Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Idiopathic systemic capillary leak syndrome (ISCLS) flares are frequently preceded by infections, particularly respiratory virus infections including coronavirus disease 2019.1,2 Hemodynamic collapse occurs at the onset of episodes, typically followed by massive peripheral edema resulting from intravenous (IV) fluid administration. Flares may be complicated by multiorgan dysfunction syndrome, vascular thrombosis due to hemoconcentration, and compartment syndrome.1 Indefinite monthly prophylaxis with high-dose intravenous immunoglobulins (IVIGs) induces disease remission but is expensive and inconvenient to administer.

Systemic Mastocytosis (SM) is characterized by an aberrant expansion of clonal mast cells in specific tissues including the skin, marrow, liver, and the gastrointestinal tract, which may cause symptoms such as abdominal pain, diarrhea, and weight loss. Demonstration of an interplay between these manifestations and the GI and oral microbiome in patients with SM is of interest. In addition to gathering clinical and laboratory information, we prospectively collected stool and buccal swab samples from 20 patients with SM and from 10 healthy volunteers (HVs). 16S rRNA sequencing identified bacterial phylogeny and taxonomy within the samples. Qiime2 workflow was employed and correlations between microbe abundance and demographic/clinical variables were determined. We observed no significant difference in microbial alpha-diversity but detected slight clustering in the PCoA plot of Bray Curtis beta-diversity between the patient and control groups. Lefse analysis identified unique Taxa amongst the Ruminococcaceae family that were significantly more abundant in patients with SM. In stool and buccal swabs, significant correlations were identified when comparing data from those with SM and HVs between specific taxa and clinical parameters including age, quality of life, bacterial translocation markers, liver fibroscan, serum alkaline phosphatase, and serum KIT D816V allelic frequency. Comparing stool and buccal swab samples in patients with SM and HVs, we found Alpha, and Beta-diversity were not significantly different. However, specific taxa correlated with relevant clinical and laboratory parameters, suggesting a possible impact of the microbiome on clinical disease in SM and the possible use of probiotics in management of disease symptoms.

Mastocytosis is a disorder of clonal mast cell proliferation with clinical features that include episodic flushing, pruritus, abdominal pain, diarrhea, and syncope.1 The clinical manifestations of mastocytosis are thought in part to be a result of the effects of mediators released from activated mast cells.2 Physical factors, such as heat, mechanical stimulation, and exercise, have been reported to increase symptoms. In some patients with mastocytosis, exercise has been reported to provoke anaphylaxis.

BACKGROUND: Mastocytosis is a clonal mast cell disorder associated with elevated mast cell mediators, which themselves have been reported to affect lymphocyte function. However, the impact of an expanded mast cell compartment on lymphocyte subpopulations, and their correlation with clinical phenotypes in patients with indolent systemic mastocytosis (ISM), has not been explored. OBJECTIVE: To examine the immunophenotype of circulating lymphocytes in patients with ISM compared with healthy adult controls and examine relationships with aspects of clinical disease. METHODS: We examined lymphocyte subsets in 20 adult patients with ISM and 40 healthy adult volunteers by multiparameter flow cytometry. Results were correlated with clinical characteristics. RESULTS: Patients with ISM exhibited a significantly lower median frequency and absolute cell count of both circulating CD8(+) T cells and natural killer cells accompanying a significantly increased ratio of CD4(+)/CD8(+) T cells when compared with healthy volunteers. Stratification of our ISM patient cohort according to clinical manifestations revealed that CD19(+)CD21(low)CD38(low) B cells were significantly higher in patients with a history of autoimmune disease and counts of terminally differentiated CD4(+) T cells were significantly higher in patients with osteoporosis or osteopenia. CONCLUSIONS: Several circulating lymphocyte subpopulations in patients with ISM were significantly different when compared with healthy controls; in specific lymphocyte subsets, this lymphocyte skewing correlated with clinical observations including osteoporosis and autoimmune disease. These data suggest the need for further studies on abnormalities in lymphocyte subsets and the attendant clinical consequences in both mast cell proliferative and activation disorders. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

Mastocytosis is a clonal disorder of aberrant mast cell proliferation and burden. Symptoms are associated with excessive mast cell mediator release. Mast cell mediators have been reported to affect lymphocyte differentiation and function, but lymphocyte subsets have not been characterized in detail and correlated with clinical findings in patients with mastocytosis. Peripheral blood mononuclear cells (PBMCs) from 20 patients with indolent systemic mastocytosis (ISM) were analyzed to quantitate lymphocyte subpopulations by flow cytometry and correlated with clinical parameters of disease. DNA was extracted from patient PBMCs and analyzed to determine the allelic frequency of the mastocytosis-associated KITD816V mutation. The median frequency and absolute cell count of all lymphocyte subsets examined in this cohort were found to be within the normal range of healthy adult individuals. We then stratified the results according to clinical manifestations (autoimmunity, atopic disease, anaphylaxis, cancer, osteoporosis/osteopenia and chronic/recurrent infections) to determine if the lymphocytes subsets correlated any of these manifestations. We observed the median % (p=0.032) and absolute count (p=0.015) of CD19+CD21lowCD38lowB cells were significantly higher in patients with a history of autoimmune disease. Counts of terminally differentiated CD4+ T cells were significantly higher in patients with osteoporosis (p=0.038) or osteopenia (p=0.045). Lymphocyte subsets in the peripheral blood of patients with ISM were in general not significantly different from those of the general population. Extensive lymphocyte phenotyping of PBMCs may, however, be able to help predict or monitor some specific clinical manifestations associated with ISM.

GATA proteins are lineage-restricted transcription factors that regulate tissue-specific patterns of gene expression, principally during development. GATA-2 is expressed in hematopoietic stem cells and multilineage progenitors, where it plays essential roles in their maintenance and proliferation.1 Indeed, Gata2-null mice succumb at embryonic day 10.5 with severe anemia caused by bone marrow failure.2 GATA-2 also appears to regulate early mast cell gene expression3,4 and has been shown to positively regulate mast cell identity in model systems.

The use of allele-specific quantitative polymerase chain reaction to identify KIT D816V in the peripheral blood of adults with mastocytosis has been reported to have value in the diagnosis, assessment of disease burden and management of this disease. To examine the value of this assay in children with cutaneous manifestations of mastocytosis, we assessed data on 65 patients with all variants of paediatric-onset mastocytosis, including those known to have systemic disease, to correlate KIT mutation status with clinical findings, serum tryptase levels and bone marrow histopathology. We found that KIT D816V was not identified in the peripheral blood of children known to have only cutaneous disease (specificity 100%) but was found in those known to have both cutaneous and systemic/probable systemic disease (sensitivity of 85·2%). These findings were the basis of the development of an algorithm to assist in the decision for when to perform a bone marrow biopsy in children presenting with cutaneous manifestations of mastocytosis.

Peripheral T-cell lymphomas (PTCLs) are a rare group of lymphoid neoplasms with high relapse rates after initial therapy and poor prognosis. Most patients are aged 60 years and are often not candidates for aggressive salvage therapies. Romidepsin, a potent class I histone deacetylase inhibitor, has shown significant single-agent activity in relapsed/refractory PTCL. We evaluated the efficacy and tolerability of romidepsin in elderly patients in this setting. Ninety-five patients aged 60 years were identified from 2 prospective phase 2 registration trials of romidepsin, and comparative analyses were performed with younger patients from these trials. Response rates, progression-free survival, and overall survival were not statistically different for younger vs older patients. The toxicity profile in older and younger patients was similar in both trials. Romidepsin demonstrated similar efficacy and tolerability in younger and older patients and presents an attractive treatment option for relapsed/refractory PTCL regardless of age.

Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naïve. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

Background PTCL is a heterogeneous group of mature, post-thymic, T- and natural killer–cell disorders associated with a poor prognosis in most subtypes. Anthracycline-based therapies (eg, CHOP) are most often used in the frontline treatment of PTCL, although they do not typically lead to durable remissions. Older patients may not be eligible for additional chemotherapeutic regimens due to comorbidities and/or poor performance status. Thus, it is important to identify appropriate treatment strategies for older patients with PTCL, particularly in the salvage setting. Romidepsin is a potent class I histone deacetylase inhibitor approved by the FDA for the treatment of patients with PTCL who have received ≥ 1 prior therapy and patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy. Approval of PTCL was based on results from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL (N = 131) that demonstrated durable clinical benefit and tolerability and was supported by a similar study from the National Cancer Institute (N = 47). The objective herein is to present efficacy and safety data for romidepsin specific to older patients (≥ 60 years) with relapsed/refractory PTCL in the pivotal and supportive trials. Methods In both trials, patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles. For the pivotal trial, the primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee. For the supportive trial, the primary endpoints were objective response rate (ORR) and rate of CR by investigator assessment. In this analysis, efficacy and safety data for patients ≥ 60 years old were examined and compared with those for the overall study population. Results In the pivotal study , the overall median age was 61 years (range, 20-83); 71/130 patients (55%) were ≥ 60 years old (median 67 years [range, 60-83]) with a median of 2 prior systemic therapies (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 25% ORR for both populations, including 14% and 15% with CR/CRu for older vs overall populations, respectively. Also, in both the older and overall populations, the median DOR was 28 months, with the longest response ongoing at 48 months (median follow-up 22.3 months). Of the 10 older patients who achieved CR/CRu, 6 had a DOR of ≥ 12 months. Survival was also similar, with 5 and 4 months PFS and 12 and 11 months OS for the older vs overall populations, respectively. In the supportive trial , the overall median age was 60 (range, 27-84); 23/47 patients (49%) were ≥ 60 years old (median 68 years [range, 61-84]) with a median of 2 prior regimens (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 32% and 38% ORR, including 14% and 18% with CR, respectively. The median DOR was 5 months (range, 3-49) and 9 months (range, 2-74+) for the older vs overall populations, respectively. One 79-year-old patient with 6 prior systemic therapies achieved CR on romidepsin and stopped therapy after 6 cycles in consideration of his age. Off therapy, disease progression was observed; romidepsin was restarted per protocol and patient achieved a second CR, receiving an additional 22 cycles of therapy. In both the pivotal and supportive trials , rates of grade ≥ 3 adverse events were similar for the overall vs older patient populations ([Table][1]). View this table: Table Grade ≥ 3 Adverse Events Reported in ≥ 5% of Patients in the Pivotal Study, % Conclusions In phase 2 trials of romidepsin for the treatment of relapsed/refractory PTCL, patients aged ≥ 60 years comprised approximately half of patients. Both efficacy and safety were similar for the older vs overall populations. Thus, data were not skewed due to age, and romidepsin is suitable for use in elderly patients with relapsed/refractory PTCL. Disclosures: Shustov: Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Coiffier: Celgene Corporation: Consultancy; Spectrum Pharmaceuticals: Consultancy. Horwitz: Celgene Corporation: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Gen: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Kyowa Hakko Kirin Pharma: Research Funding; Millenium: Consultancy, Research Funding; Genzyme: Consultancy; Janssen: Consultancy. Sokol: Celgene Corporation: Consultancy, Speakers Bureau; Gloucester: Research Funding. Pro: Celgene Corporation: Honoraria. Nielsen: Celgene Corporation: Employment, Equity Ownership. Balser: Celgene Corporation: Consultancy. Prince: Celgene Corporation: Honoraria, Research Funding. Allen: Celgene Corporation: Honoraria. Bates: Celgene Corporation: Research Funding. [1]: #T1