Elevated Soluble IL-2 Receptor Research Articles

Rapid Clinical Resolution in Patients with Indeterminate Pediatric Liver Failure and Immune Dysregulation Hepatitis Treated with Ruxolitinib

IntroductionIndeterminate pediatric acute liver failure (iPALF) is a rare, life-threatening diagnosis associated with high rates of liver transplant and reduced survival. Immune dysregulation hepatitis shares many of the same clinical features as iPALF but is defined by an INR ≤ 1.5. Both present with progressive new-onset hepatocellular injury with predominant cytotoxic T-cell mediated inflammation and diffuse cytokine release. Importantly, the optimal medical therapy for these conditions of severe hepatic injury is not known. Here, we present two pediatric cases of steroid-refractory liver dysfunction where use of ruxolitinib, a JAK-STAT pathway inhibitor, led to significant clinical improvement. Case DescriptionsA 12-year-old male (patient A) presented with iPALF, while a 7-year-old female (patient B) presented with immune dysregulation hepatitis. Both patients had coagulopathy, transaminitis and hyperbilirubinemia (Table 1). Ischemia, toxin exposure, autoimmune hepatitis, and infection screens were negative. Immune evaluation demonstrated significantly elevated soluble IL-2 receptor, CXCL9, and sCD163, with mild hyperferritinemia (Table 1). Patient B had IgM EBV antibodies on repeat testing, which may have contributed to her immune dysregulation. Each patient’s next generation sequencing for inborn errors of immunity were negative. Both liver biopsies revealed a cytotoxic T-cell infiltrate, activated Kupffer cells, absence of iron, and absent plasma cell activity. During initial management, patient A received methylprednisolone 2 mg/kg daily, while patient B received 10 mg/kg daily before weaning to 2 mg/kg daily. Steroid-refractory disease was highlighted by ongoing liver damage on serial labs with worsening jaundice and fatigue. Both patients were transitioned to JAK-STAT inhibition with ruxolitinib. Patient A was loaded with 10 mg BID for one week before transitioning to 5 mg BID for 3 months, while patient B started and remained on 5 mg BID for 4 months. Both patients experienced rapid clinical improvement within one week and normalization of immune dysregulation on serial lab work by one month without need for further invasive interventions. Therapy was well tolerated without infectious or thrombotic complications.Table 1Maximum lab values prior to ruxolitinib initiationSoluble IL-2R (175.3–858.2 pg/mL)CXCL9 (< = 647 pg/mL)sCD163(<991 ng/mL)Ferritin (7–271 ng/mL)INRAST (< =60 U/L)ALT (10–49 U/L)Total Bilirubin (0.2–1.0 mg/dL)Patient A8664199731 0965971.62226275815.6Patient B243615 41881994291.43010228411.4Table 1. (abstract: 96) Selected laboratory test results. Values below or above reference are indicated with blue and red respectively. Not shown: IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17 were normal. Fecal blood testing at baseline was negative. T cell memory population percentages were normal. T cell proliferation studies were normal. Pre-SCIG = pre-subcutaneous IgG (SCIG) treatment. Post-SCIG = post-SCIG treatment sample obtained after ~4 months of SCIG. n/a = sample not available. ConclusionThese cases suggest in iPALF and severe acute hepatitis where immune dysregulation is present, JAK-STAT inhibition may have benefit and deserves consideration for preventing disease progression and reducing morbidity and mortality.

A Case of Macrophage Activation Syndrome During the Treatment of Adult-onset Still's Disease With Tocilizumab.

Macrophage activation syndrome (MAS) is a fatal complication of adult-onset Still's disease (AOSD). Although anti-cytokine agents have been recommended for refractory AOSD or complicated with MAS, MAS cases have been rarely reported during anti-cytokine treatment. Herein, we describe the first AOSD case complicated with MAS during the treatment with tocilizumab in Korea. Two years after tocilizumab maintenance therapy, high fever and hypertransaminasemia recurred. MAS was diagnosed based on hyperferritinemia, elevated soluble IL-2 receptor levels, and the presence of hemophagocytic histiocytes in the bone marrow. However, she had normal white blood cell counts and acute phase reactant levels. High-dose glucocorticoid and anakinra therapies were not effective, but her disease improved with etoposide. This case shows that tocilizumab may not prevent MAS development and can modify clinical features making it challenging to diagnose. Cytotoxic therapy such as etoposide may be required in MAS cases that develop during anti-cytokine therapy.

