ABSTRACT
BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.
ABSTRACT
Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1-2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2-12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions.
ABSTRACT
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.
Subject(s)
Eosinophilia , Hypereosinophilic Syndrome , Hypersensitivity , Humans , Eosinophils/pathology , Eosinophilia/diagnosis , Eosinophilia/etiology , Eosinophilia/drug therapy , Syndrome , Hypersensitivity/complications , Hypereosinophilic Syndrome/etiology , Hypereosinophilic Syndrome/complicationsABSTRACT
We sought to evaluate the efficacy of the purine analogue cladribine in 79 patients with advanced systemic mastocytosis (AdvSM) using data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. The overall response rate according to modified Valent criteria (46 evaluable patients) for first- (1L) and second-line (2L) cladribine treatment was 41% (12/29) and 35% (6/17, P = 0.690), respectively, and the median overall survival (OS, all patients evaluable) was 1.9 years (n = 48) and 1.2 years (n = 31; P = 0.311). Univariate and multivariable analyses of baseline and on-treatment parameters identified diagnosis of mast cell leukemia (hazard ratio [HR] 3.5, 95% confidence interval [CI, 1.3-9.1], P = 0.012), eosinophilia ≥ 1.5 × 109/L (HR 2.9 [CI 1.4-6.2], P = 0.006) and < 3 cycles of cladribine (HR 0.4 [CI 0.2-0.8], P = 0.008) as independent adverse prognostic parameters for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1) on OS. In consequence, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) was predictive for OS. Modified Valent criteria were superior to a single factor-based response assessment (HR 2.9 [CI 1.3-6.6], P = 0.026). In conclusion, cladribine is effective in 1L and 2L treatment of AdvSM. Mast cell leukemia, eosinophilia, application of < 3 cycles and a lack of response are adverse prognostic markers.
Subject(s)
Leukemia, Mast-Cell , Mastocytosis, Systemic , Humans , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/drug therapy , Mastocytosis, Systemic/genetics , Cladribine/therapeutic use , Leukemia, Mast-Cell/drug therapy , Leukemia, Mast-Cell/genetics , Prognosis , RegistriesABSTRACT
COVID-19 in patients with hematological diseases is associated with a high mortality. Moreover, preventive vaccination demonstrated reduced efficacy and the knowledge on influencing factors is limited. In this single-center study, antibody levels of the SARS-CoV-2 spike protein were measured ≥ 2 weeks after 2nd COVID-19 vaccination with a concentration ≥ 0.8 U/mL considered positive. Between July and October 2021, in a total of 373 patients (median age 64 years, 44% women) with myeloid neoplasms (n = 214, 57%), lymphoid neoplasms (n = 124, n = 33%), and other diseases (n = 35, 10%), vaccination was performed with BNT162b2 (BioNTech), mRNA-1273 (Moderna), ChADOx1 (AstraZeneca), or a combination. A total of 229 patients (61%) were on active therapy within 3 months prior vaccination and 144 patients (39%) were previously treated or treatment naïve. Vaccination-related antibody response was negative in 56/373 patients (15%): in 39/124 patients with lymphoid neoplasms, 13/214 with myeloid neoplasms, and 4/35 with other diseases. Active treatment per se was not correlated with negative response. However, rituximab and BTK inhibitor treatment were correlated significantly with a negative vaccination response, whereas younger age and chronic myeloid leukemia (CML) disease were associated with positive response. In addition, 5 of 6 patients with myeloproliferative neoplasm (MPN) and negative vaccination response were on active treatment with ruxolitinib. In conclusion, a remarkable percentage of patients with hematological diseases had no response after 2nd COVID-19 vaccination. Multivariable analysis revealed important factors associated with response to vaccination. The results may serve as a guide for better protection and surveillance in this vulnerable patient cohort.
Subject(s)
Antibody Formation , COVID-19 Vaccines , COVID-19 , Hematologic Diseases , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Hematologic Diseases/complications , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Male , Middle Aged , Myeloproliferative Disorders/complications , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Treatment Failure , VaccinationABSTRACT
BACKGROUND: 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. OBJECTIVE: To determine the incidence and severity of CMIHR in all subtypes of SM. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Arthropod Venoms , Mastocytosis, Systemic , Mastocytosis , Adult , Contrast Media/adverse effects , Humans , Magnetic Resonance Imaging , Retrospective StudiesABSTRACT
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.
