Lymphoproliferative Malignancies Research Articles

Seroprevalence of human T-lymphotropic virus antibodies among patients with lymphoid malignancies at a tertiary center in Lagos, Nigeria.

BackgroundThere is a significant association of human T-lymphotropic viruses (HTLV) with lymphoid malignancies. HTLV causes a lymphoproliferative malignancy of CD4-activated cells called adult T-cell leukemia/lymphoma (ATL) and a chronic myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). This study aims to determine the prevalence of HTLV among patients with lymphoid malignancies at a tertiary center in Lagos.MethodsA cross-sectional study was carried out at the hematology clinic of the Lagos State University Teaching Hospital. After obtaining consent, approximately 5 mL of venous blood was collected from each subject. The serum was separated and stored at −20°C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV-1 and -2. Western blot confirmatory testing was done on reactive samples. All patients were also screened for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) by rapid kits.ResultsA total of 39 patients with lymphoid malignancies were enrolled, consisting of 24 (61.5%) with solid malignancies, while 15 (38.5%) had leukemia. Only two patients (5.1%) with lymphoid malignancies were reactive on the ELISA test. On confirmatory testing with Western blot, two patients (5.1%) with lymphoid malignancies were also positive for HTLV. All patients were HIV negative, but four were positive to HBsAg and HCV. There was no association between history of previous blood transfusion and positivity to HTLV (P=0.544).ConclusionA prevalence of 5.1% of HTLV among patients with lymphoid malignancies was found in this study, and previous history of blood transfusion was not found to be a significant cause of HTLV infection.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients.

Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

Tyrosine 129 of the murine gammaherpesvirus M2 protein is critical for M2 function in vivo.

A common strategy shared by all known gammaherpesviruses is their ability to establish a latent infection in lymphocytes – predominantly in B cells. In immunocompromised patients, such as transplant recipients or AIDS patients, gammaherpesvirus infections can lead to the development of lymphoproliferative disease and lymphoid malignancies. The human gamma-herpesviruses, EBV and KSHV, encode proteins that are capable of modulating the host immune signaling machinery, thereby subverting host immune responses. Murine gamma-herpesvirus 68 (MHV68) infection of laboratory strains of mice has proven to be useful small-animal model that shares important pathogenic strategies with the human gamma-herpesviruses. The MHV68 M2 protein is known to manipulate B cell signaling and, dependent on route and dose of virus inoculation, plays a role in both the establishment of latency and virus reactivation. M2 contains two tyrosines that are targets for phosphorylation, and have been shown to interact with the B cell signaling machinery. Here we describe in vitro and in vivo studies of M2 mutants which reveals that while both tyrosines Y120 and Y129 are required for M2 induction of IL-10 expression from primary murine B cells in vitro, only Y129 is critical for reactivation from latency and plasma cell differentiation in vivo.

Risk of lymphoma and solid cancer among patients with rheumatoid arthritis in a primary care setting.

BackgroundSeveral studies have demonstrated an association between rheumatoid arthritis (RA) and lymphoproliferative malignancies, but pathogenic mechanisms remain unclear. We investigated 1) the risk of lymphoproliferative malignancies and solid tumors in adults with RA identified in primary care and 2) the possible mediating role of blood eosinophilia in the clonal evolution of cancer in these patients.MethodsFrom the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 356,196 individuals with at least one differential cell count (DIFF) encompassing the eosinophil count between 2000–2007. From these, one DIFF was randomly chosen (the index DIFF). By linking to the Danish National Patient Register, we categorized the selected individuals according to known longstanding (≥3 years) or recent onset (<3 years) RA prior to the index DIFF. In addition, the cohort was stratified according to management in primary or secondary care. From the Danish Cancer Registry we ascertained malignancies within four years following the index DIFF. Using multivariable logistic regression, odds ratios (OR) were calculated and adjusted for sex, age, year, month, eosinophilia, comorbid conditions and C-reactive protein (CRP).Results921 patients had recent onset RA and 2,578 had longer disease duration. Seventy three percent of RA patients were managed in primary care. After adjustment for sex, age, year, and month, neither recent onset nor long-standing RA was associated with incident lymphoproliferative malignancies or solid cancers. These risk estimates did not change when eosinophilia, CRP, and comorbidities were included in the models.ConclusionsIn this large cohort of patients with RA of short or long duration recruited from a primary care resource, RA was not associated with an increased risk of lymphoproliferative or solid cancers during 4 years of follow-up, when the models were adjusted for confounders. Blood eosinophilia could not be identified as a mediator of cancer development in the present setting.