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan.

The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p=.006) and 15.93 (95% CI: 2.45-103.8, p=.004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.

Diagnostic Performance of Electronic Nose Technology in Sarcoidosis

BackgroundDiagnosing sarcoidosis can be challenging, and a noninvasive diagnostic method is lacking. The electronic nose (eNose) technology profiles volatile organic compounds in exhaled breath and has potential as a point-of-care diagnostic tool.Research QuestionCan eNose technology be used to distinguish accurately between sarcoidosis, interstitial lung disease (ILD), and healthy control subjects, and between sarcoidosis subgroups?Study Design and MethodsIn this cross-sectional study, exhaled breath of patients with sarcoidosis and ILD and healthy control subjects was analyzed by using an eNose (SpiroNose). Clinical characteristics were collected from medical files. Partial least squares discriminant and receiver-operating characteristic analyses were applied to a training and independent validation cohort.ResultsThe study included 252 patients with sarcoidosis, 317 with ILD, and 48 healthy control subjects. In the validation cohorts, eNose distinguished sarcoidosis from control subjects with an area under the curve (AUC) of 1.00 and pulmonary sarcoidosis from other ILD (AUC, 0.87; 95% CI, 0.82-0.93) and hypersensitivity pneumonitis (AUC, 0.88; 95% CI, 0.75-1.00). Exhaled breath of sarcoidosis patients with and without pulmonary involvement, pulmonary fibrosis, multiple organ involvement, pathology-supported diagnosis, and immunosuppressive treatment revealed no distinctive differences. Breath profiles differed between patients with a slightly and highly elevated soluble IL-2 receptor level (median cutoff, 772.0 U/mL; AUC, 0.78; 95% CI, 0.64-0.92).InterpretationPatients with sarcoidosis can be distinguished from ILD and healthy control subjects by using eNose technology, indicating that this method may facilitate accurate diagnosis in the future. Further research is warranted to understand the value of eNose in monitoring sarcoidosis activity.

Hemophagocytic Lymphohistiocytosis: A Single Institution Experience

Background: Hemophagocytic lymphohistiocytosis [HLH], is a rare life-threatening syndrome of excessive immune activation. It can be primary due to genetic predisposition or secondary due to infections, immune disorders or malignancies. With nonspecific clinical presentation, a high index of suspicion is required to make the diagnosis. Prompt treatment of underlying etiology and HLH specific therapy is warranted to prevent adverse clinical outcome. Methods: After IRB approval, we conducted a retrospective chart review of adult patients (pts) ≥ 18 years diagnosed with HLH between January 1st, 2010 and June 30th, 2019. We recorded age at diagnosis, gender, cause of HLH, symptoms, laboratory testing, bone marrow pathology, imaging, treatment and outcome. Results: We found a total of 15 patients in the time interval. Pt age ranged from 22 to 64 years with a median of 46 years. 60% were females and 40% were males. 14 pts had secondary HLH and one pt tested positive for HLH gene mutations. Etiology of HLH was malignancy in 6 (40%), infection in 5 (33%), rheumatological disease in 3 (20%) and cause was unclear in one pt but suspected to be an infection. One pt had prior allogenic stem cell transplant and one pt developed HLH even after completion of treatment for lymphoma. On presentation, 14 (93%) had fever, 6 (40%) had respiratory symptoms, 6 (40%) had neurological symptoms, 2 (13%) had a skin rash, 2 (13%) had bleeding manifestations and 3 (20%) required pressor support. Hemoglobin ranged from 5.5 to 13.3 g/dL on presentation, with median of 10.1 g/dL and 14 (93%) had Hb &lt;9 g/dL. Absolute neutrophil count ranged from 0.3 to 16.94 x 103/uL with median of 2.87x103/uL and decreased to &lt; 1000x103/uL in 11 (73%) and &lt; 500x103/uL in 7 (46%). Platelet counts on presentation ranged from 18 to 244x103/uL with median of 82x103/uL and decreased to &lt;100x103/uL in 14 (93%) and &lt;20x103/uL in 8 (53%). 14 (93%) had bicytopenia. Initial ferritin levels ranged from 1,552 to 2,62,080 ng/ml with median of 5,515 ng/ml and increased to &gt;10,000 ng/ml in 10 (66%) and highest level was 4,57,970 ng/ml. All 15 pts had some degree of hepatic dysfunction and one pt had acute kidney injury. Triglyceride levels were &gt;265 mg/dL in 6 (40%). 10 (66%) had laboratory evidence of disseminated intravascular coagulation (DIC), one pt had clinical DIC. Blood cultures were negative in everyone, except 2 pts who developed infection during the hospital course, one with Candida krusei and the other with methicillin sensitive staphylococcus aureus. Bone marrow biopsy was performed in 14 (93%) and all of them demonstrated hemophagocytosis. 3 (20%) underwent lumbar puncture and 2 had elevated CSF protein. 11 (73%) had immunological testing and all of them had elevated soluble IL-2 receptor alpha (sCD25 or sIL-2R). Of the 3 pts who had HLH genetic testing, one had HLH associated mutations. Organomegaly was noted in 11 (73.3%) (4 had hepatosplenomegaly, 6 had splenomegaly, one had hepatomegaly). 6 (40%) had lung infiltrates. MRI brain was done in 5 (33%) and 2 had patchy hyperintensities. 11 (73.3%) were treated with HLH-94 protocol with etoposide and dexamethasone. One pt had matched unrelated donor Allogenic stem cell transplant. 13 (86.6%) had initial recovery. At the time of data cut off, 10 (66%) were alive. Of the 3 pts who initially recovered, one pt died of relapsed lymphoma, one died of HLH relapse and one developed Clostridium difficile infection with bowel perforation. [Refer to Table 1]. Conclusion: Even though literature suggests that malignancy associated HLH has a worse prognosis, our small series did not suggest that. We also noted that HLH associated with rheumatological diseases leads to a superior outcome if the underlying disease is adequately treated. The most significant finding in our series was a patient with diffuse large B cell lymphoma who was diagnosed to have primary HLH with HLH associated mutations. Typically, primary HLH presents in the first few years of life. This patient case points to the fact that patients with primary HLH can have a late presentation and can also be associated with immunological disorders with a predisposition to malignancy. This finding suggests that all patients diagnosed with HLH should have genetic testing done for HLH associated mutations, as this will impact treatment decisions and these patients will benefit from more intense treatment which may include an allogenic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TRIGGERED BY ADENOVIRUS PNEUMONIA: A RARE COMPLICATION OF A COMMON DISEASE

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Adenovirus (ADV) pneumonia is a common disease with many extrapulmonary complications. We report a case of a 71-year old lady with history of follicular lymphoma who developed ADV pneumonia triggering hemophagocytic lymphohistiocytosis (HLH) CASE PRESENTATION: A 71-year-old female presented to our hospital with fever and cough. Chest X-ray revealed pneumonia. Additional labs upon admission showed pancytopenia. Six months prior to presentation, she was diagnosed with follicular lymphoma and she completed six cycles of R-CHOP (last cycle being four weeks prior to presentation). A PET-CT scan performed five days prior to admission revealed complete metabolic response, and a complete blood count was normal. Empiric antibiotics did not result in improvement prompting a CT scan of the chest that showed dense consolidation in the left lower lobe, ground glass opacities in upper lobes and trace pleural effusions. Bronchoscopy was performed. Bronchial wash cultures grew ADV. Other bacterial, fungal and viral serology/cultures were all negative. ADV was also isolated from serum. Patient remained febrile and had progressive pancytopenia with counts reaching a nadir of 0.0K/uL neutrophils, 5.8 g/dL hemoglobin and 34K/uL platelets. Further labs showed elevated ferritin at >40,000ng/ml , elevated soluble IL-2 receptor alpha and transaminitis. HLH was suspected and steroids were started empirically. Bone Marrow biopsy confirmed HLH without evidence of lymphoma or metastatic carcinoma. Patient continued to decline, she developed rectus sheath hematoma, hypotension, acute kidney injury and delirium. Family decided to withdraw all active treatments and take the route of comfort care which eventually lead to her unfortunate demise on day nine of admission. DISCUSSION: ADV pneumonia can occur in both immunocompetent and immunocompromised hosts(1). Both outbreaks and sporadic cases have been described. ADV-pneumonia can be fatal with poor prognostic factors including: viremia, multilobar infiltrates and parapneumonic effusions(2, 3). CT commonly shows dens consolidation with surrounding ground glass opacities. ADV infection induced HLH has been well described in children. This phenomenon is rare in adults with only a few reported cases, mostly described in hematopoietic stem cell transplant recipients. Older age, markedly elevated ferritin and underlying lymphoma are considered poor prognostic factors in HLH. Our patient’s history of follicular lymphoma had probably put her at higher risk for developing this immunological catastrophe. She had all of the aforementioned poor prognostic of both ADV-pneumonia and HLH. CONCLUSIONS: Our case signifies that HLH should be suspected in the setting of ADV infection and pancytopenia. Early diagnosis and treatment might be associated with better outcomes in this rare-life threatening- hematological complication. Reference #1: Shen CF, Wang SM, Ho TS, Liu CC. Clinical features of community acquired adenovirus pneumonia during the 2011 community outbreak in Southern Taiwan: role of host immune response. BMC infectious diseases. 2017;17(1):196. Reference #2: Gu L, Qu J, Sun B, Yu X, Li H, Cao B. Sustained Viremia and High Viral Load in Respiratory Tract Secretions Are Predictors for Death in Immunocompetent Adults with Adenovirus Pneumonia. PloS one. 2016;11(8):e0160777. Reference #3: Yoon H, Jhun BW, Kim SJ, Kim K. Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia. Respirology (Carlton, Vic). 2016;21(7):1243-50. DISCLOSURES: No relevant relationships by Muhammad Hamza, source=Web Response No relevant relationships by Khalid Mohamed Ahmed, source=Web Response No relevant relationships by Mahum Shahid, source=Web Response No relevant relationships by Qazi Ahmed Waqas, source=Web Response

INFLAMMATORY MYOPATHIES: P.162IgG-4 related myositis - a new entity among inflammatory myopathies

IgG4-related diseases (IgG4RD) are exceedingly rare, have only been recently discovered and the nosological spectrum is only beginning to be understood. Affected patients suffer from subacute non-specific general complaints often associated with organ-specific affection typically of the salivary or lacrimal glands, formation of so-called pseudo-tumours with fibrous characteristics, and interestingly often multi-organ affections. Gold standard for diagnosis of IgG4RD is the histopathological analysis, highlighting the characteristic lymphocytoplasmic infiltrates, storiform fibrosis and obliterative phlebitis in combination with IgG4-positive Plasma cells. We present a 55-year-old female patient with a 30-year history of atypical rheumatoid arthritis suffering from a 12-year history of axial muscle weakness including paravertebral muscles. No other organs were involved. Her laboratory markers included eosinophilia, elevated soluble IL-2 receptor and IgG4. On muscle biopsy an unusually dense lymphomonocytic infiltrate including numerous Eosinophils and Giant cells as well as numerous IgG4-positive plasma cells were detectable. In general, IgG4-RD responds well to treatment, especially to B cell depletion, however our patient did not. As a second-line treatment, she received a JAK1 and JAK2 inhibitor, which dramatically improved her muscle strength over a 3 months period. This report highlights that myositis can be the sole presentation of IgG4 related disease and that treatment may require alternative approaches, which in turn open speculations about pathophysiological underpinnings of the disease.

Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome that occurs secondary to severe systemic immune activation.1 Cytotoxic T-cell proliferation leads to increased cytokine production and activation of tissue resident macrophages. Ultimately, multi-system end organ damage caused by massive inflammation may lead to a fatal outcome without timely diagnosis and initiation of appropriate therapy.2 Hemophagocytic lymphohistiocytosis affects patients of all ages and occurs as an inherited disease, or secondarily in the setting of predisposing conditions that alter the normal immune response. The inherited form of the disease presents in early childhood and is associated with homozygous mutations in genes involved in CD8+ T-cell- and NK-cell-mediated immunity.3 These genetic forms of HLH are uniformly fatal without hematopoietic cell transplant or gene therapy. Secondary HLH may occur sporadically in healthy individuals, but is more often encountered in patients with hematologic malignancy, autoimmune disease, and iatrogenic immunosuppression. Virtually all cases are thought to require an infectious or noninfectious trigger to initiate the aberrant immune response, regardless of the underlying immune dysfunction.4–7 Hemophagocytic lymphohistiocytosis presents abruptly over a period of several days to weeks with a consistent pattern of fever, pancytopenia, and splenomegaly. Common laboratory abnormalities include hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated soluble IL-2 receptor, and abnormal liver func tion tests.1 The most widely used diagnostic criteria for HLH were developed for inclusion in the HLH-2004 trial which requires genetic evidence of a mutation associated with HLH or fulfillment of 5 of 8 clinical criteria including fever, splenomegaly, bicytopenia, hypertriglyceridemia or hypofibrinogenemia, evidence of hemophagocytosis in bone marrow or other tissues, low or absent NK-cell activity, elevated ferritin, and elevated soluble IL-2 receptor.3 Although not validated for adults, these HLH-2004 criteria are broadly applied in patients of all ages. Pathologists play a critical role in the diagnostic workup of patients suspected of having HLH. Bone marrow examination is performed to evaluate for hemophagocytosis, identify underlying malignancy, and exclude benign or neoplastic mimics. The presence of hemophagocytosis in the marrow fulfills one of the HLH-2004 diagnostic criteria; however, no accepted diagnostic threshold or reporting guidelines have been established. The lack of evidence-based guidelines leads to considerable uncertainty among pathologists as to what degree of hemophagocytosis is sufficient to satisfy this criterion. Adding to the challenge is that hemophagocytosis is not specific to the diagnosis of HLH in the absence of other clinical features of the disease. Rare erythrophagocytosis is commonly seen in bone marrow aspirates and increased hemophagocytosis may be encountered in the setting of sepsis, blood transfusions, hematopoietic transplantation, chemotherapy, and myelodysplastic syndrome.8–11 Given the lack of a defined threshold to fulfill the criterion for diagnosis of HLH, we designed this retrospective study to interrogate whether quantitative or qualitative morphological features of hemophagocytosis in bone marrow aspirates are predictive of the eventual diagnosis of HLH. We identified a cohort of patients presenting with clinical characteristics that were of concern for HLH and their aspirates were examined blindly. Hemophagocytes were enumerated per 1000 nucleated cells according to the lineage of their ingested hematopoietic contents [mature red blood cells (RBCs), nucleated RBCs (nRBCs), granulocytes, and lymphocytes] (Figure 1). In addition to quantitative features, we evaluated a binary morphological feature, the presence of multiple nucleated cells within a single hemophagocyte, as a possible predictive characteristic of HLH. Open in a separate window Figure 1. Examples of hemophagocytosis in patients with hemophagocytic lymphohistiocytosis (HLH). (A) Histiocytes in patients with HLH often display rounded contour with cytoplasmic projections. (B-D) Hemophagocytes with a single ingested mature red blood cell (RBC), nucleated RBC progenitor, and granulocyte, respectively. Hematopoietic progenitor cells (HPCs) often contain single nucleated hematopoietic cells in addition to multiple mature RBCs (E); however, the presence of multiple nucleated cells within the cytoplasm of a single HPC (F and G) is highly predictive of the diagnosis of HLH. (H) An example of a histiocyte with degenerating nuclear debris, indistinct cytoplasmic contour, and equivocal intracytoplasmic nucleated RBCs that we do not consider to be a definite hemophagocyte.

Elevated soluble IL-2 receptor levels correlate with tumor bulk of follicular lymphomas with intestinal involvement

ObjectivesEstablish a correlation between serum soluble interleukin 2 receptor (sIL-2R) levels and clinical characteristics of follicular lymphoma patients with gastrointestinal involvement. Design and methodsPatients (n=44) presenting with follicular lymphoma lesions in the gastrointestinal tract were enrolled into the study and divided into 2 groups based on sIL-2R levels (normal vs. elevated). Clinical characteristics were also analyzed between groups. ResultsPatients with elevated sIL-2R levels likely had systemic follicular lymphoma involvement (Ann Arbor system staging IIIES/IV or Lugano system staging II-2/IV), involvement of 5 or more nodal areas, and presentation of bulky tumors in the gastrointestinal tract. These patients also presented a high Follicular Lymphoma International Prognostic Index (FLIPI) score, suggestive of poor prognosis. No differences were found among other clinical characteristics including sex, age at lymphoma diagnosis, histological grade, LDH levels, bone marrow involvement, hemoglobin levels, and identification of tracer accumulation in gastrointestinal lesions by positron-emission tomography scanning. ConclusionssIL-2R levels can be used as an independent prognostic index in follicular lymphoma patients based on the correlation with the FLIPI score. Moreover, since high sIL-2R levels were associated with a large tumor bulk, sIL-2R may serve as a good indicator for monitoring disease relapse or progression.

Secondary Hemophagocytic Lymphohistiocytosis As a Presentation For Peripheral T-Cell Lymphoma

Hemophagocytic lymphohistiocytosis (HLH) is often an elusive diagnosis in adults. HLH can be primary or secondary, with treatment of secondary HLH based on the cause. It is important to identify malignancy if present to help best optimize outcomes long term.HLH is characterized clinically by highly activated, ineffective immune response with cytopenia. HLH patients often present with subtle and generalized symptoms such as fever, hepatosplenomegaly, pancytopenia and lymphadenopathy. In secondary HLH, several factors serve as triggers. These are divided into infectious, malignant, rheumatologic, and during immunosuppression. Infection and malignancy are the most common causes. One study reported 28 patients with secondary HLH, 13/28 (46%) had infectious cause (11 positive EBV serology and two patients had leishmaniasis); lymphoma was identified in 11/28 (39%) and autoimmune disease in 3 (10%)1. Another study included 56 patients with secondary HLH, 43 (76%) patients had malignancy, and 23 (41%) patients had infectious etiology. Underlying immune deficiency was present in 38 (67.8%) patients2.Although primary HLH is well documented in the literature, secondary or acquired HLH is only reported in the form of cases, small retrospective studies and single institutional case series reports. Secondary HLH is highly underreported due to its rarity and nonspecific presentation. Here we present a case of secondary HLH from T-cell lymphoma; discuss clinical features and importance of initial accurate diagnosis in optimizing outcomes.A 41 y/o gentleman with past medical history of Crohn's disease for 5 years, presented to the emergency room for fevers of approximately 2-week duration. His therapy for Crohn's disease included, steroids, azathioprine and two doses of adalimumab. He had pancytopenia and bone marrow biopsy demonstrated hemophagocytosis. The HLH diagnosis was further supported by elevated ferritin and elevated soluble IL-2 receptor. Cytogenetics of bone marrow sample demonstrated complex karyotype. The infectious work up demonstrated Epstein Barr Virus (EBV) by PCR. Genetic testing was unremarkable. Patient was managed based on 2004-HLH protocol with dose reduction for pancytopenia. He was maintained on oral cyclosporine and stopped after 6 months when he started having fevers and pancytopenia again. Repeat bone marrow biopsy demonstrated no reactivation of HLH but noted lymphocytosis, consistent with peripheral T cell lymphoma. Cytogenetic studies demonstrated the same complex clone but now with evolution. He received CHOP chemotherapy and etoposide was added after his cerebrospinal fluid was positive for lymphoma. PET-CT showed extensive changes in the bone marrow, spleen and T1 vertebral body. Patient responded poorly and care was drawn on d28 after CHOP.Secondary HLH is an uncommon disease usually triggered by an infection, hematologic malignancy or it may occur in the setting of a rheumatologic disease. Lymphoma is common in secondary HLH and peripheral T cell lymphoma is more commonly resistant at relapse. Clonal abnormalities may help to earlier identify individuals with an underlying malignancy. Patients may benefit from thorough evaluation at presentation for underlying hematologic malignancy as management differs completely. Studies such as PET scan should be considered to search for underlying occult malignancy and cytogenetic studies need to be performed on marrow samples. In our case, repeat cytogentic studies revealed the same clone that was diagnosed at presentation. Initial appropriate therapy for Peripheral T cell lymphoma may have improved this outcome.1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Apr;18(2):463-5.Intensive Care Med. 2010 Oct;36(10):1695-702. Disclosures:No relevant conflicts of interest to declare.

Numbers and Percentages Of Peripheral Monocytes Is a Prognostic Marker For CNS Involvement In Diffuse Large B-Cell Lymphoma

