mesylate is approved for aggressive sm. We present an unusual patient with disabling pruritus from telangiectasia macularis eruptiva perstans, a subtype of cm, and cmml, but with no evidence of systemic mast cell disease. She was treated with imatinib and experienced marked improvement in her pruritus. Concomitant cm and cmml have not previously been reported, and the present report is the first of successful imatinib therapy in an adult patient with cm.

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

Cited by 25 publications

References 92 publications

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

Bone marrow mast cell burden and serum tryptase level as markers of response in patients with systemic mastocytosis

Symptomatic Response to Imatinib Mesylate in Cutaneous Mastocytosis Associated with Chronic Myelomonocytic Leukemia

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