The use of flow cytometry for immunophenotyping lymphoproliferative disorders in cats: a retrospective study of 19 cases.

Flow cytometric immunophenotyping is a useful step in the diagnosis of lymphoproliferative malignancies in human and veterinary medicine. The purpose of this study was to assess the usefulness of this technique for the diagnosis of lymphoproliferative disorders in cats. Nineteen cats were retrospectively enrolled in this study and allocated into two groups. Group 1 consisted of 13 cats with lymphoma, whereas group 2 consisted of 6 cats with non-neoplastic lymphoproliferative disorders. Fine-needle aspiration biopsies were analysed by flow cytometry in order to evaluate the immunophenotype. Flow cytometric analysis identified a neoplastic lymphoid population in 12 of the 13 cats of group 1, confirming the diagnosis of lymphoma and further characterizing it. The six cats in group 2 showed a mixed lymphoid population, which was not suggestive of a neoplastic disorder. Flow cytometry is a valuable and powerful tool for refining the diagnosis of feline lymphoproliferative disorders.

Thrombocytopenia in cancer patients

Thrombocytopenia is a frequent complication of cancer and its treatment. The causes of thrombocytopenia in cancer patients can be diverse and multifactorial. Systemic chemotherapy is the most frequent cause of thrombocytopenia. The degree and duration thrombocytopenia depends upon whether the chemotherapeutic treatment is myeloablative, as used in stem cell transplants, or non-myeloablative, as typically used in solid non-hematologic malignancies. Additional causes of significant thrombocytopenia include tumor involvement of bone marrow and spleen; microangiopathic disorders such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura or hemolytic uremia syndrome. Lymphoproliferative malignancies can also be associated with secondary immune thrombocytopenia. Due to the broad differential diagnosis associated with cancer related thrombocytopenia, a careful diagnostic evaluation is indicated. The goal of treatment should be to maintain a safe platelet count to allow effective treatment of the underlying malignancy, prevent bleeding complications and to minimize the use of platelet product transfusion.

Disseminated Mycobacterium genavense infection in a patient with immunosuppressive therapy and lymphoproliferative malignancy

We present the case of a 51-year-old woman who presented a right supraclavicular mass corresponding to lymphadenitis with atypical mycobacterium (Mycobacterium genavense). Later, she developed subcutaneous purulent small nodules containing the same germ. The presence of this mycobacterium was in the context of recurrent peripheral T-cell lymphoma and immunosuppressive therapy for seronegative inflammatory polyarthritis.

MP68-07 THE HIGH PREVALENCE OF HYPOGONADISM IN NEWLY DIAGNOSED MALE CANCER PATIENTS PRESENTING FOR FERTILITY PRESERVATION CONSULTATION

