Zusammenfassung
Hintergrund
Die systemische Mastozytose (SM) ist eine klonale Stammzellerkrankung mit heterogenem klinischem Erscheinungsbild und Prognose.
Ziel
Im vorliegenden Artikel werden ...Diagnostik, Prognosemodelle und Therapieoptionen bei der SM erörtert.
Material und Methoden
Es handelt sich um eine selektive Literaturrecherche und Auswertungen des eigenen Patientenkollektivs.
Ergebnisse
Während Patienten mit einer indolenten Verlaufsform eine normale Lebenserwartung haben, ist das Überleben bei Patienten mit fortgeschrittener Erkrankung (AdvSM) oft eingeschränkt. Blutbild- und Leberwertveränderungen finden sich insbesondere bei der AdvSM, eine Erhöhung der Serumtryptase ist i. d. R. in allen Verlaufsformen zu beobachten, was sich auch in den Diagnosekriterien widerspiegelt. Klinische Symptome treten unabhängig von der Krankheitsschwere in allen Subentitäten auf, sodass eine symptomatische Therapie (u. a. Antihistaminika, Mastzellstabilisatoren, Cortison) je nach der Klinik bei der indolenten SM und bei der AdvSM Anwendung findet. Demgegenüber ist der Einsatz von KIT-Inhibitoren (Nachweis einer
KIT
-Mutation, v. a.
KIT
D816V in > 90 %) i. d. R. Patienten mit AdvSM vorbehalten. Der Multikinaseinhibitor Midostaurin und der spezifische KIT-Inhibitor Avapritinib (ab der Zweitlinie) verbessern hier die mastzellbedingte Organdysfunktion.
Schlussfolgerung
Die variable Klinik macht Diagnostik und Therapie der SM zu einer Herausforderung, eine interdisziplinäre Beurteilung je nach führender Symptomatik ist daher erforderlich. Die KIT-Inhibitortherapie hat zu einer signifikanten Verbesserung der Prognose von AdvSM-Patienten geführt, einzig kurative Therapie bleibt jedoch weiterhin die allogene Stammzelltransplantation in bestmöglicher Remission.
To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.
The study included 383 patients with AdvSM from the German ...Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).
In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 10
/L), presence of one high molecular risk gene mutation (ie, in
,
, and/or
), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years;
< .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival (
< .001).
The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.
Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE‐induced organ damage is ...often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be “non‐clonal” cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.
On the basis of data from the German Registry on Disorders of Eosinophils and Mast Cells, we compared the efficacy of midostaurin and cladribine in patients with advanced systemic mastocytosis ...(AdvSM).
Patients with AdvSM (n = 139) were treated with midostaurin only (n = 63, 45%), cladribine only (n = 23, 17%), or sequentially (midostaurin-cladribine, n = 30, 57%; cladribine-midostaurin, n = 23, 43%). Prognosis was assessed through the Mutation-Adjusted Risk Score (MARS). Besides the comparison of efficacy between midostaurin and cladribine on response (eg, organ dysfunction, bone marrow mast cell MC infiltration, and tryptase), overall survival (OS), and leukemia-free survival, we focused on the impact of treatment on involved non-MC lineages, for example, monocytes or eosinophils, and the
D816V expressed allele burden.
Midostaurin only was superior to cladribine only with effects from responses on MC and non-MC lineages conferring on a significantly improved OS (median 4.2
1.9 years,
= .033) and leukemia-free survival (2.7
1.3 years,
= .044) on the basis of a propensity score-weighted analysis of parameters included in MARS. Midostaurin compensated the inferior efficacy of cladribine in first- and second-line treatment. On midostaurin in any line, response of eosinophilia did not improve its baseline adverse prognostic impact, whereas response of monocytosis proved to be a positive on-treatment parameter. Multivariable analysis allowed to establish three risk categories (low/intermediate/high) through the combination of MARS and the reduction of the
D816V expressed allele burden of ≥ 25% at month 6 (median OS not reached
3.0 years
1.0 year;
< .001).
In this registry-based analysis, midostaurin revealed superior efficacy over cladribine in patients with AdvSM. In midostaurin-treated patients, the combination of baseline MARS and molecular response provided a compelling three-tier risk categorization (MARSv2.0) for OS.
O presente artigo tem como objetivo discutir a aplicabilidade dos royalties repassados pela Hidrelétrica Binacional de Itaipu, observando seusimpactos no campo educacional. A assinatura do Tratado de ...Itaipu, em 1973, ocorreu mediante tensões políticas a partir dos interesses geopolíticos, no contexto da Guerra Fria em face do modelo nacional-desenvolvimentista em plena Ditadura Civil-Militar (1964-1985). A construção da usina produziu mudanças significativas no cenário econômico, social e territorial nos municípios lindeiros ao lago de Itaipu. Grande parte da população que vivia em áreas rurais foi evacuada, deixando terras produtivas submersas a uma grande quantidade de água, para assim, dar lugar ao projeto da construção da maior hidrelétrica do mundo da época. A formação do reservatório inundou uma grande área dos municípios ao lago de Itaipu, estando Santa Helena e Itaipulândia entre os maiores atingidos, vindo a perder uma grande parte de suas áreas produtivas, sendo, portanto, os maiores recebedores das parcelas dos royalties, conforme previsto na Constituição Federal de 1988, em seu Art. 20. A partir de pesquisa bibliográfica e documental, procuramos fazer uma análise dos investimentos realizados na educação nesses municípios. Os repasses efetuados criaram possibilidades, expectativas e perspectivas de ampliação e melhorias das escolas públicas na região oeste do Paraná.
Abstract
Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm associated with poor overall survival (OS). This study (NCT04695431) compared clinical outcomes between patients with AdvSM ...treated with avapritinib in the Phase 1 EXPLORER (NCT0256198) and Phase 2 PATHFINDER (NCT03580655) trials (
N
= 176) and patients treated with best available therapy (BAT;
N
= 141). A multi-center, observational, retrospective chart review study was conducted at six study sites (four European, two American) to collect data from patients with AdvSM who received BAT; these data were pooled with data from EXPLORER and PATHFINDER. Comparisons between outcomes of OS, duration of treatment (DOT), and maximum reduction in serum tryptase were conducted between the treatment cohorts, with adjustment for key covariates. The results indicated that the avapritinib cohort had significantly better survival (adjusted hazard ratio (HR) (95% confidence interval (CI)): 0.48 (0.29, 0.79);
p
= 0.004) and significantly longer DOT (HR: 0.36 (0.26, 0.51);
p
< 0.001) compared to the BAT cohort. Additionally, the mean difference in percentage maximum reduction in serum tryptase levels was 60.3% greater in the avapritinib cohort (95% CI: −72.8, −47.9;
p
< 0.001). With no randomized controlled trials comparing avapritinib to BAT, these data offer crucial insights into the improved efficacy of avapritinib for the treatment of AdvSM.
Background:
In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts ...compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited.
Aim:
To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders.
Patients and methods:
In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim.
Results:
Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented.
In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative (<0.8 U/mL) in 27/175 (15.4%) patients. The distribution of the negative cohort regarding the disease subgroups were as followed: myeloid neoplasms 7/27 (25.9%), lymphoid neoplasms 16/27 (59.3%), non-malignant hematological disease 4/27 (14.8%). Within the negative cohort, 21/27 (77.8%) were treated on active therapy, 6/27 (22.2%) were previously treated or treatment naïve.
In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response.
In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL).
In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result.
Conclusion:
A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients.
Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials.
Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; ...FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 10
/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 10
/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
Systemic mastocytosis (SM) is characterized by expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between ...indolent SM (ISM) and advanced SM (AdvSM). ISM patients usually present with a low mast cell burden and have a nearly normal life expectancy while AdvSM patients have a high disease burden, multiple organ damage and poor prognosis. In ISM patients, measurement of the bone mineral density (BMD) frequently reveals osteopenia and osteoporosis (lumbar spine BMD T-score of ≤ −2.5 standard deviation SD). In contrast, the association between increased BMD and osteosclerosis, respectively, and the various SM subtypes is unclear. We therefore sought to evaluate the BMD in 61 patients (ISM, n = 29, 48%; AdvSM, n = 32, 52%) and correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters and prognosis. All patients were scanned on the same 16 row CT Scanner (SOMATOM Emotion 16, Siemens Healthcare Sector, Forchheim, Germany). The results were expressed as T-score (SD below the mean of young healthy adults) and as Z-score (SD below the age- and gender-matched mean reference value). According to established WHO criteria, osteoporosis was defined as a lumbar spine BMD T-score of ≤ −2.5 SD. Increased BMD and osteosclerosis were defined as Z-score > 1 SD and > 2 SD, respectively. Osteoporosis was detected in 11/29 (38%) patients with ISM and 2/32 (6%) patients with AdvSM (p = 0.004). Bone marrow mast cell infiltration (median 10% versus 20%, p=0.035) and serum tryptase levels (median 31 µg/L versus 58 µg/L, p = 0.047) were significantly lower in ISM patients with osteoporosis as compared to those without osteoporosis (n=18, 62%). No significant differences were seen regarding age, gender, blood counts, and overall survival. An elevated BMD was detected in 1/29 (3%) patient with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD were older (median 77 years versus 68 years, p = 0.0043), had lower platelet counts (median 111 x 109/L versus 238 x 109/L, p = 0.041) and higher levels of bone marrow mast cell infiltration (50% versus 10%, p=0.002), serum tryptase (median 262 µg/L versus 62 µg/L, p = 0.003) and alkaline phosphatase (238 U/L versus 74 U/L, p < 0.0001). In consequence, prognosis of AdvSM patients with increased BMD was significantly inferior as compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). In conclusion, i) osteoporosis is a common feature in ISM but not in AdvSM patients, ii) an increased BMD is frequent in AdvSM but not in ISM patients, iii) osteosclerosis is restricted to AdvSM patients, and iv) an elevated BMD is associated with a more aggressive phenotype and inferior survival (Figure A-B).
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Fabarius:Novartis: Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement.
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