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Competing Interests: Jorge J. Castillo reports consulting or advisory roles with AbbVie/Pharmacyclics, BeiGene, Cellectar, Janssen, and Roche/Genentech; and research funding from AbbVie, AstraZeneca, Cellectar, LOXO, Pharmacyclics, and TG Therapeutics, outside the submitted work. Mohit Narang reports consulting or advisory roles with BeiGene, Bristol Myers Squibb, Celgene, DSI, and Takeda; and speakers bureau with BeiGene, Bristol Myers Squibb, and Takeda, outside the submitted work. Habte A. Yimer reports stock/stock options from Karyopharm, and speakers bureau with Amgen, AstraZeneca, BeiGene, GSK, Janssen, Karyopharm, Pharmacyclics, and Sanofi, outside the submitted work. Jason M. Melear reports consulting or advisory roles with TG Therapeutics, and speakers bureau with AstraZeneca and BeiGene, outside the submitted work. Morton Coleman reports stocks/stock options from Immunomedics, and receives research funding from AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Genentech, Gilead, InnoCare, Merck, Pfizer, and Roche, outside the submitted work. Charles M. Farber reports stocks/stock options from Alexion; receiving honoraria from Bristol Myers Squibb; consulting or advisory roles with ADC Therapeutics, BeiGene, Gilead, MorphoSys/Incyte, and TG Therapeutics; speakers bureau with ADC Therapeutics, Genentech, Gilead, MorphoSys/Incyte, Seagen, and TG Therapeutics, outside the submitted work. Jonah Shulman reports receiving honoraria from Seagen and TG Therapeutics, and consulting or advisory roles with Seagen and TG Therapeutics, outside the submitted work. Emily H. Mantovani is an employee of BeiGene, with regard to the submitted work, reports former employment with Bristol Myers Squibb, and reports stocks/stock options from BeiGene and Bristol Myers Squibb, outside the submitted work. Xiaowei Zhang and Aileen Cohen are employees of BeiGene, with regards to the submitted work, and report stocks/stock options from BeiGene, outside the submitted work. Jane Huang was an employee of BeiGene at the time of the study, with regards to the submitted work; reports receiving royalties from BeiGene; receiving support for attending meetings and/or travel from BeiGene and Protara; receiving research funding from BeiGene; patents, royalties, or other intellectual property with BeiGene; a leadership role with BeiGene and Protara; and stock/stock options from BeiGene and Roche, outside the submitted work. Edwin C. Kingsley and Constantin A. Dasanu have no relevant disclosures.

Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015., (© 2020 by The American Society of Hematology.)

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.

A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect ® CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.5, and 0.6 years for patients with Rai stage 0, 1, and ≥2, respectively. Only 60% of patients with Rai stage 0/1 underwent FISH/cytogenetic testing prior to initiation of a new line of therapy. Lymphocytosis and lymphadenopathy were the most common reasons for treatment initiation. Lymphocytosis as a reason for treatment initiation was associated with inferior event-free survival at Rai stage 0/1. Short treatment duration was associated with inferior overall survival regardless of Rai stage; sensitivity analyses confirmed the association. The Connect CLL registry provides valuable information on a real-world population of patients with CLL, clarifying both the timing and rationale for initiating therapy.