You have accessJournal of UrologyInfertility: Evaluation1 Apr 2014MP68-07 THE HIGH PREVALENCE OF HYPOGONADISM IN NEWLY DIAGNOSED MALE CANCER PATIENTS PRESENTING FOR FERTILITY PRESERVATION CONSULTATION Phil Bach, Vidit Sharma, Daniel Oberlin, Jeremy T. Choy, and Robert E. Brannigan Phil BachPhil Bach More articles by this author , Vidit SharmaVidit Sharma More articles by this author , Daniel OberlinDaniel Oberlin More articles by this author , Jeremy T. ChoyJeremy T. Choy More articles by this author , and Robert E. BranniganRobert E. Brannigan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2186AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Curative therapies for cancer can often have a detrimental effect on various aspects of men’s reproductive health. With the increased awareness of fertility preservation, men of reproductive age who are diagnosed with cancer are now commonly being referred to a fertility specialist for sperm banking. While the detrimental effects of cancer therapies are well documented, there is little information on the baseline androgen status of these men as they present for sperm cryopreservation. Testosterone, which plays an essential role in spermatogenesis, also drives energy, mood, bone health, and overall sense of well-being, Each of these important clinical parameters can also be diminished in the setting of oncologic diagnosis. The objective of this study is to investigate the baseline androgen levels in newly diagnosed male cancer patients presenting for fertility preservation. METHODS We performed an IRB-approved, single center, retrospective study at a tertiary care center by querying the institutional database for all male patients with a new oncologic diagnosis presenting for a fertility preservation consult. Demographic information, oncologic diagnosis, and serum LH and testosterone levels were queried. Hypogonadism was defined a serum total testosterone level < 300ng/dL. RESULTS Our search identified 357 male patients with a new oncologic diagnosis presenting for fertility preservation consultation. The mean age of the population was 32.2 (range 18-55, median age 31). The predominant malignancies identified included 139 patients with lymphoproliferative malignancies (38.9%), 109 patients with testicular malignancies (30.5%), 22 patients with prostate malignancies (15.8%), 22 patients with gastrointestinal malignancies (15.8%), and 18 patients with brain malignancies (5.0%). Of the 357 patients, 198 (55%) had a serum testosterone level measured and 97 (27%) had a serum LH level measured. Of the 198 patients with a testosterone level measured, 95 (48%) were hypogonadal. Of the 97 patients with an LH level measured, 4 (4%) had elevated levels. There were no statistically significant differences in rates of hypogonadism amongst the cancer subtypes. CONCLUSIONS Our study suggests that hypogonadism is highly prevalent in males presenting for fertility preservation consultation. Given the high rates of hypogonadism among all cancer types and the negative effects of low testosterone on men’s health and well being, physicians should consider assessing the androgen status of men newly diagnosed with cancer. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e800-e801 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Phil Bach More articles by this author Vidit Sharma More articles by this author Daniel Oberlin More articles by this author Jeremy T. Choy More articles by this author Robert E. Brannigan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Translocation t(2;7)(p11;q21) associated with the CDK6/IGK rearrangement is a rare but recurrent abnormality in B-cell lymphoproliferative malignancies

Structural abnormalities of chromosome 7q have been regularly reported in chronic B-cell lymphoproliferative disorders. They include chromosomal translocations involving 7q21, leading to overexpression of the CDK6 gene. Three different translocations, t(7;14)(q21;q32), t(7;22)(q21;q11), and t(2;7)(p11;q21), leading to the juxtaposition of the CDK6 gene with a immunoglobulin gene enhancer during B-cell differentiation, have been described. In the past 2 years, we identified three patients with lymphoproliferative malignancy associated with a t(2;7)(p11;q21). Fluorescent in situ hybridization using an IGK probe and a library of bacterial artificial chromosome (BAC) clones located in bands 7q21.2 and 7q21.3, containing CDK6, revealed that the telomeric part of the IGK probe was translocated on the der(7) within a 51-kb region upstream of the transcriptional start site of CDK6. A total of 23 patients with indolent B-cell lymphoproliferative disorders and juxtaposition of the IG and CDK6 genes, including 20 with IGK and CDK6 juxtaposition, have been reported thus far. This rearrangement leads to the overexpression of CDK6, which encodes a cyclin-dependent protein kinase involved in cell cycle G1 phase progression and G1/S transition.

Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience

Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.

Hampered influenza-specific IgG B cell responses whereas IgM and IgA responses are maintained in monoclonal gammopathy of undetermined significance

Introduction As a precursor condition to multiple myeloma (MM), MGUS does not present with clinical features of MM or other lymphoproliferative malignancies [1]. However, it is characterized by monoclonal immunoglobulin <30g/L, normal to decreased levels of IgG as well as by B lymphocyte percentages ranging from low to normal [2-4]. Additionally,

Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene

Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders.

Analysis of FNAC of cervical lymph nodes: Experience over a two years period

Background: Cervical lymphadenopathy is a common clinical presentation across patients of all age group. The aetiology may range from a benign nonspecific inflammation to lymphoproliferative disorders and metastatic malignancy. Aims & Objective: The present study was undertaken to study non neoplastic and neoplastic lesions of enlarged lymph nodes by Fine needle aspiration cytology (FNAC) in patients presenting with cervical lymphadenopathy referred to cytopathology department from the OPD/IPD of Civil Hospital, Ahmedabad over a period of two years (November 2011 to November 2013). Materials and Methods: A total of 2018 patients were subjected to FNAC of cervical lymph nodes over two years period (November 2011 to November 2013). Since in 113 patients, either the aspirate was inadequate or the opinion equivocal, the remaining 1905 cases were analysed. Results: Overall tuberculous lymphadenitis was the most common finding (898/1905, 46%), followed by reactive hyperplasia (624/1905, 33%). Malignant pathology accounted for 16% (306/1905) of cervical lymph node enlargement, most of which was due to metastatic squamous cell carcinoma (179/306, 58%). Conclusion: FNAC is an excellent first line of investigation and when used with a proper combination of experience and diligence, it can efficiently help at arriving in exact diagnosis.

Unexpected FDG-PET uptake in the gastrointestinal tract: endoscopic and histopathological correlations.

To investigate the nature and significance of unexpected positron emission tomography with fluorodeoxyglucose (FDG-PET) uptake within the gastrointestinal tract (GIT). Patients with unexpected FDG-PET findings in the GIT were evaluated. All patients had a previous confirmed malignancy, either solid or lymphoproliferative. The radiologic reports were performed by experienced radiologists with an exclusive PET expertise. Endoscopy, i.e., esophagogastroduodenoscopy (EGD) and colonoscopy, and histopathological evaluation of all findings was performed in all patients in accordance to the FDG-PET results. The findings from each of these modalities were compared to each other. Both clinically significant and insignificant findings were assessed. Seventy-two patients were endoscopically evaluated. Twenty-seven patients (37.5%) had primarily a lymphoproliferative tumor and 45 (62.5%) had solid tumors. In 50 patients (69.4%) the endoscopic examination revealed lesions in the same anatomical areas as the FDG-PET findings. Among these 50 patients, malignant and premalignant lesions i.e., adenomatous polyps were found in 16 (32%) and 9 (18%) patients, respectively. Inflammation was noted in an additional 20 patients (40%). Compared to primary solid tumors, a background of primary lymphoproliferative malignancy was more likely to reveal an additional primary malignancy (15.6% vs 33.3%, respectively, P < 0.01). EGD compared to colonoscopy, revealed altogether 11 (25.6%) new malignancies compared to 5 (17.2%), respectively, P = 0.12. No GIT clinically significant findings were overseen by the FDG-PET. Unexpected FDG uptake in the GIT is commonly encountered and may contain significant findings. Endoscopy evaluation is justified in order to detect these additional findings.