BackgroundIn the rituximab era, there are several studies that have reported the risk factors for central nervous system (CNS) involvement in non-Hodgkin lymphoma, but the same factors emerge, such as high international prognostic index (IPI) score, >1 extranodal site, elevated lactate dehydrogenase (LDH) level, poor performance status (PS), advanced stage, bone marrow involvement. Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Recently, elevated peripheral blood monocyte counts have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. Patients and methodsWe reviewed data from a total of 1238 lymphoma patients(1185 non-Hodgkin lymphoma, 53 Hodgkin lymphoma) at our institution between February 2005 and May 2013. Of these, 42 patients (3.4%) developed CNS complications during the clinical course. Thirty patients out of these 42 (71.4%) were diagnosed with diffuse large B-cell lymphoma (DLBCL). Therefore, we focused on DLBCL. In this study, we retrospectively analyzed data from a total of 557 DLBCL patients, 30 patients (5.4%) who developed CNS involvement and 527 patients with DLBCL but without CNS involvement. This study was approved by the Institutional Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The clinical features of all 557 DLBCL patients, including 30 patients with CNS involvement, are summarized in Table 1. CNS involvement was defined by the presence of at least one histologically confirmed CNS involvement; neuroimaging findings compatible with CNS involvement with lymphoma, in conjunction with consistent clinical presentation; and the absence of other clinically feasible diagnosis or positive cerebrospinal fluid (CSF) (lymphoma cells detected by cytology). The absolute monocyte counts (AMC) and monocyte ratio were derived from pre-treatment complete blood counts.Table 1Characteristics of DLBCL patients with or without CNS involvementCharacteristicsDLBCL with CNS involvement n=30, n (%)DLBCL without CNS involvement n=527, n (%)PGender; male21 (70)295 (56.0)0.1840Age ≤60 years16 (53.3)172 (32.6)0.0277Stage III-IV23 (76.7)208 (39.5)<0.0001IPI score 3-519 (63.3)175 (33.2)0.0013PS 2-412(40.0)47 (8.9)<0.0001Elevated LDH level18 (60)231 (43.8)0.0916Elevated soluble IL-2R level28 (93.3)380 (72.1)0.0096Monocyte count ≥0.6 (×109/L)12 (40)117 (22.2)0.0420Monocyte ratio ≥8 (%)17 (56.7)192 (36.4)0.0325 Pathological studiesImmunohistochemical analysis was carried out using mAbs against CD68 at our institution. ResultsThe incidence of CNS involvement was 5.4%, 1.3% having CNS involvement at diagnosis with DLBCL. Intriguingly, absolute monocyte counts (AMC) ≥0.6 (×109/L) at diagnosis were significantly frequent in 30 DLBCL patients (p=0.0420) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. Furthermore, the monocyte ratio ≥8% in peripheral blood at diagnosis was significantly frequent in 30 DLBCL patients (p=0.0325) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. DLBCL patients with CNS involvement showed age ≤60 years, stage III-IV, IPI score ≥3, and PS ≥2, elevated soluble IL-2 receptor levels was significantly frequent, compared with in DLBCL patients without CNS involvement. Neither gender, elevated LDH level, white blood cell counts (WBC) differed significantly in the two groups. With regard to pathological immunohistochemistry, the numbers of CD68 positive cells in or around lymphoma samples did not differ in the 14 DLBCL patients with CNS involvement that we were able to analyze, compared with DLBCL patients without CNS involvement. CNS involvement free survival rate in DLBCL patients was significantly lower in AMC ≥0.6 (×109/L) and/or the monocyte ratio ≥8% (Log-rank test, P=0.0102) in peripheral blood at diagnosis, compared with in AMC less than 0.6 (×109/L) and the monocyte ratio less than 8%. ConclusionsThese results suggest that in DLBCL patients, AMC and monocyte ratios in peripheral blood at diagnosis are closely correlated with the risk of eventual CNS involvement. AMC and monocyte ratios in peripheral blood at diagnosis in DLBCL patients could be a useful prognostic marker for the risk of CNS involvement during the clinical course. Disclosures:Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy.

T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency

AbstractIn common variable immunodeficiency (CVID) defects in early stages of B-cell development, bone marrow (BM) plasma cells and T lymphocytes have not been studied systematically. Here we report the first morphologic and flow cytometric study of B- and T-cell populations in CVID BM biopsies and aspirates. Whereas the hematopoietic compartment showed no major lineage abnormalities, analysis of the lymphoid compartment exhibited major pathologic alterations. In 94% of the patients, BM plasma cells were either absent or significantly reduced and correlated with serum immunoglobulin G levels. Biopsies from CVID patients had significantly more diffuse and nodular CD3+ T lymphocyte infiltrates than biopsies from controls. These infiltrates correlated with autoimmune cytopenia but not with other clinical symptoms or with disease duration and peripheral B-cell counts. Nodular T-cell infiltrates correlated significantly with circulating CD4+CD45R0+ memory T cells, elevated soluble IL2-receptor and neopterin serum levels indicating an activated T-cell compartment in most patients. Nine of 25 patients had a partial block in B-cell development at the pre-B-I to pre-B-II stage. Because the developmental block correlates with lower transitional and mature B-cell counts in the periphery, we propose that these patients might form a new subgroup of CVID patients.