Introduction: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy., Patients and Methods: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown., Results: Cytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment., Conclusion: The present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) promotes clonal evolution of aggressive clones, which in some patients may lead to early progression of disease (POD). We studied the prognostic value of early POD in a cohort of patients with CLL enrolled between 2010 and 2014 in the Connect CLL Registry. Overall, 829 eligible patients receiving first-line therapy were categorized into 3 groups: early POD (progression <2 years after treatment initiation), late POD (progression ≥2 years after treatment initiation), and no POD as of 1 May 2017. Baseline demographics, treatment characteristics, and overall survival (OS) were analyzed. Logistic regression models identified independent predictors of early POD; Cox regression models were used to evaluate the risk of early POD. With a median follow-up of 48.8 months, 209 (25.2%), 162 (19.5%), and 458 (55.3%) patients had early, late, and no POD, respectively. Patients with early POD were older and had inferior response to similar first-line treatment regimens vs late and no POD groups (overall response rate: 53% vs 80% vs 84%). Patients with early POD were more likely to have unfavorable-risk cytogenetics (del[11q]/del[17p]) than patients with no POD (34% vs 20%; P = .04). Early POD was associated with an inferior OS across all patients (hazard ratio, 3.6; 95% confidence interval, 2.6-5.1; P < .01) and in patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab ( P < .05). Early POD within 2 years of first-line therapy is a robust clinical prognostic factor for inferior OS in patients with CLL. The Connect CLL Registry was registered at www.clinicaltrials.gov as #NCT01081015., Competing Interests: Conflict-of interest disclosure: C.M.F. received research funding from Genentech and Gilead; received consulting and lecturing fees from Celgene Corporation, Genentech, Gilead, Janssen, Pharmacyclics, and Seattle Genetics; served on the advisory committee for Celgene Corporation; and received honoraria from Janssen. M.S.D. received research funding and served at the scientific advisory board for Genentech, Infinity, Pharmacyclics, and TG Therapeutics, and received consulting fees from AbbVie, Celgene Corporation, Gilead, Infinity, Janssen, Merck, and AstraZeneca. D.L.G. received consulting and lecturing fees from Celgene Corporation. N.E.K. received research funding from Gilead, Morphosys, Celgene Corporation, and Pharmacyclics. N.L. received research funding from AbbVie, Genentech, Gilead, Infinity, and Pronai; received consulting fees from AbbVie, Genentech, Gilead, Pharmacyclics, and Pronai; and served on the advisory committee for Celgene Corporation. A.M. received research funding from AbbVie, Gilead, Pronai, and TG Therapeutics; received consulting fees from AbbVie; and received lecturing fees from Celgene Corporation. C.N. is an employee of Cardinal Health. P.K., A.S.S., E.D.F., and K.S. are employees of Celgene Corporation and have equity ownership in Celgene Corporation. J.P.S. received consulting fees from Celgene Corporation, Genentech, Gilead, Pharmacyclics, and TG Therapeutics, and received lecturing fees from Gilead. C.R.F. received research funding from AbbVie, Acerta, Gilead, Millennium, Infinity, Janssen, Pharmacyclics, Spectrum, and TG Therapeutics, and received consulting fees from Bayer, Celgene Corporation, Genentech/Roche, Gilead, Millennium, Optum Rx, and Seattle Genetics. I.E.A. declares no competing financial interests.