A case of warm autoimmune haemolytic anaemia with intravascular haemolysis: a rare presentation

Autoimmune haemolytic anaemia (AIHA) is a rare (prevalence 0.2 -1.0 per 100,000 population) but a potentially fatal condition. Diagnosis of AIHA is based mainly on Direct Agglutination Test (DAT/Coomb's test). AIHA is classified into warm (optimal autoantibody reactivity at 37°C) and cold (optimal autoantibody reactivity at 4°C) types. Based on the presence or absence of an underlying cause, it is divided into primary (idiopathic) and secondary (secondary to lympho proliferative disorders, autoimmune disease, drugs and non-haematological malignancies). Warm type accounts for about 70% of cases with AIHA. It can occur at any age, but mostly after 40 years. Haemolysis in warm AIHA is mediated by IgG alone or IgG with complement. Once immunoglobulins are bound, the red cells are taken up by the macrophages of the reticulo-endothelial system which has receptors for the Fc fragments of the immunoglobulins. As the red cells are haemolysed extravascularly this occurs mainly in the spleen. Intravascular haemolysis is unusual in warm AIHA, although it can occur rarely, as warm autoantibodies can fix complements. We report severe warm AIHA in an adult with evidence of intravascular haemolysis, which is an unusual presentation.

Prolonged Survival Of Poor Risk Follicular Lymphoma Patients Following Primary Treatment With Rituximab-Supplemented CHOP Or HDS With Autograft: Long-Term Results Of The Multicenter Randomized GITMO/FIL Trial

▪ IntroductionA randomized multicenter study of 134 Follicular Lymphoma (FL) patients, selected for age less than 60 yrs. and poor prognostic features according to age-adjusted IPI (2-3) and IIL-score (3 or greater) was conducted between March 2000 and May 2005, among 30 Italian Centers. The study compared efficacy and tolerability of CHOP-R vs. R-HDS with autograft as primary treatment in poor-risk FL. Initial results have been already reported (Ladetto M et al, Blood 2008), showing superior disease control with R-HDS without any survival advantage. We have recently updated the long-term outcome and the results at long-term are here presented at a median follow-up of 9.5 yrs. Patients and MethodsOf the original 134 randomized patients, the long-term outcome has been updated for 125 patients, 61 of CHOP-R and 64 of R-HDS arms. Clinical characteristics at study entry and treatment schedules have been already reported. Briefly, the main features of the updated patients included: median age 51 yrs. (22-60), M/F ratio 74/51, aaIPI 2-3 90%, FLIPI >2 (retrospectively assigned) 60%, high LDH 49%, bulky disease 62%, B-symptoms 45%, BM involvement 86%. Clinical characteristics were balanced among the two arms. Treatment schedule consisted of: i. standard arm: 6 courses of cyclo-phosphamide/doxorubicin/vincristine/prednisone followed by 4-weekly rituximab courses (CHOP-R); ii. experimental arm: rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS). The analysis was intention to treat with event-free survival as the primary endpoint. Minimal residual disease was evaluated post treatment in 58 patients with a bcl-2/IgH MBR or mcr translocation confirmed at diagnosis by nested PCR. The trial was registered at www.clinicaltrials.gov as no. NCT00435955. The long-term outcome has been updated in July 2013 by 28 out of 30 participating Centers accounting for 125 patients (93% of the whole series). ResultsComplete remission (CR) was achieved by 88 (70.4%) patients, including 35 (57%) with CHOP-R and 53 (83%) with R-HDS (p < .001); in addition, 37 out of 58 (64%) patients achieved a Molecular Remission (MR). At a median follow-up (MFU) of 9.5 yrs., 88 patients (70.4%) are alive. Overall, 19 patients died for lymphoma progression (11 in the CHOP-R, 8 in the R-HDS arms), there were nine deaths for secondary malignancy (3 in the CHOP-R, 6 in the R-HDS arms), nine more patients died for other causes, including four early toxic deaths. The overall survival projection for the whole series is 78% and 70% at 5 and 10 yrs., respectively. As shown in Figure 1, there were no main differences in the long-term OS between the two arms, with 5 and 10 yrs projections respectively of 75% and 70% for CHOP-R and 81% and 70% for R-HDS (p=0.96). Response to primary treatment had a major impact on the OS, with 5 and 10 yr survival projections respectively of 90% and 80% for patients achieving CR, and of 49 and 43 for those with less than CR (p < .001) (Figure 2A). Similarly, MR achievement was associated with prolonged overall survival, with 5 and 10 yr survival projections respectively of 89% and 83% for patients with PCR-ve on BM cells, and of 76 and 57 for those with persistent PCR-positivity (p = .03) (Figure 2B). [Display omitted] [Display omitted] ConclusionThe long-term follow-up of the randomized CHOP-R vs. R-HDS trial indicate that: i. poor risk FL may now experience a prolonged survival, with approximately 70% of patients alive at 10 yrs., due to the combined efficacy of both primary chemo-immunotherapy and salvage treatments; ii. the superior disease control of R-HDS compared to CHOP-R does not translate in any survival advantage, with analogous OS regardless of which treatment is used; iii. also in FL like in other lymphoproliferative malignancies, achieving CR and MR is crucial not only for the disease control but also for long-term overall survival; iv. lymphoma progression remains the major cause of death, while secondary neoplasms, in particular secondary leukemias represent the second cause of treatment failure. Thus, efforts are still needed in order to increase the anti-tumor efficacy while reducing any potential late effect in treatment options for FL. Disclosures:Tarella:Roche Co.: support and honoraria for Conference participation Other. Ladetto:Roche: Honoraria, Research Funding, Speakers Bureau.

