Goodbye etoposide? Taking the leap to ruxolitinib in haemophagocytic lymphohistiocytosis.

Fang et al. report a retrospective analysis of paediatric patients with haemophagocytic lymphohistiocytosis (HLH) associated with autoimmune/autoinflammatory disorders treated with ruxolitinib. Responses were impressive and rapid, and ruxolitinib was well tolerated. This study demonstrates that a subset of patients with HLH can be treated with JAK inhibition without the need for cytotoxic chemotherapy. Further work will be needed to better define patient selection for therapy, as some patient groups and HLH triggers, such as malignancy-associated HLH, may be better suited for etoposide-based therapy. Commentary on: Fang et al. Ruxolitinib-based regimen in children with autoimmune disease or autoinflammatory disease related hemophagocytic lymphohistiocytosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19803.

Rosai-Dorfman-Destombes disease in adults: a single center experience.

Recent advances in Rosai-Dorfman-Destombes disease (RDD), notably molecular testing, targeted therapy, and PET-CT imaging, hold promise for better recognition and improved outcomes. This study presents patients diagnosed and treated in a "real world" setting, where navigating limited resources must be considered. This retrospective single-center review includes 15 adult patients diagnosed with RDD at Vancouver General Hospital between November 2015 and October 2023. The cohort comprised five males and ten females with a median age 53 years (range 19-80 years). All 15 patients had extra-nodal disease; 11 patients exclusively had extra-nodal disease, and four patients also had lymph node involvement. Seven patients had tissue next-generation sequencing, identifying MAP2K1 mutations in four cases and a KRAS p.K117N mutation in one case that was treated with targeted therapy using trametinib. PET-CT was used for disease staging in four cases. Six patients with refractory disease tolerated lenalidomide and dexamethasone without significant toxicity; three patients achieved complete response, and three had partial response. This study highlights RDD's diverse extra-nodal manifestations. Lenalidomide combined with dexamethasone is an effective and well-tolerated treatment option for select patients, especially those with refractory disease. Broad utilization of NGS and PET-CT can positively influence management decisions.

Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans. CASE SERIES: The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation. RESULTS: All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis. CONCLUSIONS: This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.

CRP and sCD25 help distinguish between adult-onset Still's disease and HLH.

OBJECTIVE: Adult-onset Still's disease (AOSD) and secondary hemophagocytic lymphohistiocytosis (sHLH) are both hyperferritinemic cytokine storm syndromes that can be difficult to distinguish from each other in hospitalized patients. The objective of this study was to compare the inflammatory markers ferritin, D-dimer, C-reactive protein (CRP), and soluble CD25 (sCD25) in patients with AOSD and sHLH. These four markers were chosen as they are widely available and represent different aspects of inflammatory diseases: macrophage activation (ferritin); endothelialopathy (D-dimer); interleukin-1/interleukin-6/tumour necrosis factor elevation (CRP) and T cell activation (sCD25). METHODS: This was a single-center retrospective study. Patients diagnosed by the Hematology service at Vancouver General Hospital for AOSD or sHLH from 2009 to 2023 were included. RESULTS: There were 16 AOSD and 44 sHLH patients identified. Ferritin was lower in AOSD than HLH (median 11 360 µg/L vs. 29 020 µg/L, p = .01) while D-dimer was not significantly different (median 5310 mg/L FEU vs. 7000 mg/L FEU, p = .3). CRP was higher (median 168 mg/L vs. 71 mg/L, p <.01) and sCD25 was lower (median 2220 vs. 7280 U/mL, p = .004) in AOSD compared to HLH. The combined ROC curve using CRP >130 mg/L and sCD25< 3900 U/mL to distinguish AOSD from HLH had an area under the curve (AUC) of 0.94 (95% confidence interval 0.93-0.97) with sensitivity 91% and specificity 93%. CONCLUSIONS: These findings suggest that simple, widely available laboratory tests such as CRP and sCD25 can help clinicians distinguish AOSD from HLH in acutely ill adults with extreme hyperferritinemia. Larger studies examining a wider range of clinically available inflammatory biomarkers in a more diverse set of cytokine storm syndromes are warranted.

VEXAS syndrome: A review of bone marrow aspirate and biopsies reporting myeloid and erythroid precursor vacuolation.