Intrathecal chemotherapy for patients with meningeal carcinomatosis

Background Meningeal carcinomatosis (MC) is increasing, and these patients have a poor prognosis. We analyzed the effects of intrathecal (IT) chemotherapy for these patients. Methods Patients received both methotrexate (MTX) (15 mg/m 2) and prednisolone (10 mg/m 2) 6 times in 2 weeks by Ommaya reservoir, along with cytosine arabinoside (10 mg/m 2) for 4 doses of MTX. A cycle consisted of a 2-week period during which patients received these drugs and then 2 weeks off. Treatments were repeated 3 to 6 cycles depending on the clinical status. Cerebrospinal fluid (CSF) samples were also analyzed for cytology and a few markers. Results Of the 58 patients treated the most common tumor was lymphoma (30 patients), followed by lung and breast. Elevated soluble IL-2 receptor levels were observed in 23 of 30 patients with lymphomatous meningitis. Median survival of MC patients with malignant lymphoma, lung cancer, and breast cancer was 32.8 ± 9.8, 13.0 ± 4.1, and 18.4 ± 7.4 months, respectively. Thus, the patients with lymphoma responded best, both by clearing the CSF and clinically. Conclusions Our treatment regimen can improve the neurologic status of patients with MC. In particular, early IT chemotherapy can be effective for patients with lymphoma.

Serum-soluble IL-2 receptor and IL-6 levels in patients with melanoma.

Elevated soluble IL-2 receptor (sIL-2R) and IL-6 serum concentrations have been reported as adverse prognostic factors in several types of cancer. In order to determine whether these factors are predictive of metastatic progression in melanoma, sIL-2R and IL-6 levels were measured in sera from 172 patients with melanoma and 60 in healthy controls. Mean sIL-2R values were significantly higher in the patients than in normal controls and the highest values were observed in those that developed metastasis during follow-up. However, no correlation was found with the stage of the disease. Serum IL-6 levels were found to be correlated with age and sex, but not correlated with sIL-2R levels. Statistical analysis was based on logistic and Cox regression models. The factors considered were age, sex, stage, disease-free interval and serum sIL-2R and IL-6 levels. The analysis showed that only the sIL-2R value is significantly linked to metastatic progression. This finding suggests that high serum levels of sIL-2R could be a predictive factor of metastatic progression in malignant melanoma.

Low‐dose recombinant interleukin‐2 therapy in advanced multiple myeloma

In vitro data have demonstrated autologous T-lymphocytes with anti-tumour activity in multiple myeloma (MM). Therefore a phase I/II trial was conducted to study the feasibility, the effect on several immunological parameters, and the tumour response induction of low-dose recombinant interleukin-2 (rIL-2) in MM patients. 18 MM patients of advanced stages in progress, who had failed on standard chemotherapy received 9 x 10(6) IU/m2 rIL-2 twice daily on days 1 and 2 and 0.9 x 10(6) IU/m2 twice daily for 5 subsequent days per week subcutaneously from days 3 to 56 (repeated every 12 weeks until progression). Patients were treated for between 8 and 1086 + d (mean 241 d) without serious side-effects. 6/17 patients experienced tumour response (2/17 objective tumour mass reduction, 4/17 long-lasting stable disease following tumour progression before initiation of rIL-2 treatment). During therapy the number of eosinophils increased 15-fold, CD4+ T lymphocytes were activated as demonstrated by enhanced CD25 antigen expression, and CD56+ NK cells expanded in the peripheral blood. Furthermore, a diminished pre-treatment ratio of CD4+/CD8+ lymphocytes was normalized during rIL-2 treatment. NK cell activity and lymphokine activated killer (LAK) cell activity was significantly enhanced. Endogenous IL-2 production and elevated soluble IL-2 receptor serum concentrations were induced. Low-dose rIL-2 can stimulate immune enhancement in MM despite the characteristic tumour-induced immunodeficiency. The treatment has proven though limited efficacy in advanced MM. Because most of the responders experienced termination of tumour progression rather than tumour regression, rIL-2 maintenance of chemotherapy-induced remissions should be investigated.