Update On The Safety and Efficacy Of The Pan Class I PI3K Inhibitor SAR245408 (XL147) In Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients

BackgroundConstitutive activation of phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway by various mechanisms has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). There is mounting evidence suggesting that along with PI3Kγ, PI3Kα may be involved in CLL/NHL. SAR245408 is a potent and selective inhibitor of all α, γ and δ class I PI3K isoforms. It has been shown to inhibit PI3K signaling and impact tumor growth in preclinical tumor models. The impact of SAR245408 on safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor effect was evaluated in patients with relapsed/refractory CLL and NHL from the Sanofi sponsored phase 1 single-agent study (NCT00486135) [Brown et al. ASH Annual Meeting Abstracts 2011. 118 (21): 2683]. MethodsSAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 25 patients were enrolled at the maximum tolerated dose identified in solid tumor patients as part of the expansion cohort in relapsed/refractory lymphoproliferative malignancies. Plasma cytokines and chemokines were evaluated using the Myriad RBM Human Discovery MAP250+ panel (> 250 analytes) and ELISA assays. ResultsAmong the 25 patients (pts), 40% (n=10) had refractory CLL and 60% (n=15) had various relapsed/refractory lymphomas (R/RL), including follicular lymphoma (FL) (n=5), diffuse large B-cell lymphoma (DLBCL) (n=4), Waldenstrom's macroglobulinemia (WM) (n=3), Hodgkin lymphoma (n=2) and B-cell prolymphocytic leukemia (n=1). The median age was 65 years (range 28–83), and 56% were female. Eighty percent of pts had stage III-IV disease and 48% had bulky disease. Five pts were categorized as having refractory disease and the median number of prior regimens was 1 (range 1-7) for CLL pts and 3 (range 0-9) for R/RL pts. For all 25 patients, the median starting absolute lymphocyte count was 1.15 x 103/μL (range 0.3–37.2), the median starting hemoglobin was 11.4 g/dL (range 9.1–15) and the median platelet count was 162 x 103/μL (range 60–431). The median number of cycles administered in CLL pts was 10 (range 5-24) and 5 (range 1-26) in R/RL pts. Six CLL pts experienced an increase in absolute lymphocyte counts within 2-4 weeks of treatment, as has been seen with other PI3K inhibitors. According to modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria, 4 CLL pts had partial response (PR), 1 had nodal PR with increased lymphocytosis, and 5 had stable disease (SD); the progression free survival (PFS) in the responding pts was 22, 21.2, 15.6 and 15.4 months while in the SD pts was 12.5, 9.2, 7.4, 5.6, 4.6 and 3.6 months. According to the modified International Working Group response criteria, 3 PRs were reported in R/RL pts [1 WM, 1 DLBCL (transformed) and one FL with PFS of 23.7, 18.4 and PFS 4.8 months respectively]. One hundred percent of CLL and 80% of R/RL pts reported grade 3 or higher AEs, with the most common (≥ 10% of patients) including neutropenia, diarrhea, anemia and hypotension. SAR245408 induced a reduction in levels of chemokines involved in lymphocyte trafficking in CLL subjects (n=8), including CXCL13, CCL3, CCL22 and CCL19 (64, 58, 52 and 54% reduction, respectively, p<0.05) similar to what was reported with PI3K δ specific inhibitors. In addition, a reduction of tumor necrosis factor receptor 2 (TNFR2) and interleukin-2 receptor alpha (IL-2Rα) levels was observed (63% reduction each, p<0.01). ConclusionsThe recommended phase 2 dose of SAR245408 in solid tumor patients was confirmed as safe and tolerable in patients with CLL and R/RL. Single agent SAR245408 demonstrates clinical activity in patients with relapsed or refractory CLL and promising pharmacodynamic effects on chemokine levels involved in lymphocyte trafficking. Disclosures:Brown:Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding; Avila: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy. Off Label Use: The abstract shows scientific information on SAR245408 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Egile:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau.

SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study

SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study

Treatment of rheumatoid arthritis with etanercept with reference to disease-modifying anti-rheumatic drugs: long-term safety and survival using prospective, observational data

The objective of this study was to examine the long-term safety of etanercept (ETN) in comparison with conventional DMARDs in a large observational cohort of RA patients in the UK. Data were made available from the British Society of Rheumatology Biologics Register for a cohort of patients with RA treated with ETN and a reference cohort of RA patients treated with conventional DMARDs (maximum follow-up 10 years). The adjusted risk of events was compared using Cox proportional hazards models. There were 3529 eligible ETN-treated patients (16,919 person-years) and 2864 conventional DMARD-treated patients (11,095 person-years), with notable differences between groups at baseline. Crude mortality rates were 12.0 vs 20.1 events per 1000 person-years for ETN and conventional DMARD patients, respectively, with an adjusted hazard ratio (aHR) of 0.72 (95% CI 0.54, 0.96). There was no difference in the long-term risk of serious infections (aHR = 1.02, 95% CI 0.83, 1.25). However, the risk was increased for ETN in the first 2 years (aHR = 1.56, 95% CI 1.16, 2.09; aHR = 1.32, 95% CI 1.06, 1.65). The aHRs (95% CIs) of various outcomes were cancer, 0.84 (0.68, 1.03); lymphoproliferative malignancy specifically, 0.51 (0.28, 0.95); all other serious adverse events, 0.70 (0.56, 0.87) and cardiac events specifically, 0.52 (0.37, 0.72). There was no evidence of adverse outcome from long-term exposure to ETN. There was evidence of improved survival, reduced cardiovascular events and reduced lymphoproliferative malignancies.

Cancer-free survival of psoriasis patients treated with methotrexate and cyclosporine combination

Context: Combination of methotrexate and cyclosporine was used and reported to be effective for recalcitrant psoriasis patients. Also each agent is accused for development of malignancies.Objective: To evaluate the cancer-free survival of psoriasis patients who received methotrexate and cyclosporine treatment at the same time.Methods: Psoriasis patients who had been treated with combination of cyclosporine and methotrexate between March 2000 and April 2005 were questioned in 2011. A diagnosis of new cancer during follow-up period was asked and also each patient was evaluated by a questionnaire.Results: Seventeen psoriasis patients were not treated due to a diagnosis of new cancer during the follow-up period. Also none of them complained of possible symptoms of skin or lymphoproliferative malignancies. The median follow-up time was 76 months.Conclusion: Psoriasis patients who had been treated with methotrexate and cyclosporine combination did not report a detected malignant disease.