Background: Peripheral T-cell lymphomas (PTCLs) represent a rare and heterogeneous group of malignancies that do not have consensus treatment recommendations. Strategies extrapolated from B-cell lymphoma have met with limited efficacy, although T-cell-specific salvage therapies have been recently developed., Methods: To determine treatment patterns and associated outcomes in PTCL not otherwise specified (PTCL-NOS), anaplastic large T-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL), a retrospective analysis was undertaken at a large US community oncology network among patients treated between January 2010 and April 2015., Results: Among 93 patients (44 PTCL-NOS, 30 ALCL, 19 AITL), 23 unique treatments were used in 66 first-line patients and 12 unique second-line treatments were used in 24 relapsed/refractory patients. First-line CHOP and CHOP-like regimens were used in 74% of patients, providing 4-year overall survival (OS) outcomes of 34% (95% confidence interval [CI], 14%-83%) in patients without transplant consolidation (82% in ALCL, 37% in PTCL-NOS, and 0% in AITL). Upfront stem cell transplantation trended toward improved 4-year progression-free survival 77% (95% CI, 54%-100%) versus 34% (95% CI, 14%-80%); (P = .08; hazard ratio [HR] 0.29) with 4-year OS 77% (95% CI, 54%-100%) versus 34% (P = .22; HR 0.41). Brentuximab was the most common second-line therapy, with multiple additional regimens used in sequence (up to 5 salvage regimens) in many., Conclusions: The significant variability in treatments used for PTCL emphasizes the lack of consensus therapy in this rarer lymphoma and calls for additional organized prospective and registry studies to evaluate comparative effectiveness., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti-tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti-CD20 monoclonal antibody, in rituximab-relapsed or -refractory patients with B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukaemia (CLL). Induction therapy (doses of 450-1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL. Patients received ublituximab maintenance monthly during cycles 3-5, then once every 3 months for up to 2 years. Enrolled patients with B-NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies. No dose-limiting toxicities or unexpected adverse events (AEs) occurred. The most common AEs were infusion-related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AEs were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression-free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well-tolerated and efficacious in a heterogeneous and highly rituximab-pre-treated patient population., (© 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti-CD20 monoclonal antibody with single-agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2-6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty-one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high-risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long-term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156)., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect ® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YAs), defined as diagnosis at ≤40 years, is uncommon. No standard approaches exist guiding the treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insights into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged >40 years., Patients and Methods: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and >80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CIs) from multivariable Cox models., Results: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YAs. Of YA patients, 69% had advanced disease, 80% had low-grade histology, and 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, and 46% received chemoimmunotherapy [in 59% of these: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone)]. With a median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached)., Conclusions: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years, with favorable OS and PFS in YAs. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL., Clinical Trial Number: Roche/Genentech ML01377 (U2963n)., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death., Patients and Methods: In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility., Results: Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index-adjusted hazard ratio, 19.8)., Conclusion: In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

New applications are always being developed for immunoglobulins; new recommendations are regularly published. We wished to know the indications used in a large hospital. A hundred and thirty-six adult patients were prescribed immunoglobulins from January to December 2008. Three preparations in intravenous immunoglobulins were available (one liquid, 2 freeze-dried). Fourteen charts were rejected for clerical errors. A hundred and twenty two charts were available for statistical study. Thirty-six patients were on immunoglobulins for antibody deficiency, 19 were followed in haematology for chronic lymphoid leukaemia or multiple myeloma, 19 were treated after lung transplantation, 17 had received a kidney transplant, 1 after heart transplantation: these indications were substitution. Twenty for Guillain Barré and chronic demyelinating polyneuropathy, 10 in immune thrombocytopenic purpura: this was for immunomodulation. Recommendations were followed by the prescribers; charts were reviewed in March and November 2009. Side-effects were rare. (0.6%) (1).

The following recommendations, which aim at standardising and rationalising the clinical indications for administering polyclonal immunoglobulins in Belgium, were drawn up by a working group of the Superior Health Council. To this end, the Superior Health Council organised an expert meeting devoted to"Guidelines for the use of immunoglobulins". The experts discussed the indications for immunoglobulin use, the'ideal'immunoglobulin preparation, its mechanisms of action, the practical issues involved in administering immunoglobulins and their potential side effects. The recommendations formulated by the experts were validated by the Superior Health Council working group with the purpose of harmonising immunoglobulin use in Belgium

Objective: The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD)., Methods: This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations., Results: Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients., Conclusion: MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma., (Copyright © 2011 by the American Academy of Pediatrics.)

Background: Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies., Design and Methods: A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2(nd) generation anti-CD20 antibody veltuzumab in patients with CD20(+) indolent non-Hodgkin's lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers., Results: Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 μg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab antibody were negative., Conclusions: Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin's lymphoma. (Clinicaltrials.gov identifier: NCT00546793).

A tired 32-year-old woman complaining of tiredness was referred for work-up of a possible immune deficiency. She had a history of recurrent infections since birth, which usually responded to antibiotics within a few days. Her mother, a nurse, had reported that early charts had disappeared. Munchausen's by proxy was suspected for years. Careful anamnesis indicated possible recurrent fever. Serum IgD levels were high, which led us to suspect Hyper IgD Syndrome. Sequencing of the mevalonate kinase gene revealed 2 mutations, leading to amino acid substitutions: one already described (V3771) and R40W: never reported before. Mevalonate kinase activity was very low in the patient's peripheral blood cells. We used the "Poly Phen" prediction program successfully. Our experiments confirmed the diagnosis of mevalonate kinase deficiency. We used steroids to abort recurrent crises.

