Advanced systemic mastocytosis (advSM) is characterized by the presence of an acquired KIT D816V mutation in >90% of patients. In the majority of patients, KIT D816V is not only detected in mast ...cells but also in other hematopoietic lineages. We sought to investigate the effects of the KIT-inhibitors midostaurin and avapritinib on single-cell-derived myeloid progenitor cells using granulocyte-macrophage colony-forming-units of patients with KIT D816V positive advSM. Colonies obtained prior to treatment were incubated in vitro with midostaurin (n = 10) or avapritinib (n = 11) and showed a marked reduction (≥50%) of KIT D816V positive colonies in 3/10 (30%) and 7/11 (64%) patient samples, respectively. Three of those 7 (43%) avapritinib responders were resistant to midostaurin in both, in vitro and in vivo. Colonies from four patients with high-risk molecular profile and aggressive clinical course were resistant to both drugs. The in vitro activity of midostaurin strongly correlated with clinical and molecular responses, e.g., relative reduction of KIT D816V allele burden and the proportion of KIT D816V positive colonies obtained after six months midostaurin-treatment in vivo. We conclude that the colony inhibition assay provides useful information for prediction of responses on midostaurin and that avapritinib has a superior in vitro activity compared to midostaurin.
In 70 patients with KIT D816V positive systemic mastocytosis (SM) including 36 patients with advanced SM (AdvSM), we correlated the extent of reported mucosal mast cell (mMC) infiltration of the ...upper and/or lower gastrointestinal tract (UGIT, n = 63; LGIT, n = 64; both, n = 57) with symptoms and markers of MC burden/subtype. GI symptoms were reported by all patients (mean 2.1 number of symptoms). A strong mMC infiltration was identified in 24 patients (UGIT, 17/63, 27%; LGIT, 19/64, 30%). Concurrent involvement of UGIT and LGIT (n = 12) correlated with female gender (75%) and a higher symptom burden (mean 2.7) but not with MC burden or subtype. Significant differences between non-AdvSM and AdvSM were reported regarding food intolerance (54% vs. 17%), cramping (54% vs. 22%) and weight loss (0% vs. 64%). KIT D816V was identified in 54/56 (96%) available biopsies. In 46 patients, digital PCR revealed a correlation with low albumin levels (r = - 0.270, P = 0.069) and the KIT D816V VAF in peripheral blood (r = 0.317, P = 0.036) but not with the extent of mMC infiltration or markers of MC burden/subtype. Although MC mediator triggered GI symptoms have a substantial impact on the quality of life, correlation to objective disease parameters is lacking thus making its systematic assessment challenging.
Abstract
Systemic mastocytosis (SM) is characterized by multifocal accumulation of neoplastic mast cells (MCs), predominately affecting the bone marrow (BM). Imaging with computed tomography (CT) is ...used for assessment of bone mineral density and structure. However, the value of functional imaging with dual-energy CT (DECT) and the assessment of virtual-non-calcium attenuation values (VNCa-AV) for visualization of BM disease burden in SM has not yet been assessed. DECT of the axial skeleton was performed in 18 patients with SM (indolent SM ISM, n = 6; smoldering SM SSM/advanced SM AdvSM, n = 12) and 18 control subjects. VNCa-AV were obtained in 5 representative vertebraes per patient and correlated with laboratory, morphologic and molecular parameters. VNCa-AV strongly correlated with quantitative BM MC infiltration (r = 0.7, R
2
= 0.49,
P
= 0.001) and serum tryptase levels (r = 0.7, R
2
= 0.54,
P
< 0.001). Mean VNCa-AV were significantly higher in SSM/AdvSM as compared to ISM (− 9HU vs. − 54HU,
P
< 0.005) and controls (− 38HU,
P
< 0.005). Nine of 10 (90%) patients with a VNCa-AV > − 30HU and 7/7 (100%) patients with a VNCa-AV > − 10HU had SSM or AdVSM. BM VNCa-AV provide information about the MC burden of SM patients and correlate with SM subtypes. DECT may therefore serve as a supplementary tool for SM diagnosis, subclassification and monitoring in a one-stop-shop session.
In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the
D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples ...of 161 patients (indolent SM (ISM),
= 40; advanced SM, AdvSM,
= 121) at referral and during follow-up for the
D816V variant allele frequency (VAF) at the DNA-level and the
D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (
> 0.99,
> 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (
0.91, coefficient of determination,
0.84) but only to a lesser extent in AdvSM (
0.71;
= 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years;
= 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (
= 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of
D816V may play an important role in the pathophysiology of SM.
Within our nationwide registry, we identified a
D816V mutation (
D816V
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
D816V-negative (D816V
) AdvSM. In 19 D816V
patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a)
D816H- or Y-positive SM (
D816H/Y
,
= 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative
sequencing (
MCL,
= 7) and (c)
SM with associated hematologic neoplasm (
SM-AHN,
= 5). Although >70% of patients in the two MCL cohorts (
D816H/Y
and
) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a
D816V
MCL control cohort (
= 29; 1.7 vs. 0.9 vs. 2.6 years;
< 0.04). The
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
patients.