Myeloid and erythroid precursor vacuolation is a common dysplastic finding associated with myeloid malignancies, toxins, drug, and nutritional deficiencies. It has been described as a core morphologic feature in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. We sought to determine the number of cases attributable to VEXAS syndrome in bone marrow biopsies and aspirates (BAMB) reporting myeloid precursor vacuolation. We reviewed 1318 individual BAMB reports from January 2020 to July 2021 where "vacuole(s)," "vacuolation," or "vacuolated" was reported. Bone marrow biopsies with vacuolation confined to blasts or those completed as routine workup prior to stem cell transplant or post induction chemotherapy for AML (acute myeloid leukemia) were excluded. Myeloid and erythroid precursor vacuolation was noted in 219 reports representing 210 patients. The most common etiology was myelodysplastic syndrome (MDS) (38.6%), AML (16.7%), lymphoproliferative disorders and multiple myeloma (7.6%), drug or toxin exposure (5.2%) myeloproliferative neoplasm (MPN) or MPN/MDS overlap syndrome (4.3%). VEXAS syndrome was determined to be the etiology in 2.9% of patients. Two additional cases of VEXAS syndrome with bone marrow biopsies reported in the specified time frame did not explicitly report myeloid or erythroid precursor vacuolation but were identified based on clinical suspicion and repeat BAMB review. Myeloid and erythroid precursor vacuolation is a dysplastic feature attributable to VEXAS syndrome in at least 2.9% of cases. Standardized reporting of vacuolization, triaging of molecular sequencing and optimal treatment of this disorder are critical issues facing those seeing patients with suspected VEXAS syndrome.

A young woman with persistent sore throat, Epstein-Barr virus, lymphadenopathy, and aberrant CD4 + CD7- T-cells.

A young woman with persistent EBV viremia and lymphocytosis had an abnormal CD4- T cell population with aberrant loss of CD7. She had a diagnosis of chronic active EBV (CAEBV), a lymphoproliferative disorder for which she ultimately required allogeneic hematopoietic stem cell transplantation.

Inflammatory diseases in hematology: a review.

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category is monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations that may be germline (e.g., deficiency of ADA2 or GATA2 deficiency) or somatic [e.g., vacuoles, enzyme E1, X-linked, autoinflammatory, somatic (VEXAS) syndrome]. The second category is the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis, and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-γ, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. Although this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, noninvasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and underrecognized diseases.

IgG4-related prostatitis manifesting as urinary obstruction in a 28-year-old male.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and tumefactive lesions that can involve nearly every organ system. Involvement of the prostate is rare but has been reported in limited cases. CASE PRESENTATION: A 28-year-old man of Asian descent with a history of sinusitis and priapism presented to hospital with rigors and voiding symptoms. He was diagnosed with IgG4-RD one month prior to presentation, following pathological analysis of a submandibular mass that demonstrated chronic sclerosing sialadenitis. On presentation, white blood cell count, C-reactive protein, and prostate serum antigen levels were all within normal limits. Examination was notable for a large, firm prostate, and a foley catheter was inserted. Contrast CT of the abdomen was unremarkable. Further workup revealed elevated serum IgG4 levels (9.22 g/L) and he was subsequently started on prednisone 35 mg daily. Imaging to screen for systemic IgG4-RD involvement demonstrated paravertebral soft tissue involvement and he was given rituximab 1000 mg IV × 2 doses. MRI revealed diffuse prostatitis. Five days after starting prednisone and one day after his first dose of rituximab, he successfully passed trial of void and was discharged home. CONCLUSIONS: IgG4-related prostatitis is a rare and underrecognized manifestation of IgG4-RD. Our case highlights the need to consider IgG4-related prostatitis as an etiology of urinary obstruction in young individuals. Resolution of symptoms following treatment with steroids may be diagnostic of IgG4-related prostatitis, and may potentially avoid the need for invasive diagnostic procedures such as prostate biopsy.

Treatment of lymphocyte-variant hypereosinophilic syndrome (L-HES): what to consider after confirming the elusive diagnosis.

Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin-5 (IL-5). Treatment is challenging because L-HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L-HES. In all, 25 studies were selected; two were randomised controlled trials of IL-5 blockade, which included some patients with L-HES, and the rest were observational studies. Corticosteroids are often used as first-line therapy, but patients with L-HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon-alpha (IFN-α), anti-IL-5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T-cell activation and proliferation, or IL-5 directly. Although effective, IFN-α and cyclosporine were commonly reported to cause side-effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti-IL-5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L-HES.

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.

Causes of hypereosinophilia in 100 consecutive patients.

BACKGROUND: Hypereosinophilia (HE, persistent peripheral blood eosinophilia > 1.5 × 109 /L) and hypereosinophilic syndrome (HES, HE with end-organ damage) are classified as primary (due to a myeloid clone), secondary (due to a wide variety of reactive causes), or idiopathic. Diagnostic evaluation of eosinophilia is challenging, in part because secondary causes of HE/HES such as lymphocyte-variant HES (L-HES) and vasculitis are difficult to diagnose, and emerging causes such as immunoglobulin G4-related disease (IgG4-RD) have rarely been examined. OBJECTIVE AND METHODS: We reviewed 100 consecutive patients with HE/HES who underwent extensive evaluation for primary and secondary eosinophilia at a single tertiary care center to determine causes of HE/HES in a modern context. RESULTS: Six patients had primary HE/HES, 80 had a discrete secondary cause identified, and 14 had idiopathic HE/HES. The most common causes of secondary eosinophilia were L-HES/HES of unknown significance (L-HESus) (20), IgG4-RD (9), and eosinophilic granulomatosis with polyangiitis (EGPA) (8). CONCLUSIONS: In contrast to other large published series of HE/HES, most patients in this study were found to have a discrete secondary cause of eosinophilia and only 14 were deemed idiopathic. These findings highlight the importance of extensive evaluation for secondary causes of eosinophilia such as L-HES, IgG4-RD, and EGPA.

IgG4-related disease: what a hematologist needs to know.

IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.

Resolution of Spurious Immunonephelometric IgG Subclass Measurement Discrepancies by LC-MS/MS.

BACKGROUND: The Binding Site immunonephelometric (IN) IgG subclass reagents (IgG1, IgG2, IgG3, IgG, BSIN) are used for assessment of both immunodeficiency and IgG4-related disease (IgG4-RD). In our laboratory, suspected analytic errors were noted in patients with increases in IgG4: The sum of the individual IgG subclasses was substantially greater than the measured total IgG concentrations (unlike samples with normal IgG4), and the IgG4 concentration was always less than the IgG2 concentration. METHODS: We developed a tryptic digest LC-MS/MS method to quantify IgG1, IgG2, IgG3, and IgG4 in serum. Samples with IgG4 concentrations ranging from <0.03 g/L to 32 g/L were reanalyzed by LC-MS/MS, and a subset was also reanalyzed by Siemens IN (SIN) subclass measurements. RESULTS: Multivariate linear regression identified 3 subclass tests with multiple predictors of the measured subclass concentration. For these 3 subclasses, the predominant predictors were (in terms of LC-MS/MS IgG subclass measurement coefficients) BSIN IgG1 = 0.89·IgG1 + 0.4·IgG4; BSIN IgG2 = 0.94·IgG4 + 0.89·IgG2; and SIN IgG2 = 0.72·IgG2 + 0.24·IgG4. CONCLUSIONS: There is apparent IgG4 cross-reactivity with select IN subclass measurements affecting tests from both vendors tested. These findings can be explained either by direct cross-reactivity of the IN reagents with the IgG4 subclass or unique physicochemical properties of IgG4 that permit nonspecific binding of IgG4 heavy chain to other IgG immunoglobulin heavy chains. Irrespective of the mechanism, the observed intermethod discrepancies support the use of LC-MS/MS as the preferred method for measurement of IgG subclasses when testing patients with suspected IgG4-RD.

Comparing Physical Examination With Sonographic Versions of the Same Examination Techniques for Splenomegaly.

OBJECTIVES: To determine whether sonographic versions of physical examination techniques can accurately identify splenomegaly, Castell's method (Ann Intern Med 1967; 67:1265-1267), the sonographic Castell's method, spleen tip palpation, and the sonographic spleen tip technique were compared with reference measurements. METHODS: Two clinicians trained in bedside sonography patients recruited from an urban hematology clinic. Each patient was examined for splenomegaly using conventional percussion and palpation techniques (Castell's method and spleen tip palpation, respectively), as well as the sonographic versions of these maneuvers (sonographic Castell's method and sonographic spleen tip technique). Results were compared with a reference standard based on professional sonographer measurements. RESULTS: The sonographic Castell's method had greater sensitivity (91.7% [95% confidence interval, 61.5% to 99.8%]) than the traditional Castell's method (83.3% [95% confidence interval, 51.6% to 97.9%]) but took longer to perform [mean ± SD, 28.8 ± 18.6 versus 18.8 ± 8.1 seconds; P = .01). Palpable and positive sonographic spleen tip results were both 100% specific, but the sonographic spleen tip method was more sensitive (58.3% [95% confidence interval, 27.7% to 84.8%] versus 33.3% [95% confidence interval, 9.9% to 65.1%]). CONCLUSIONS: Sonographic versions of traditional physical examination maneuvers have greater diagnostic accuracy than the physical examination maneuvers from which they are derived but may take longer to perform. We recommend a combination of traditional physical examination and sonographic techniques when evaluating for splenomegaly at the bedside.