The mycolyl transferase antigen 85 complex is a major secreted protein family from mycobacterial culture filtrate, demonstrating powerful T cell stimulatory properties in most HIV-negative, tuberculin-positive volunteers with latent M.tuberculosis infection and only weak responses in HIV-negative tuberculosis patients. Here, we have analyzed T cell reactivity against PPD and Ag85 in HIV-infected individuals, without or with clinical symptoms of tuberculosis, and in AIDS patients with disease caused by nontuberculous mycobacteria. Whereas responses to PPD were not significantly different in HIV-negative and HIV-positive tuberculin-positive volunteers, responses to Ag85 were significantly decreased in the HIV-positive (CDC-A and CDC-B) group. Tuberculosis patients demonstrated low T cell reactivity against Ag85, irrespective of HIV infection, and finally AIDS patients suffering from NTM infections were completely nonreactive to Ag85. A one-year follow-up of twelve HIV-positive tuberculin-positive individuals indicated a decreased reactivity against Ag85 in patients developing clinical tuberculosis, highlighting the protective potential of this antigen.

Few studies have evaluated prognostic factors among patients with multiple myeloma (MM) since new therapies have become available. Monthly zoledronic acid (ZOL) has been incorporated into many treatment regimens to reduce skeletal-related events (SREs), but outcomes among patients receiving this bisphosphonate have not been well-defined. The aim of this retrospective study was to determine baseline and on-treatment prognostic factors in these patients. Data were collected from the date of diagnosis on 300 consecutive MM patients treated with ZOL. Median duration of ZOL was 18 months (range 1-121 months). The skeletal morbidity rate was 0.116 events per patient year. Five-year overall survival (OS) was 69%. Risk factors for shortened OS included SREs, increased serum creatinine, and International Staging System (ISS) Stage II or III. Thirty-four (11%) patients showed worsening renal function. In 28 of these patients, ZOL was discontinued and restarted in half of these patients following a brief delay. Only 5 of the 34 patients showed worsening of their renal function. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ). All patients with ONJ are in remission or with stable disease except one patient who died of a myocardial infarction while in remission. Only two patients showed some worsening of ONJ despite of ongoing monthly ZOL. Overall, these results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ and renal deterioration may infrequently occur with ZOL, most patients do not experience worsening of these conditions with ongoing treatment with this bisphosphonate., (© 2010 Wiley-Liss, Inc.)

Purpose: Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection associated with AIDS. It usually affects the peripheral retina, sparing the macula. We describe an atypical CMV retinitis exclusively confined to the macula., Methods: A 43-year-old man with the diagnosis of AIDS developed a white retinal lesion confined to the macula of the right eye. Two weeks later, a more typical granular appearance was observed leading to presumption of CMV retinitis., Results: The patient was treated with ganciclovir without success. With foscarnet, a good response was obtained, leading to total healing of the lesion., Conclusions: CMV retinitis has to be taken into consideration in all lesions confined to the macula in immunodepressed patients. An early diagnosis is crucial to avoid blindness.

Physicians of the unit have first taken care of patients with acquired Immunodeficiency in 1981. We have become an independent "Reference Centre" in 1998. The multidisciplinary team follows more than 300 patients on a regular basis. AIDS has been amply publicized, but other immuno-deficiencies have not. Primary immunodeficiencies are "orphan" diseases; they can be as serious, or more severe even, than AIDS. About 60 patients with "PID" are followed by the team. We are involved in research, and have participated in the identification of a mutation of an HIV co receptor that protects against HIV infection. We also studied the pathogenesis of Kaposi's sarcoma, and the immunological basis of adverse reactions to intravenous gammaglobulins.