Sustained elevation of eosinophils above 5 × 10
9
/l in peripheral blood (PB) should prompt further investigation. Clonal eosinophilia accounts for the much smaller proportion of eosinophilias ...(< 10%), but exclusion of such a neoplasia is prognostically and therapeutically relevant. Molecular genetic analysis from PB, cytogenetics from bone marrow, and bone marrow histology are primarily used to exclude clonal eosinophilia. Far more common is reactive eosinophilia, the cause of which may be drugs, allergies, solid tumors, lymphomas, worm infections, autoimmune diseases, or idiopathic hypereosinophilic syndrome (HES). Because of the diverse organ infiltration patterns in eosinophilia, a specific search for possible organ involvement (including heart, lung, gastrointestinal tract, kidney, skin, etc.) should be performed, depending on the patient’s symptoms. The diagnosis of HES is made when organ infiltration with consecutive dysfunction is diagnosed in persistent eosinophilia after exclusion of other causes. Therapeutically, oral corticosteroids (OSC) are used in HES. This can also be helpful in the differential diagnosis, as patients with clonal eosinophilia are usually not expected to achieve remission with OCS. When OCS requirements are high, other immunosuppressants (e.g., methotrexate MTX, cyclophosphamide) and the interleukin (IL)-5 antagonist mepolizumab are used. In clonal eosinophilia, tyrosine kinase inhibitors are the first-line therapy, depending on the underlying genetic alteration.
Patients with systemic mastocytosis (SM) are at increased risk of hypersensitivity reactions (HRs). Although Hymenoptera venoms are the predominant triggers, cases of contrast media-induced HR ...(CMIHR) have also been reported and prophylactic premedication is often performed. However, data from larger series are limited and differences between indolent and advanced SM have not yet been investigated.
To determine the incidence and severity of CMIHR in all subtypes of SM.
We analyzed 162 adult patients with SM (indolent systemic mastocytosis ISM, n = 65; advanced systemic mastocytosis advSM, n = 97). First, the cumulative incidence of CMIHR was retrospectively assessed in the patient's history. Second, at our institution, patients underwent 332 contrast media (CM)-enhanced imaging including 80 computed tomography (CT) scans with iodine-based contrast agent and 252 magnetic resonance imaging (MRI) with a gadolinium-based contrast agent, and tolerance was assessed.
Previous CMIHRs to CT (vomiting, n = 1, erythema, n = 1, cardiovascular shock, n = 1), and MRI (dyspnea, n = 1, cardiovascular shock, n = 1) had been reported by 4 out of 162 (2.5%) patients (ISM, n = 3; advSM, n = 1). In contrast, during or after 332 CM-enhanced CT or MRI examinations at our institution, no CMIHRs were reported. Premedication was solely given to 3 patients before CT scans, including 1 with previous CMIHR, who tolerated the imaging well.
We conclude that: (1) there is a substantial discrepancy between the perception and prevalence of HRs to CM in SM; (2) reactions are scarce in ISM and even rarer in advSM; and (3) in SM patients without previous history of CM hypersensitivity, prophylactic premedication before CM-enhanced CT or MRI is dispensable.
Abstract Purpose of Review In this review, we aim to explore the optimal approach to patients presenting with eosinophilia, considering recent advances in diagnostic and therapeutic strategies. ...Specifically, we focus on the integration of novel therapies into clinical practice to improve patient outcomes. Recent Findings Advanced insights into the clinical and genetic features of eosinophilic disorders have prompted revisions in diagnostic criteria by the World Health Organization classification (WHO-HAEM5) and the International Consensus Classification (ICC). These changes reflect a growing understanding of disease pathogenesis and the development of targeted treatment options. The therapeutic landscape now encompasses a range of established and novel therapies. For reactive conditions, drugs targeting the eosinophilopoiesis, such as those aimed at interleukin-5 or its receptor, have demonstrated significant potential in decreasing blood eosinophil levels and minimizing disease flare-ups and relapse. These therapies have the potential to mitigate the side effects commonly associated with prolonged use of oral corticosteroids or immunosuppressants. Myeloid and lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions are managed by various TK inhibitors with variable efficacy. Summary Diagnosis and treatment rely on a multidisciplinary approach. By incorporating novel treatment options into clinical practice, physicians across different disciplines involved in the management of eosinophilic disorders can offer more personalized and effective care to patients. However, challenges remain in accurately diagnosing and risk-stratifying patients, as well as in navigating the complexities of treatment selection.
Summary
We report on 45 patients with myeloid neoplasms and concurrent Janus kinase 2 (JAK2) V617F and KIT proto‐oncogene, receptor tyrosine kinase (KIT) D816V (JAK2pos./KITpos.) mutations, which are ...individually identified in >60% of patients with classical myeloproliferative neoplasms (MPN) and >90% of patients with systemic mastocytosis (SM) respectively. In SM, the concurrent presence of a clonal non‐mast cell neoplasm SM with associated haematological neoplasm (SM‐AHN) usually constitutes a distinct subtype associated with poor survival. All 45 patients presented with a heterogeneous combination of clinical/morphological features typical of the individual disorders (e.g. leuco‐/erythro‐/thrombocytosis and elevated lactate dehydrogenase for MPN; elevated serum tryptase and alkaline phosphatase for SM). Overlapping features identified in 70% of patients included splenomegaly, cytopenia(s), bone marrow fibrosis and additional somatic mutations. Molecular dissection revealed discordant development of variant allele frequency for both mutations and absence of concurrently positive single‐cell derived colonies, indicating disease evolution in two independent clones rather than monoclonal disease in >60% of patients examined. Overall survival of JAK2pos./KITpos. patients without additional somatic high‐risk mutations HRM, e.g. in serine and arginine‐rich splicing factor 2 (SRSF2), additional sex combs like‐1 (ASXL1) or Runt‐related transcription factor 1 (RUNX1) at 5 years was 77%, indicating that the mutual impact of JAK2 V617F and KIT D816V on prognosis is fundamentally different from the adverse impact of additional HRM in the individual disorders.
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