Subject(s)
Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Point Mutation , Proto-Oncogene Proteins c-kit/genetics , Adult , Aged , Aged, 80 and over , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Humans , Male , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/pathology , Middle Aged , Myeloproliferative Disorders/pathologyABSTRACT
The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Disease Management , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Systemic/drug therapy , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Diphosphonates/therapeutic use , Expert Testimony , Glucocorticoids/adverse effects , Histamine Antagonists/therapeutic use , Humans , Immunosuppressive Agents/adverse effects , Mast Cells/drug effects , Mast Cells/immunology , Mast Cells/pathology , Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/epidemiology , Mastocytosis, Cutaneous/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/epidemiology , Mastocytosis, Systemic/pathology , Myeloablative Agonists/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Precision Medicine/methods , Risk Factors , SARS-CoV-2 , Vitamin D/therapeutic useABSTRACT
Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is KIT p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in TET2, SRSF2, ASXL1, RUNX1, CBL and JAK2, and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (IL13, IL6, IL6R, IL31, IL4R) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased TPSAB1 copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.
Subject(s)
Cytokines/genetics , Mastocytosis, Systemic/genetics , Polymorphism, Genetic , Proto-Oncogene Proteins c-kit/genetics , Toll-Like Receptor 2/genetics , Humans , Interleukin-13/genetics , Interleukin-6/genetics , Interleukins/genetics , Mast Cells/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/metabolism , Mastocytosis, Systemic/physiopathology , Nerve Tissue Proteins/genetics , Phospholipase C gamma/genetics , Proto-Oncogene Proteins c-kit/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, Neuropeptide/genetics , Toll-Like Receptor 2/metabolismABSTRACT
In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the KIT D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), n = 40; advanced SM, AdvSM, n = 121) at referral and during follow-up for the KIT D816V variant allele frequency (VAF) at the DNA-level and the KIT D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (r > 0.99, R2 > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (r = 0.91, coefficient of determination, R2 = 0.84) but only to a lesser extent in AdvSM (r = 0.71; R2 = 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; p = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (p = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of KIT D816V may play an important role in the pathophysiology of SM.
Subject(s)
Mastocytosis, Systemic/genetics , Mutation , Proto-Oncogene Proteins c-kit/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Bone Marrow/metabolism , DNA/blood , DNA/genetics , DNA/metabolism , Female , Gene Frequency , Humans , Male , Mastocytosis, Systemic/blood , Mastocytosis, Systemic/metabolism , Middle Aged , Phenotype , Prognosis , Proto-Oncogene Proteins c-kit/metabolism , RNA/blood , RNA/genetics , RNA/metabolism , Transcription, GeneticABSTRACT
We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.
Subject(s)
Hematologic Neoplasms , Myeloproliferative Disorders , Oncogene Proteins, Fusion , Protein Kinase Inhibitors/administration & dosage , Protein-Tyrosine Kinases , Adult , Aged , Disease-Free Survival , Female , Follow-Up Studies , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/enzymology , Hematologic Neoplasms/genetics , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/enzymology , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/mortality , Oncogene Proteins, Fusion/antagonists & inhibitors , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Protein Kinase Inhibitors/adverse effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Survival RateABSTRACT