Twelve HIV-1-infected, nine HIV-2-infected patients and eight HIV-negative subjects were given a 40IU booster dose of tetanus toxoid (TT). Blood was collected on days 0, 7 and 30 after immunization. Changes in HIV-1 or HIV-2 RNA load were evaluated by nested PCR. TT-IgG antibody levels were quantified by ELISA. CD4 cell counts as well as activation, memory and maturation markers of T lymphocyte subsets were determined by flow cytometry. The induction of apoptosis was investigated using 7-aminoactinomycin D (AAD) and propidium iodide (PI) staining. Proliferative responses to TT and pokeweed mitogen (PWM) were determined by the level of [(3)H] thymidine incorporation. Seven and 30 days after immunization, there was no detectable increase in HIV-1 or HIV-2 plasma load. There were also no changes in CD4 cell counts, CD69, HLA-DR and memory CD45RO or naive CD45RA antigens. Immunization did not increase the spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ T cells subsets neither in controls nor in HIV-infected patients. Similarly, apoptosis induced in vitro by PWM or by the specific TT recall antigen did not vary during the study period. The proliferative response to PWM and to the TT recall antigen was decreased both in HIV-1- and HIV-2-infected patients compared to HIV-negative controls. Immunization significantly increased the TT-IgG levels in healthy controls and in HIV-infected patients. However, the anti-TT-IgG response, as measured by the fold-increase index between days 0 and 30, was significantly higher in healthy controls than in HIV-1- (P=0.036) and HIV-2-infected patients (P=0.003). In conclusion, we found no deleterious immunologic or virologic effect was detected in healthy HIV-1- and HIV-2-infected individuals after antigenic challenge with a TT booster. However, the response to TT vaccination was lower in HIV-1- and in HIV-2-infected individuals than in healthy HIV-negative controls.

Severe primary immunodeficiencies (PID) are rare; their global incidence is comparable to that of childhood leukemia; they include more than 100 different entities. Clinical manifestations are: unusually severe or frequent infections or infections that do not respond to adequate treatment; an increased risk of certain malignancies; sometimes auto-immune manifestations. Delayed diagnosis and management of PID can lead to severe and irreversible complications or to death. PID can become manifest only in the adult; in common variable immune deficiency, the median age at diagnosis is between the 2nd and the 3rd decade of life. PID are often transmitted genetically; recent progresses in molecular biology have allowed more precise and earlier, including antenatal, diagnosis. Molecular treatment of 3 infants with a severe immunodeficiency has recently been achieved in April 2000. Those progresses were mostly based on the study of immunodeficiency databases. We present here the work of a Belgian group specialized in PID; meetings have started in June 1997. This group establishes guidelines for the diagnosis and treatment of PID, adapted to the local situation. The elaboration of a national register of PID is also underway; this has to provide all guaranties of anonymity to patients and families. Such a register already exists at the European level; it has provided the basis for new diagnostic and therapeutic possibilities. The inclusion of Belgian data in this register should allow essential progresses essential for our patients.

Increased programmed cell death (PCD) or apoptosis has been detected in the T cells of HIV-infected subjects; it is held partially responsible for the continuous loss of CD4+ T cells during the natural course of HIV infection. Highly active antiretroviral therapy (HAART) decreases the viral load and leads to an increase of CD4+ count in vivo. In this study we evaluated PCD in total peripheral blood mononuclear cells, CD8+ and CD4+ lymphocytes before and four weeks after initiation of HAART. Seven HIV-1-infected patients were investigated. Viral load was assessed by RT-polymerase chain reaction and PCD by flow cytometry using apoptosis by 7 amino actinomycin D (7AAD) and propidium iodide (PI). After four weeks of HAART, CD4+ T and CD8+ T cell levels were stable, and plasma HIV-RNA copies were significantly decreased. In four of the patients (4/7), HIV-RNA levels were reduced to undetectable levels (fewer than 400 copies per milliliter). A statistically significant reduction of apoptosis among CD4+ cells was observed (P < 0.03), though neither in the CD8+ T cell population nor in peripheral blood mononuclear cells (PBMCS). These results demonstrate the beneficial effect of HAART on apoptosis of CD4+ cells in the early treatment stage.

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposi's sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron-oxide-rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS-derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS-derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast-growth-factor-stimulated cells. These results may point to a novel therapeutic approach to KS.

Kaposi's sarcoma (KS) is an angioproliferative disease characterized by proliferating spindle-shaped cells, angiogenesis, and inflammatory cell infiltration. Several lines of evidence suggest that KS is a multifocal cytokine-mediated disease of vascular origin. Because metalloproteinases (MMPs) are important enzymes involved in angiogenesis, we studied their activity in five different KS-derived cell lines and compared these data with those obtained with human umbilical vein endothelial cells (HUVEC). We focused on the activity of the 72- and 92-kd type IV collagenases because these enzymes are thought to play an important role in the process of tumoral invasion. Nonstimulated HUVEC released a weak 72-kd collagenase activity and no 92-kd collagenase activity, as determined by zymographic analysis. Stimulation of HUVEC with phorbol myristate acetate (PMA) or TNF-alpha increased the 72-kd collagenase activity and also induced a 92-kd collagenase activity. By contrast, KS-derived cells constitutively released significant 72- and 92-kd collagenase activities. The basal release of these enzymes by KS cells was further enhanced by TNF-alpha or PMA. Conversely after in vivo exposure to chemotherapy, KS-derived cells showed a downregulation of the production of MMPS that could be reversed by the addition of TNF or PMA. These results suggest that KS cells have constitutive features of activated cells that have an invasive and metastasizing potential.

We present the case of an asymptomatic HIV carrier, who presented with acute myeloblastic leukemia in third relapse and successfully underwent autologous stem cell transplantation as a rescue treatment. This observation supports the conclusion that tolerance of autologous bone marrow or stem cell transplant in patients with HIV may correlate with a low viral burden and relatively good immune function.

A patient with the Acquired ImmunoDeficiency Syndrome (AIDS) treated with a daily low dose of corticosteroids for chronic atopic dermatitis experienced a sudden episode of unilateral knee arthritis. Culture of the purulent synovial liquid yielded a pure culture of Streptococcus Equisimilis. A four week period of intravenous antibiotherapy combined with repeated drainages allowed a complete recovery of articular function.

Human myeloid leukemia cells (HL-60) transport only the oxidized form of vitamin C (dehydroascorbic acid) and accumulate the vitamin in the reduced form, ascorbic acid. We performed a detailed study of the role of glutathione in the intracellular trapping/accumulation of ascorbic acid in HL-60 cells. Uptake studies using HL-60 cells depleted of glutathione by treatment with L-buthionine-(S,R) sulfoximine and diethyl maleate, revealed no changes in the cells' ability to transport dehydroascorbic acid and accumulate ascorbic acid. Similar transport and accumulation rates were obtained using HL-60 cells containing intracellular glutathione concentrations from 6 mM to 1 microM. HL-60 cells, containing as little as 5 microM glutathione, were able to accumulate up to 150 mM ascorbic acid intracellularly when incubated with dehydroascorbic acid. Glutathione was capable of reducing dehydroascorbic acid by a direct chemical reaction, but only when present in a greater than 10-fold stoichiometric excess over dehydroascorbic acid. The accumulation of ascorbic acid by HL-60 cells was strongly temperature-dependent and was very inefficient at 16 degrees C. On the other hand, the direct chemical reduction of dehydroascorbic acid by excess glutathione proceeded efficiently at temperatures of 16 degrees C. Our data indicate that glutathione-dependent reductases in HL-60 cells are not responsible for the ability of these cells to accumulate millimolar concentrations of ascorbic acid. These findings indicate that alternative enzymatic mechanisms are involved in the cellular reduction of dehydroascorbic acid.