In advanced systemic mastocytosis (advSM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 [S/A/Rpos in >60% of cases]). In a recently reported phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/Rneg (n = 12) and S/A/Rpos (n = 23) patients (ORR: 75% vs 39%, P = .04; OS: P = .01, HR 4.5 [1.3-16.2]). Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, patients were classified as KIT responders (≥25%, n = 17) or KIT nonresponders (<25%, n = 11). In univariate analyses at month 6, reduction of KIT D816V EAB ≥25%, tryptase ≥50%, and alkaline phosphatase ≥50% were significantly associated with improved OS. In multivariate analysis, only KIT D816V EAB reduction ≥25% remained an independent on-treatment marker for improved OS (P = .004, HR 6.8 [1.8-25.3]). Serial next-generation sequencing analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly affect response, progression, and prognosis.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Mastocytosis, Systemic/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-kit/genetics , Staurosporine/analogs & derivatives , Aged , Alleles , Biomarkers, Tumor/metabolism , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , Disease Progression , Female , Gene Expression , Humans , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Male , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/mortality , Middle Aged , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleophosmin , Prognosis , Proto-Oncogene Proteins c-kit/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , Staurosporine/therapeutic use , Survival AnalysisABSTRACT
Systemic mastocytosis (SM) is broadly subcategorized according to mast cell (MC) burden and organ involvement into indolent (ISM), smoldering (SSM), and advanced SM (AdvSM). However, the pattern and extent of bone involvement remains controversial. In this institutional review board (IRB)-approved study, 115 patients with different forms of SM (ISM (n = 37, 32%), SSM (n = 9, 8%), and AdvSM (n = 69, 60%)) underwent a whole-body magnetic resonance imaging including sagittal and coronal T1 and turbo inversion recovery magnitude (TIRM) sequences of the spine. The evaluation included the pattern and extent of pathologic bone marrow (BM) signals in the spine and extremities, osteolytic lesions, and vertebral fractures. A pathologic BM pattern was observed in 4/37 (11%), 8/9 (89%), and 66/69 (96%); affection of the appendicular skeleton in 3/37 (8%), 8/9 (89%), and 67/69 (97%); and vertebral fractures in 7/37 (19%), 0/9, and 13/69 (19%) patients with ISM, SSM, and AdvSM, respectively. In AdvSM, pathologic BM pattern included activated (62%), diffuse sclerotic (25%), and small-spotted BM (9%), respectively. Only activated/sclerotic BM was associated with significantly higher MC burden, organ damage, and inferior median survival (2.9 years, p = 0.04). Vertebral fractures resembled classical multi-segmental osteoporotic fractures in ISM but not in AdvSM in which they were only found in activated/sclerotic BM. Only one patient with AdvSM had a focal osteolytic lesion in the femur. Activated/sclerotic BM changes of the spine and affection of the appendicular skeleton are indicative for SSM or AdvSM. Osteolytic lesions, which are very rare, and osteoporotic fractures are ineligible for the diagnosis of AdvSM.
Subject(s)
Bone Marrow/diagnostic imaging , Magnetic Resonance Imaging , Mastocytosis, Systemic , Whole Body Imaging , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Mastocytosis, Systemic/diagnostic imaging , Mastocytosis, Systemic/mortality , Middle Aged , Retrospective Studies , Survival RateABSTRACT
The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n = 102, 94%) with indolent (ISM, n = 26) and advanced SM (n = 83) with (n = 73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype, additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, for example, monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n = 7) or mast cell leukemia (n = 1) within a median of 40 months (range 2-190, P = .04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P < .0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM ± AHN because these investigations greatly support prognostication and treatment decisions.
Subject(s)
Mastocytosis, Systemic/genetics , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Chromosome Disorders , Cytogenetic Analysis/methods , Cytogenetics/methods , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Humans , Incidence , Karyotyping , Male , Mastocytosis, Systemic/metabolism , Middle Aged , Mutation , Phenotype , Prognosis , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 µg/mL) compared with CD30(-) HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM.
Subject(s)
Immunoconjugates/pharmacology , Ki-1 Antigen/biosynthesis , Mast Cells/metabolism , Mastocytosis, Systemic/metabolism , Animals , Apoptosis/drug effects , Brentuximab Vedotin , Cell Proliferation/drug effects , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Heterografts , Humans , Immunohistochemistry , Ki-1 Antigen/antagonists & inhibitors , Mast Cells/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Polymerase Chain ReactionABSTRACT
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 µg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.
Subject(s)
Disease Progression , Hematologic Neoplasms/complications , Leukemia, Mast-Cell/genetics , Mutation , Cladribine/therapeutic use , Core Binding Factor Alpha 2 Subunit/genetics , Female , Humans , Leukemia, Mast-Cell/complications , Leukemia, Mast-Cell/drug therapy , Leukemia, Mast-Cell/mortality , Male , Mastocytosis, Systemic/mortality , Middle Aged , Prognosis , Repressor Proteins/genetics , Serine-Arginine Splicing Factors/genetics , Staurosporine/analogs & derivatives , Staurosporine/therapeutic use , Survival RateABSTRACT
We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13)â. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,
Subject(s)
Blast Crisis , Eosinophilia , Gene Rearrangement , Hematologic Neoplasms , Imatinib Mesylate/administration & dosage , Receptor, Platelet-Derived Growth Factor beta/genetics , Abnormal Karyotype , Adult , Aged , Aged, 80 and over , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/mortality , Blast Crisis/pathology , Disease-Free Survival , Eosinophilia/drug therapy , Eosinophilia/genetics , Eosinophilia/mortality , Eosinophilia/pathology , Female , Follow-Up Studies , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/genetics , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Sex Factors , Survival RateABSTRACT
BACKGROUND: Bone marrow (BM) histology/immunohistochemistry, KIT D816V mutation analysis and serum tryptase measurements are mandatory tools for diagnosis of systemic mastocytosis (SM). MATERIALS AND METHODS: Within the 'German Registry of Disorders on Eosinophils and Mast Cells', we identified 65 patients with SM who had two consecutive BM biopsies. The first biopsy was evaluated by a local pathologist (LP) and the second biopsy by a reference pathologist (RP) of the 'European Competence Network on Mastocytosis (ECNM)'. RESULTS: Final diagnoses by RP were SM (n = 27), SM or aggressive SM (ASM) with associated clonal haematological non-mast cell lineage disease [(A)SM-AHNMD, n = 34)] or mast cell leukaemia ± AHNMD (n = 4). In 15 of 65 patients (23%), initial diagnoses by LP were incorrect (by overlooking SM), for example primary myelofibrosis (n = 3), myelodysplastic/myeloproliferative neoplasm unclassified (n = 3) or B-cell lymphoma (n = 2). Fourteen of 15 patients (93%) with incorrect diagnosis had an advanced SM, mostly (A)SM-AHNMD. In the 50 concordantly diagnosed patients, immunohistochemical markers for quantitative assessment of mast cell infiltration, for example CD117 (KIT) or CD25, were applied by LP in only 34 of 50 patients (68%), and mutational analysis for KIT D816V was performed or recommended in only 13 of 50 patients (26%). Finally, the subclassification of SM was discordant because LP did not diagnose AHNMD in nine of 50 (18%) patients. CONCLUSIONS: In summary, adequate diagnosis and subclassification of SM requires an in-depth evaluation of the BM by experienced haematopathologists (preferably in a reference centre) in combination with molecular genetics, serum tryptase level and clinical parameters.
Subject(s)
Bone Marrow/pathology , Diagnostic Errors , Mastocytosis, Systemic/pathology , Pathology, Clinical/organization & administration , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , Female , Humans , Immunohistochemistry , Interleukin-2 Receptor alpha Subunit/metabolism , Leukemia, Mast-Cell/diagnosis , Leukemia, Mast-Cell/pathology , Lymphoma, B-Cell/diagnosis , Male , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/metabolism , Middle Aged , Mutation , Myelodysplastic Syndromes/diagnosis , Myeloproliferative Disorders/diagnosis , Pathology, Clinical/standards , Primary Myelofibrosis/diagnosis , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Retrospective StudiesABSTRACT
The FIP1L1-PDGFRA (FP) fusion gene is identified in a substantial proportion of patients with eosinophilia-associated myeloproliferative neoplasms (MPN-eo) who subsequently achieve rapid and durable remissions on imatinib. In the initial diagnostic work-up of hypereosinophilia (HE), histologic and immunohistochemical evaluation of a bone marrow (BM) core biopsy is considered essential for the differentiation between reactive hypereosinophilia (HER), MPN-eo and hypereosinophilic syndrome (HES). We therefore retrospectively analysed the initial reports of BM core biopsies from 116 patients who were subsequently identified as FP positive (FP+, n = 56) or FP negative/corticosteroid-responsive HER or HES (n = 60). Compared to HER or HES, detection of FP was more frequently associated with increased numbers of blasts (11/56 vs. 2/60, p = 0.007) and mast cells (23/33 vs. 7/23, p = 0.006; with expression of CD25 [11/18 vs. 2/13, p = 0.025]), and/or fibrosis (25/35 vs. 1/23, p < 0.0001). In FP+ patients, HE was correctly associated with an underlying clonal haematologic disorder in only 36/56 (64 %) of cases, but final BM diagnoses included a variety of diagnoses such as MPN-eo (n = 15), acute myeloid leukaemia (n = 8), systemic mastocytosis (n = 6), chronic myeloid leukaemia (n = 5) or unclassified MPN (n = 2). We conclude that the final evaluation of BM core biopsies in the diagnostic work-up of HE should include comprehensive morphologic (stains for myeloid blast cells, mast cells and fibres) and genetic analyses before a final diagnosis is established.
Subject(s)
Bone Marrow/pathology , Hypereosinophilic Syndrome/diagnosis , Hypereosinophilic Syndrome/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy/methods , Biopsy/standards , Female , Humans , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Retrospective Studies , Young Adult , mRNA Cleavage and Polyadenylation Factors/geneticsABSTRACT
In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5'-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions.