Allogeneic Stem Cell Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 Myeloma – An Interim Analysis of the German DSMM V Trial.

Abstract Abstract 51 Background Allogeneic stem cell transplantation (allo SCT), a treatment modality based on transfer of immunocompetent donor lymphocytes offers curative potential to subjects with a variety of hematological cancers. In multiple myeloma (MM), high-dose melphalan followed by autologous stem cell transplantation (auto SCT) is adopted as a standard of care. However, it remains palliative since virtually all patients (pts) relapse and renders allo SCT an option of interest. Deletion of chromosome 13q14 (13q-) in MM has been shown to negatively impact prognosis. Therefore, improvement of therapy for 13q- pts is highly desirable. Patients and methods A prospective two-arm multi…

Relapsed and/or Refractory Mantle Cell Lymphoma: What Role for Temsirolimus?

Mantle Cell Lymphoma (MCL) is associated with a dismal prognosis. Recently, along with the improved understanding of the pathophysiology of this disease, new first line regimens have been established and in addition novel treatment options have entered the clinical arena. In consequence, prognosis of the disease has fortunately improved. We here focus on the rationale, current clinical knowledge and future concepts of Temsirolimus, an inhibitor of mTOR, in the treatment of MCL. At this time this drug has been shown to be effective as single agent for relapsed disease and early combination data show promising results. In addition, with a brief outline of other treatment options, we aim to g…

Results of a Phase II Study of Pixantrone in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma.

Abstract Background: Pixantrone is a novel aza-anthracenedione with less cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in murine leukemia and lymphoma tumor models. Pixantrone as single agent therapy led to major responses in patients (pts) with multiply relapsed aggressive non-Hodgkin’s lymphoma (NHL), including diffuse large B-cell lymphoma (DLCL). In a phase I dose-ranging study of pixantrone (80 to 180 mg/m2) replacing doxorubicin (CPOP) in a CHOP-like regimen, the optimal dose (RD) from that study was found to be 150 mg/m2. Methods: In this international, multi-center, phase II study the primary objective was to assess the efficacy and safety of the CPOP…

Current results on the use of imatinib mesylate in patients with relapsed philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation

Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and …

Hepatocellular expression of lymphocyte function—associated antigen 3 in chronic hepatitis

T lymphocyte-mediated cytolytic immune reactions are considered a major cause of hepatocyte injury in chronic viral and autoimmune hepatitis. To further investigate local immune responses, we studied the expression of lymphocyte antigens and cell-cell interaction molecules known to be involved in effector-target cell interactions by light and electron microscopy in liver biopsy specimens from patients with chronic viral and autoimmune hepatitis. CD8+ lymphocytes were found to be the predominant population of cells in the inflammatory infiltrate in chronic hepatitis B and non-A, non-B hepatitis. In contrast, CD4+ cells constituted a comparably higher proportion of cells and were more numerou…

Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engag…

Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy

Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median C(max) and C(trough) values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher C(max) and C(trough) values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas …

IBRUTINIB VS TEMSIROLIMUS: THREE-YEAR FOLLOW-UP OF PATIENTS WITH PREVIOUSLY TREATED MANTLE CELL LYMPHOMA FROM THE PHASE 3, INTERNATIONAL, RANDOMIZED, OPEN-LABEL RAY STUDY

Y-90 Ibritumomab Tiuxetan as Consolidation Following Three Cycles of Fludarabine-Cyclophosphamide-Rituximab Chemoimmunotherapy in Patients with Relapsed Follicular, Indolent or Mantle-Cell Lymphoma: A Prospective “Dose”-Finding Study.

Abstract BACKGROUND: Tumed sequential treatment with fludarabine/cyclophosphamide/rituximab (FC-R) followed by Y-90 ibritumomab tiuxetan (IT) radioimmunotherapy may improve progression-free survival in patients (pts) with CD20+ NHL. However, even unpretreated pts submitted to four to six cycles of a fludarabine-containing combination and then IT at an Y-90 activity of 15 MBq/kg will experience severe prolonged, transfusion-dependent and only partially reversible pancytopenia, thus limiting its use in a non-curative setting (Jurczak et al., ASH 2005). AIM: We report on a trial including anthracycline-pretreated pts with relapsing CD20+ lymphoma > age 50 and unsuitable for myeloablative tr…

Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia

We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete respo…

Ofatumumab (OFA) in Combination with CHOP for Previously Untreated Follicular Lymphoma: Follow-up Results

Abstract Abstract 1632 Background: OFA is a fully human monoclonal antibody that binds to both the large and small extracellular loops of CD20. OFA is currently approved for patients (pts) with refractory chronic lymphocytic leukemia and has demonstrated activity in non-Hodgkin's lymphomas, including follicular lymphoma (FL). We previously reported results of a phase II study of OFA in combination with CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg daily for 5 days) chemotherapy (O-CHOP) in pts with previously untreated FL (Czuczman et al. Br J Haematol. 2012;157:438). We now report updated efficacy, safety and pharmacokinetic (PK) follow-up…

Ofatumumab Combined With Fludarabine and Cyclophosphamide (O-FC) Shows High Activity in Patients With Previously Untreated Chronic Lymphocytic Leukemia: Results From a Randomized, Multicenter, International, Two-Dose, Parallel-Group Phase II Trial

Abstract 207 Introduction: Chemoimmunotherapy regimens have become the treatment standard for patients with CLL. Ofatumumab is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity. Recent studies demonstrated single-agent ofatumumab activity, with high overall response rates (ORR) in patients with refractory CLL. We conducted an international, randomized, parallel group, Phase II trial with two doses of ofatumumab combined with fludarabine and cyclophosphamide (FC) in previously untreated patients with CLL to evaluate the efficacy and tolera…

Inhibition of expression of natural UAG suppressor glutamine tRNA in HIV-infected human H9 cells in vitro by Avarol.

HTLV-IIIB-infected H9 cells are shown to contain a high level of the natural UAG suppressor glutamine tRNA(UmUG Gln); this tRNA has been demonstrated to be required for the synthesis of Moloney murine leukemia virus (Mo-MuLV)-encoded protease. After cultivation of HTLV-IIIB-infected H9 cells with Avarol at a concentration (1 microgram/ml), previously found to protect the cells against the cytopathic effects of HTLV-III, an almost complete inhibition of the synthesis of the tRNA(UmUG Gln) was observed. Moreover, we obtained some evidence that the processing of the HTLV-III precursor protein p53 to p24 is inhibited by Avarol in infected cells, suggesting that the compound interferes with the …

Hepatitis C virus antibody secretion in vitro by peripheral blood lymphocytes.

A recombinant polypeptide corresponding to a virus-specific cDNA clone (c100-3) serves as the antigen for a hepatitis C virus (HCV) antibody assay. Previous investigations have shown an 80% prevalence of HCV antibodies in sera of patients suffering from post-transfusional chronic hepatitis non-A, non-B, but positive results were also obtained for 30 to 70% of sera from patients with chronic hepatitis B or autoimmune hepatitis. In this study we show that HCV antibodies are secreted by peripheral blood lymphocytes (PBL) in vitro. PBL from 12/35 patients with chronic non-A, non-B hepatitis and 1/6 patients with chronic active hepatitis B spontaneously secreted HCV antibodies in cell culture su…

Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study

Purpose Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed or refractory disease. This study evaluated the efficacy and tolerability of belinostat, a novel histone deacetylase inhibitor, as a single agent in relapsed or refractory PTCL. Patients and Methods Patients with confirmed PTCL who experienced progression after ≥ one prior therapy received belinostat 1,000 mg/m2 as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary end point was overall response rate. Secondary end points included …

e System and intrahepatocelullar HBcAG and HBsAG in HBsAG positive patients with liver diseases and healthy carriers.

Patients with hepatitis-B surface antigen positive liver diseases and healthy carriers were studied for the presence of e-antigen and anti-e as well as for intrahepatocellular HBsAG and hepatitis-B core antigen. The e-antigen was demonstrated in 9 out of 12 patients with chronic perisitent hepatitis, in 15 out of 39 patients with chronic active hepatitis, in 3 out of 40 patients with acute type B hepatitis, and in 2 out of 9 patients with a protracted course of type B hepatitis. No e-antigen was found in healthy HBsAG carriers nor in patients with complete recovery from type B hepatitis one year after onset of the disease. Anti-e was detected in 24 out of 61 healthy HBsAG carriers with a no…

Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial.

Abstract Background The single‐arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment. Methods Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer‐related genes was examined. Responder‐ versus nonresponder‐associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created …

The significance of the pre-S region of the hepatitis B virus

Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Coug…

Modification of the immune response against hepatitis B virus by the human immunodeficiency virus.

Hepatitis B virus and the human immunodeficiency virus are similarly transmitted. Individuals with preexisting HIV infection have a higher chance to become HBsAg carriers than do anti-HIV negative persons. Cytotoxic T cells with specificity for HBcAg, that are under the control of HBcAg-specific helper T cells, are responsible for liver injury. There is good evidence that HIV infection lowers inflammatory activity, is associated with milder liver histology, high levels of viral replication and low seroconversion rates. In addition interferon alpha therapy is less effective in anti-HIV positive subjects. The immune response against HBsAg is helper T-cell dependent and vaccination against hep…

An open-label phase II study of ibrutinib in patients with refractory follicular lymphoma

TPS8614^ Background: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) and comprises approximately 22% of all NHL cases. Most patients treated eventually relapse and subsequent responses and duration of responses become shorter. Patients ultimately become resistant to chemoimmunotherapy and repeated treatment-related toxicity commonly outweighs the benefit of treatment. Ibrutinib is a potent inhibitor of BTK (downstream of the B-cell receptor, BCR) that binds covalently to Cys-481 in the active site, abrogating intrinsic survival pathways (eg, ERK1/2, NF-kB, AKT) as well as survival signals from the microenvironment (eg, TNF family members: BAFF, CD40L; cytokine…

Viral Hepatitis — An Update

In 1973, Feinstone and co-workers [52] were the first to report the visualization of virus-like particles by immune electron microscopy in acute phase stool specimens of human volunteers who developed hepatitis following inoculation with MS-1 strain of hepatitis A virus [18]. Soon thereafter morphologically identical particles were recovered from the stool of individuals acquiring hepatitis during natural outbreaks of the disease [39, 64].

Control Of Organ Transplant-Associated Graft-versus-Host Disease By Activated Host Lymphocyte Infusions

Background Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. Methods Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). Results Adoptive trans…

Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)

Abstract Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefi…

Minimum tolerable interval of 90yttrium ibritumomab-tiuxetan to autologous stem cell transplantation after high-dose chemotherapy with carmustin, etoposide, cytarabine, and melphalan for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

6543 Background: High-dose therapy and autologous stem cell transplantation (ASCT) in patients (pts) with aggressive B-NHL failing from immunochemotherapy including rituximab show poor outcome with 3y PFS of 39% (Gisselbrecht et al. JCO 2010). Combining BEAM with 90yttrium ibritumomab tiuxetan is a promising option to enhance the efficacy of the high-dose regimen. Methods: Pts without disease progression during salvage therapy of relapsed or refractory CD20+ aggressive B-NHL were included in this prospective, multicenter, phase I/II trial. Primary endpoint was the maximum tolerated dose of 90Yttrium ibritumomab tiuxetan given as close as possible to ASCT defined as <2 pts with dose limi…

Association of hepatitis Be antigen (HBeAg) with the core of the hepatitis B virus (HBcAg).

— Three substances (pronase E, sodium dodecylsulfate (SDS) and guanidine hydrochloride) with different chemical actions partially convert HBcAg to HBeAg. This process retains the integrity of the HBcAg particle, which was not different between HBcAg subpopulations, and does not generate HBcAg or HBeAg sub-units. DNA polymerase activity was destroyed by SDS and guanidine hydrochloride, but not by pronase E. Serum HBeAg could not be converted into HBcAg, suggesting that this might be an irreversible process. The data are consistent with the assumption that HBcAg and HBeAg are coded for by the same gene (C gene of the HBV-DNA).

Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis.

The chimeric monoclonal antibody rituximab is the standard of care for patients with B-cell non-Hodgkin lymphoma (B-NHL). Rituximab mediates complementdependent cytotoxicity and antibodydependent cellular cytotoxicity of CD20-positive human B cells. In addition, rituximab sensitizes B-NHL cells to cytotoxic chemotherapy and has direct apoptotic and antiproliferative effects. Whereas expression of the CD20 antigen is a natural prerequisite for rituximab sensitivity, cell-autonomous factors determining the response of B-NHL to rituximab are less defined. To this end, we have studied rituximab-induced apoptosis in human B-NHL models. We find that rituximab directly triggers apoptosis via the m…

The role of stem cell transplantation in follicular lymphoma.

With the introduction of novel treatments paradigms to if or when to use transplantation strategies for patients with follicular lymphoma have changed substantially. Autologous transplantation has been intensively evaluated as consolidation after first induction treatment with positive effects, however the introduction of Rituximab led to comparable improvements and HDT has been moved to relapse treatment. In this indication HDT was frequently use already at first relapse, but now is dominantly used in patients with a highrisk profile, e.g. failure of response, early or multiply relapse and/or signs of transformation. The ideal place for allogeneic transplantation is even harder to define, …

Evaluation of Safety, Tolerability and Efficacy of Temsirolimus in Patients with Relapsed or Refractory Mantle Cell Lymphoma (Rel/Refr Mcl) in Routine Clinical Practice

ABSTRACT Aim: Temsirolimus (TEMS), an mTOR-inhibitor, is approved in the EU for the treatment of patients (pts) with relapsed or refractory (rel/refr) MCL. A pivotal study demonstrated significantly longer progression free survival with TEMS (175 mg weekly for 3 weeks followed by 75 mg weekly) in rel/refr MCL pts compared to investigatoŕs choice therapy (4.8 mo vs 1.9 mo; P = .0009). To evaluate safety and efficacy of TEMS in an unselected patient population during clinical routine, a prospective non-interventional study with TEMS in rel/refr MCL pts is useful. Here we report on interim results of the study. Methods: A German multicenter registry for rel/refr MCL pts treated with TEMS was s…

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma : an international, randomised, open-label, phase 3 study

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index…

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Results of the Part I Cohort of the STORM Trial

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the m…

Correlations Between Ofatumumab Exposure and Treatment Outcomes for patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Ofatumumab, Fludarabine, and Cyclophosphamide Chemoimmunotherapy

Abstract Abstract 1793 Introduction: Results: Seven pts (4 male) with a medianLittle is known about the pharmacokinetics (PK) and pharmacodynamics of CD20 monoclonal antibody (mAb) with chemotherapy in patients (pts) with CLL. Ofatumumab (O) is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Safety and efficacy of O at 2 dose levels in combination with fludarabine and cyclophosphamide (FC) were evaluated in previously untreated pts with CLL. Relationship between O PK, baseline characteristics, and clinical outcomes were studied. Pts and Methods: Pts with active CL…

Safety and feasibility of CHOP/rituximab induction treatment followed by high-dose chemo/radiotherapy and autologous PBSC-transplantation in patients with previously untreated mantle cell or indolent B-cell-non-Hodgkin's lymphoma

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Re…

Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the R…

Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT)

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and…

Effect of Prognostic Risk Classification on Temsirolimus Efficacy and Safety Outcomes in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Abstract Abstract 2708 Background: The simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) has been shown to be a good predictor of patient survival (Blood 2008;111:558–65; Blood 2010;115:1530–1533). This post hoc study analyzed data from a randomized, phase III clinical trial investigating temsirolimus (TEM) in relapsed/refractory mantle cell lymphoma (MCL) in which TEM 175/75 (175 mg for first 3 weeks then 75 mg weekly) demonstrated significantly longer progression-free survival (PFS) vs investigator's choice of therapy (INV; 4.8 vs 1.9 months, respectively; hazard ratio [HR]=0.44; P=.0009; J Clin Oncol 2009;27:3822–9). Patients receiving TEM 175/25 (175 mg for first 3 w…

Autologous Transplantation of In Vivo Purged PBSC in CML

To determine the effectiveness of different methods for the detection of tumor cell contamination of collected peripheral stem cells, we performed a study on 39 chronic myelogenous leukemia (CML) patients who were consecutively treated at our department. Analyses of tumor cell contamination by fluorescence in situ hybridization (FISH), conventional cytogenetics, and polymerase chain reaction (PCR) showed marked differences in the percentage of evaluable results: Quantitative analysis of tumor cell contamination was feasible in 60 of 105 (57%) samples evaluated with the use of conventional cytogenetic analysis and in 105 of 107 (98%) samples analyzed by FISH. PCR was evaluable in all 85 samp…

Demonstration and partial characterization of an intermediate HBcAG (Dane particle) population.

Abstract Hepatitis-B core antigen (HBcAg) was released from Dane particles previously separated from anti-HBc by repeated pelleting through sucrose gradients separated into three HBcAg populations when analysed by cesium chloride density gradient centrifugation. Heavy HBcAg particles banded at a density of 1.355 gm/ml, intermediate HBcAg particles at a density of 1.33 gm/ml, and light mediate HBcAg particles at a density of 1.30 gm/ml. Like heavy HBcAg particles, intermediate HBcAg particles contained DNA polymerase activity, but the ratio of HBcAg to DNA polymerase activity was significantly different in both populations. Intermediate HBcAg particles could not be separated from heavy HBcAg…

Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM

Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex

Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial.

Summary We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%)…

mTOR inhibition in diffuse large B-cell lymphoma: new hope?

Combined Immuno-Chemotherapy (R-CHOP) Results in Significantly Superior Response Rates and Time to Treatment Failure in First Line Treatment of Patients with Lymphomplasmocytoid/ic Immunocytoma (LP-IC) - Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Abstract Lymphomplasmocytoid/ic immunocytoma (LP-IC), including Waldenstrom’s macro-globulinemia and lymphoplasmacytoid lymphoma according to the Kiel classification (the latter one subsummed as a variant of B-CLL in the WHO classification), is an indolent lymphoma, which is incurable by conventional chemotherapy in the advanced stage of disease. The anti-CD20 antibody Rituximab has shown remarkable activity in indolent lymphomas, in particular when combined with chemotherapy. Based on these results the GLSG investigated the efficacy of a combined immuno-chemotherapy (R-CHOP: Rituximab 375 mg/m2 d0-1; cyclophosphamide 750 mg/m2 d1; doxorubicine 50 mg/m2 d1; vincristine 1.4 mg/m2 d1; prednis…

Idelalisib Impairs TREM-1 and TLR Mediated Neutrophil Activation

Abstract Introduction: Polymorphonuclear neutrophils (PMN) play an essential role in innate inflammatory processes. Their functions are strictly regulated and many activating / inhibiting mechanisms along with their pathways are only incompletely understood. Besides toll-like receptors (TLR) and NOD-like receptors (NLR), triggering receptor expressed on myeloid cells (TREM)-1 is implicated in innate immune activation of these cells and plays a role in infectious as well as non-infectious conditions. Activation of TREM-1 results in release of pro-inflammatory chemokines and cytokines, increased surface expression of cell activation markers and degranulation. In TREM-1 downstream pathways and…

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with h…

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study.

Summary Salvage therapy followed by high-dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R-DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) were eligible. R-Dexa-BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression-free-survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B-cell lymphom…

Sustained complete hematologic remission after administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML.

Abstract Imatinib mesylate, a tyrosine kinase inhibitor targeting bcr-abl, platelet-derived growth factor receptor (PDGF-R), and c-Kit, effectively induces hematologic and cytogenetic remissions in bcr-abl+ chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with only mild to moderate side effects. Here, we describe the successful treatment of a 64-year-old man with c-Kit+ secondary acute myeloid leukemia (AML) refractory to standard chemotherapy. Upon 2 weeks of imatinib mesylate administration, the patient achieved a complete hematologic remission in peripheral blood. In addition, complete clearance of leukemic blasts in bone marrow and a significant cytogenetic response…

Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy.

Recent studies have shown that both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of diabetic nephropathy. To examine whether markers of tubular damage are useful in monitoring the progression of disease, we measured urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-fatty acid-binding protein (LFABP), and kidney injury molecule-1 (KIM-1) in a 3-year intervention study of 63 type 1 diabetic patients with kidney disease. The baseline mean glomerular filtration rate (GFR) was 87 ml/min per 1.73 m(2) and urinary albumin excretion 1141 mg/24 h. Patients with the highest compared with the lowest quartile of urinary N…

Ultrastructural localization of interferon-producing cells in the livers of patients with chronic hepatitis B

Cells expressing alpha- and gamma-interferon were localized in the liver tissue of patients with chronic hepatitis B by means of light and electron microscopy using monoclonal antibodies. Interferon-positive cells were regularly seen in the infiltrating mononuclear cells, and the number showed a good correlation with the degree of the necroinflammatory activity of the disease. In chronic persistent hepatitis and in normal livers, they were infrequent or virtually absent. alpha-Interferon was shown to be positive in lymphocytes, polymorphonuclear leukocytes and fibroblasts, Kupffer cells and, weakly, in the cytoplasm of a few hepatocytes in cases of active hepatitis, whereas gamma-interferon…

Natural killer cell activity as a prognostic parameter in the progression to AIDS.

Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study

Purpose In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial. Patients and Methods As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. For…

Temsirolimus in Combination with Bendamustine and Rituximab (BeRT) for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Final Phase I/II Results

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas (Smith et al, JCO 2010). Furthermore, in relapsed MCL a phase III trial demonstrated superiority of Temsirolimus to chemotherapy. Although novel treatment options as Ibrutinib have changed the treatment landscape for MCL, no curative potential could be shown for this approach and novel concepts continue to be needed. Several trials provided promising results when Temsirolimus is combined with agents like Rituximab (Ansell et al, Lancet Oncology 2011) or chemoimmunotherapy, as shown in part I (phase I) of the reported trial (Hess, Leukemia, 2015). We now report the final analysis of…

The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL – Results From the Phase-II STORM Trial

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m(2) (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m(2) day 3, cytarabine 2 × 2  g/m(2) day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg fo…

Temsirolimus for the treatment of mantle cell lymphoma.

Although recent progress has been made in the treatment of mantle cell lymphoma (MCL) the majority of patients experience relapse and ultimately die of their disease. The translocation t(11;14) is a prerequisite for the diagnosis of MCL and results in overexpression of cyclin D1. Its protein translation is controlled by mTOR, a key element of the PI3K/Akt pathway, and mTOR constitutes an attractive therapeutic target. Temsirolimus, a specific inhibitor of mTOR, has been evaluated in two Phase II trials in patients with relapsed MCL, and promising response rates up to 40% were found. Subsequently, a randomized Phase III trial was initiated, in which superiority in remission induction and pro…

Serum hyaluronate and type III procollagen aminoterminal propeptide concentration in chronic liver disease. Relationship to cirrhosis and disease activity.

. To analyse the relationship between the presence of liver cirrhosis and hepatic inflammation and the serum concentrations of the aminoterminal propeptide of procollagen type III (P-III-NP) and of hyaluronic acid (HA) in chronic liver disease, we measured P-III-NP and HA concentrations in paired serum samples from 133 patients with various chronic liver diseases, from 22 patients with acute hepatitis and from 50 healthy age-matched controls. In 24 (of the 133) patients with autoimmune chronic liver disease, follow-up determination was performed during therapeutic treatment with immunosuppressive drugs. Compared with controls P-III-NP concentrations (medians) were significantly elevated in …

Molecular analysis of the erythropoietin receptor system in patients with polycythaemia vera

Summary Erythropoietin (EPO) is a potent regulator of the viability, proliferation and differentiation of erythroid progenitor cells. Its effect is mediated by binding to the erythropoietin receptor (EPO-R), a member of a new cytokine receptor family. Alterations of the EPO/EPO-R system have recently been shown to be involved in the pathogenesis of familial erythrocytosis and polycythaemia vera (PV). In order to define whether genetic changes in the EPO-R gene and its ligand play a role in the development of PV, the structure and expression levels of the EPO-R and EPO genes were examined in samples from bone marrow and/or peripheral blood mononuclear cells of 24 patients with PV. As expecte…

Rituximab in Combination with CHOP in Patients with Follicular Lymphoma: Analysis of Treatment Outcome of 552 Patients Treated in a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG) after a Follow up of 58 Months

Abstract We have previously reported that compared to CHOP alone the addition of Rituximab (R) to CHOP significantly increases the response rate (RR), the time to treatment failure (TTF) and also the overall survival (OS) in patients with newly diagnosed advanced follicular lymphoma. However, in the previous report, the median observation time was short with 18 months and no data were reported on the outcome of different risk groups according to the FLIPI (Hiddemann et al., Blood 2005). We now report on the treatment outcome of 552 patients with advanced stage follicular lymphoma randomized between R-CHOP versus CHOP alone after a median follow up of 58 months. Responding patients < …

Utility of presepsin (sCD14-ST) as a diagnostic and prognostic marker of sepsis in the emergency department

Presepsin (PSEP) is released during infectious diseases and can be detected in the blood. PSEP has shown promising results as sepsis marker. We examined the diagnostic and prognostic validity of PSEP in patients suspicious of sepsis on admission in the emergency department (ED). Methods One hundred twenty three patients with signs of SIRS and/or sepsis and 123 healthy individuals were enrolled. PSEP was determined on admission, after 8, 24 and 72 h. Results Mean PSEP concentrations of the control group and the patient group were 130 and 1945 pg/ml. PSEP differed between SIRS, sepsis, severe sepsis and septic shock and showed strong association with 30-day mortality ranging from 10.3% in the…

T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): Oligoclonality of PBC-derived T cell clones

Immunological events are involved in the pathophysiology of chronic active hepatitis as indicated from the accumulation of T lymphocytes at the site of tissue damage. We generated T cell clones from liver biopsies of 3 patients with chronic active hepatitis B and 2 patients with primary biliary cirrhosis. These T cell clones (n = 84) were analyzed by means of T cell receptor (TcR) beta gene rearrangements to determine whether the infiltrate consists of a polyclonal or oligoclonal T cell population. The vast majority (62 of 64) of T cell clones from three different patients with chronic active hepatitis B showed no identical rearrangements of the TcR beta chain genes. In marked contrast, in …

Quality assurance in RT-PCR-based BCR/ABL diagnostics--results of an interlaboratory test and a standardization approach.

Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 or b3a2 BCR/ABL transcripts were analyzed by PCR. In the second part of the test, cell samples containing various concentrations of BCR/ABL-positive cells were analyzed by RT-PCR. Overall PCR sensitivity was sufficient in approximately 90% of the tests, but a significant number of false positive results were obtained. There were significant differences in sensitivity in the cel…

SAFETY AND CLINICAL ACTIVITY OF TEMSIROLIMUS IN COMBINATION WITH RITUXIMAB AND DHAP IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA-REPORT OF THE PROSPECTIVE, MULTICENTER PHASE II STORM TRIAL

Clonal analysis of human T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis

Human T lymphocytes infiltrating the liver in chronic active hepatitis B (CAH-B) and primary biliary cirrhosis were isolated from liver biopsy cores, cloned by limiting dilution technique and expanded in vitro. Phenotypic and functional analysis demonstrates that this tissue infiltrate represents a heterogeneous cell population. However, when compared to peripheral blood lymphocytes of the same patients, a marked enrichment for T8+ cytotoxic T cells was found to exist at a local site in both types of chronic liver disease. These data provide support for the notion that liver cell injury in CAH-B and PBC may be mediated by a common immunologic mechanism likely executed by cells of the T line…

Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.

© 2018 The Authors.

ABCL-346: Overall Survival with Tafasitamab + Lenalidomide (LEN) vs Routinely Administered Therapies for ASCT-Ineligible Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Outcomes from the Observational RE-MIND2 Study

Context Tafasitamab+LEN, a chemotherapy-free, novel treatment for R/R DLBCL, demonstrated efficacy in ASCT-ineligible patients in the single-arm Phase II L-MIND study (NCT02399085). Objective To compare outcomes in patients treated with tafasitamab+LEN in the L-MIND study with matched patient populations treated with commonly administered NCCN-/ESMO-recommended therapies for non-transplant-eligible patients with R/R DLBCL in routine clinical practice. Design RE-MIND2 (NCT04150328) is an observational, retrospective cohort study. The L-MIND tafasitamab+LEN cohort was matched with RE-MIND2 patients using estimated propensity score-based 1:1 nearest neighbor matching balanced for nine patient …

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 …

Comparison of two doses of intravenous temsirolimus in patients with relapsed/refractory mantle cell lymphoma

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versu…

Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial

Abstract Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable d…

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and brid…

Phase 1b/3 study of avelumab-based combination regimens in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

TPS7575 Background: Approximately 50% of patients (pts) with advanced DLBCL are refractory to or relapse following first line R-CHOP therapy. Pts with R/R DLBCL have limited treatment options and a poor prognosis. This study assesses immunotherapy-based regimens containing avelumab (a fully human IgG1 anti–PD-L1 antibody) in combination with utomilumab (a novel 4-1BB agonist), azacitidine, rituximab, and/or conventional chemotherapy (CT; bendamustine) in pts with R/R DLBCL. Methods: JAVELIN DLBCL (NCT02951156) is a global, multicenter, randomized, open-label, 2-component(phase 1b followed by phase 3) study of avelumab-based combination regimens in R/R DLBCL. In phase 1b, up to 84 pts will …

Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma.

Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Am…

Hepatitis B virus and delta infection in male homosexuals

— Six hundred and sixty-six homosexuals were analysed in respect of hepatitis B virus and delta infections. Evidence of ongoing or recent hepatitis B virus infection was found in 450/666 (67.6%) homosexuals; 44 were HBsAg positive. Anti-delta was found in two HBsAg-positive homosexuals. Both individuals had a non-replicative form of HBV infection and biochemical evidence of liver disease. The study confirms that HBV infection is frequent in homosexuals and indicates that delta-infection is rare in male homosexuals.

Analysis of the p53 and MDM-2 gene in acute myeloid leukemia

The MDM-2 (murine double minute 2) gene codes for a cellular protein that can bind to the p53 tumor suppressor gene product, thereby functioning as a negative regulator of p53. In order to define the role of the MDM-2 gene in the pathogenesis of human acute myeloid leukemia, the expression and the sequence of the MDM-2 gene were examined in samples of bone marrow and/or peripheral mononuclear cells of 38 patients by using immunostaining, polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing. Immunohistochemical staining detected a weak accumulation of the MDM-2 protein in AML patients of FAB classification M4 and M5. RT-PCR analysis revealed a heterogeneou…

Treatment for patients with relapsed/refractory mantle cell lymphoma: European-based recommendations

International audience; Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy, but the disease inevitably relapses and often follows an aggressive course. Here, clinical study results published since 2008 for patients with relapsed/refractory MCL were reviewed to compare available evidence for treatment guidance. Most trials identified were non-randomized, phase II studies performed at a limited number of sites, and many evaluated MCL as one of multiple non-Hodgkin lymphoma subtypes. Additional randomized, comparative trials are needed. Treatment selection generally depends on patient need, age and fitness, time of relapse, and line of therapy. Combina…

Lack of hepatitis B virus DNA sequences in sera from patients with acute and chronic liver diseases diagnosed as non-A, non-B-hepatitis

— The sera of 15 individuals with transfusion-associated acute or chronic non A, non B hepatitis, which lacked hepatitis B virus markers, were tested for hepatitis B virus DNA by dot blot hybridization test. Three sera of two patients positive in this test, however, also gave positive results when the labeled plasmid was used as probe instead of labeled HBV-DNA, indicating false positive results in the initial test. In conclusion, the data indicated that sera of patients with confirmed non A, non B hepatitis do not contain DNA-sequences in the serum hybridizing with HBV-DNA.

Die Charakterisierung des klinisch gesunden Hepatitis-B-Antigen (HBsAg)-Trägers

Wir haben 129 Blutspender, bei denen bei Routineuntersuchungen HBsAg im Serum festgestellt wurde, zur diagnostischen Klarung einer moglichen Lebererkrankung untersucht. Zwolf hatten, als sie zur klinischen und leberbioptischen Untersuchung aufgenommen wurden, schon kein HBsAg mehr im Serum. Keiner von diesen hatte klinisch oder histologisch Anhalt fur eine entzundliche Lebererkrankung. Zwei der 129 Patienten hatten eine milde, ikterische Hepatitis, verloren das Antigen wahrend des Verlaufes und wurden anti-HBs-positiv. Die ubrigen 115 Patienten, die klinisch gesund erschienen und keine fruhere ikterische Leberkrankheit hatten, blieben HBsAg-positiv wahrend des bisherigen Verlaufes von im Mi…

Residual Abdominal Lymphadenopathy after Intensive Frontline Chemoimmunotherapy Is Associated with Inferior Outcome Regardless of MRD Status in Advanced Chronic Lymphocytic Leukemia (CLL)

Abstract Introduction: In CLL, chemoimmunotherapies (CIT) and combinations with novel agents have proven to be highly effective with regard to eradication of minimal residual disease (MRD), while complete remissions (CR) are frequently not achieved due to residual lymphadenopathy. We have previously reported that minimal residual disease (MRD) negativity after CIT is a prognostic factor irrespective of the clinical response (Kovacs et al., JCO 2016). Because inferior outcome was observed in small subgroups of patients (pts) with residual lymphadenopathy, we analyzed the prognostic value of residual lymphadenopathy after CIT in comparison to MRD detection in a larger pt population. Methods: …

Ibrutinib Vs Temsirolimus: Results from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL)

Abstract Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed o…

Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis.

Recombinant human alpha-interferon is now under intensive investigation as therapy for chronic Type B hepatitis. Recent reports have suggested that prolonged alpha-interferon therapy may induce autoimmune reactions. We have evaluated the problem of autoimmunity related to alpha-interferon therapy by testing for 15 different antibodies in the sera of 31 patients treated with alpha-interferon. No patient had autoantibodies before treatment; 27 (87%) of 31 patients developed at least one autoantibody. Eleven patients had antinuclear antibodies and 21 had smooth muscle antibodies, both of which usually developed during alpha-interferon therapy. In contrast, antibodies to endocrine organs such a…

Reference interval determination for N-terminal-B-type natriuretic peptide (NT-proBNP): A study in blood donors

We assessed reference values in a group of apparently healthy blood donors. A total of 1980 blood donors was recruited and tested for the presence of NT-proBNP using a newly developed electrochemiluminescence immunoassay (ECLIA) method. NT-proBNP clustered in all blood donors below the age of 50 years and an upper limit of normal (ULN) was found to be 84 pg/ml for males and 146 pg/ml for females. Mean NT-proBNP values increased with increasing age which was due to an increasing number of individuals exceeding the ULN. Age- and gender-appropriate NT-proBNP levels decreased with increasing hemoglobin levels. Hemoglobin but not creatinine levels influenced the NT-proBNP concentration in this c…

Expression of Pre-S-Encoded Proteins in Sera of Individuals Chronically Infected with Hepatitis D Virus

The sera of 16 individuals chronically infected with the hepatitis D virus were analyzed for hepatitis B virus (HBV) markers. The majority of these patients had a non-replicative form of viral type B hepatitis as indicated by negative tests for HBeAg and HBV-DNA. Pre-S-encoded proteins were detected in 13/16 sera. Sera that were negative for polymerized serum albumin did also not contain pre-S1-encoded proteins. The presence of pre-S-encoded proteins is probably predominantly associated with 22-nm HBsAg forms present in large amounts in sera of individuals with chronic type D hepatitis.

The diagnostic significance of intrahepatocellular hepatitis-B-surface-antigen (HB s Ag), hepatitis-B-core-antigen (HB c Ag) and IgG for the classification of inflammatory liver diseases

Liver biopsies of patients with inflammatory liver diseases and clinically healthy HBsAg-carriers were examined for presence of intracellular HBsAg, HBcAg and IgG by direct immunofluorescence. The studies revealed the following results: 1. In most cases healthy HBsAg-carriers had HBsAg in the cytoplasm, but they did never show HBcAg in the nuclei of hepatocytes. 2. In the early phase some patients with HBsAg-positive acute hepatitis had HBcAg and/or HBsAg in their hepatocytes. In a normal course with complete recovery the immunoelimination may clear either phenomenon at variable stages of the disease. 3. Cases one year after complete recovery of acute virus B-hepatitis had no HB-components …

Final Results of a Phase I/II Trial of the Combination Bendamustine and Rituximab With Temsirolimus (BeRT) in Relapsed Mantle Cell Lymphoma and Follicular Lymphoma

Abstract. In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with relapsed or refractory (r/r) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1 to 3 previous therapies received Bendamustine (90 mg/m2, day 1 + 2) and Rituximab (375 mg/m2, day 1) with Temsirolimus in doses from 25 to 75 mg in phase I and 50 mg Temsirolimus in phase II, added on day 1, 8, 15 of a 28 days cycle. The primary endpoint of the phase II was ORR at the end of treatment. Overall, 39 (29 MCL, 10 FL) patients were included. Median age was 71 years and median pretreatment number was 2. Grade 3/4 non-hematologic adverse events wer…

Elimination of Established Risk-Factors in Primary Central Nervous System Lymphoma - Impact of High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantaion - a Multicenter Retrospective Analysis

Abstract Abstract 3089 Introduction: High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in eligible patients (pts). Prognosis of PCNSL is associated with several clinical and histopathological risk factors (RF). Early complete response (CR) during chemotherapy (CHT) was recently reported to be an additional independent prognostic factor in pts undergoing polychemotherapy without HDT+ASCT. In this analysis, we examined the extent to which known RF determined survival in pts who were treated with HDT-ASCT. We additionally investigated the impact of HDT-ASCT specific factors (e…

Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL.

The purpose of this study was to evaluate feasibility and efficacy of Rituximab included into a sequential salvage protocol for CD20(+) B-NHL in relapse or induction failure. Twenty-seven patients with CD20(+) B-NHL in relapse or induction failure received Rituximab combined with DexaBEAM (R-DexaBEAM) for stem cell mobilization. Additional ex vivo selection of CD34-positive cells was performed using the CliniMacs device. Two doses of Rituximab were included in the high-dose therapy regimen (HDT). R-DexaBEAM was well tolerated and 26 of 27 patients mobilized sufficient numbers of CD34(+) blood stem cells. Application of R-DexaBEAM resulted in significant depletion of peripheral B cells. No t…

Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL)

Abstract Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL. Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 cour…

First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group

Abstract Abstract 535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 3…

Durability of complete response after blinatumomab therapy for relapsed/refractory diffuse large B-cell lymphoma

Despite advances in standards of care, the prognosis of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains poor. In these patients, 50–74% fail to respond to next line therapy,...

Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to Pre-S- and S-encoded viral surface antigens

The polymerase chain reaction was evaluated as a diagnostic tool in 72 chronic hepatitis B virus carriers. Hepatitis B virus DNA was detectable in the serum of HBsAg—positive virus carriers using aliquots as small as 100 al. The detection limit for cloned hepatitis B virus DNA was 100 ag. Primer pairs for different regions of the HBV genome resulted in different sensitivity. Detection of the amplified hepatitis B virus DNA by Southern blotting and subsequent scintillation counting or densitometry allowed a semiquantitative assay. Using several primer pairs in parallel for optimal detection, all HBeAg-positive HBsAg carriers, 80% of HBe antibody—positive symptomatic HBsAg carriers and 57% of…

Preliminary Phase II Study Results of BBR2778 in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma.

Abstract Background: Pixantrone (BBR 2778) is a novel aza-anthracenedione with superior activity compared to doxorubicin and mitoxantrone in various tumor models including hematological malignancies. Pixantrone single agent therapy led to major responses in patients (pts) with aggressive lymphoma including diffuse large B-cell lymphoma (DLCL). The safety of a CHOP-like regimen with pixantrone replacing doxorubicin (CPOP) was assessed in a dose-ranging study indicating a recommended dose of 150 mg/m² for pixantrone. Method: In this phase II study the primary objective was to assess the efficacy of the CPOP regimen (cyclophosphamide 750 mg/m² d1, pixantrone 150mg/m² d1, vincristine 1.4mg/m² d…

Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma

This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6-specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1-12 of a 21-day cycle with bortezomib 1.0 mg/m2 (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade≤3. At a bortezomib dose lower than that in other combina…

Immune blot analysis of viral surface proteins in serum and liver of patients with chronic hepatitis B virus infection

The small and the middle surface proteins of hepatitis virus form either the virion or the 22 nm particle both of which are secreted. The large surface protein by itself remains cell bound in artificially transfected cell culture unless it is accompanied by an excess of the smaller protens. Its behavior in vivo is not yet well studied. Using specific monoclonal antibodies for immunoblotting, we found an abundance of small surface protein in the serum of chronic virus carriers and moderate amounts in the liver irrespective of viremia. The large surface protein was present in the serum and the liver of viremic carriers. In nonviremic carriers, the large protein was absent from serum, but in t…

Detection of hepatitis B virus markers in sera of asymptomatic hepatitis B surface antigen carriers with special emphasis to pre-S-encoded proteins.

Sera of asymptomatic hepatitis B surface antigen (HBsAg) carriers were analyzed for the presence of pre-S-encoded proteins. Four individuals with biopsy-proven chronic hepatitis uniformly expressed pre-S1- and pre-S2-encoded proteins. Individuals who had histologically normal or largely normal livers were heterogeneous with respect to expression of pre-S-encoded proteins. This heterogeneous expression of pre-S-encoded proteins occurred most likely due to difference in serum HBsAg concentration. Alternatively differences in pre-S gene expression need to be considered. Clinically the study indicates that expression of pre-S domains in serum is unrelated to viremia or chronic liver disease.

90Yttrium-Ibritumomab Tiuxetan as First Line Treatment for Follicular Non-Hodgkin Lymphoma. 5 Year Results from an International Multicenter Phase II Clinical Trial

Abstract Purpose Updated 5 year results are presented from the multicenter phase II trial of 90Yttrium-Ibritumomab-Tiuxetan (90YIT) as first line stand-alone therapy for patients with follicular lymphoma (FL). Patients and Methods 59 patients with CD20-positive FL grade 1 to 3a in stages II with bulky disease (n=12), III (n= 26), or IV (n=21), and in need for therapy, were enrolled between 05/2007 and 06/2010. They received 90YIT according to standard procedure (rituximab 250 mg/m2 days -7 and 0, then 90YIT 15 MBq/kg (0.4mCi/kg) day 0; patients with platelet counts below 150.000/ul but above 100.000/ul received only 11 MBq/kg). Primary end point was the clinical and molecular remission rate…

B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): An open-label, randomized phase II/III trial.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label…

Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up

Introduction In MCL, progression-free survival (PFS) generally declines with each successive line of chemoimmunotherapy (CIT). We have previously published that with ibrutinib, a first-in-class oral inhibitor of Bruton's tyrosine kinase and a standard of care treatment (tx) for R/R MCL, median PFS exceeded 2 years (yrs) when used at first relapse (Rule S, et al. Haematologica. 2018;104:e211-e214). Here we present an updated pooled analysis with 15 months (mos) of additional follow-up, and for the first time, a comparison of outcomes with ibrutinib versus the prior regimen. Methods Patients (pts) enrolled in SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391…

Lymphoma Symptoms: Data from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL) Treated with Ibrutinib Vs. Temsirolimus

Abstract Introduction MCL is an incurable aggressive B-cell lymphoma with a poor overall prognosis. For patients with MCL who fail initial therapy (ie, with relapsed or refractory [R/R] disease), treatment options historically have been limited. While remission duration is generally short, the goal of therapy has been to achieve remission while balancing treatment-related toxicities. Consequently, a substantial proportion of patients continuously suffer from lymphoma symptoms and other disease signs, such as itching and trouble sleeping or concentrating. Additionally, worries and high emotional sensitivity lead to reduced functional status and well-being. Therefore, it is crucial to any tre…

Efficacy and safety of imatinib in adult patients with c-kit–positive acute myeloid leukemia

Abstract This phase 2 pilot study was conducted to determine the efficacy and safety of imatinib mesylate in patients with c-kit–positive acute myeloid leukemia (AML) refractory to or not eligible for chemotherapy. Twenty-one patients were enrolled and received imatinib 600 mg orally once daily. Five responses were seen primarily in patients, starting with relatively low blast counts in bone marrow (BM) and peripheral blood (PB): 2 patients who were considered refractory on chemotherapy on the basis of persistence of blasts in PB and BM met the criteria for complete hematologic remission, 1 patient had no evidence of leukemia, and 2 patients achieved a minor response. Treatment with imatini…

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18.6, 12.8 and 25.0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Ea…

Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial

Background The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to wh…

Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously Untreated Multiple Myeloma (German DSMM XIa Trial).

Abstract 131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficaciou…

Bone Marrow Findings in Multicentric Castleman Disease in HIV-negative Patients

Because bone marrow histology in multicentric Castleman disease in human immunodeficiency virus-negative patients is not well reported, we investigated sequential bone marrow biopsies of 3 affected human immunodeficiency virus-negative patients, of which one was human herpes virus 8 (HHV8)-positive. The histologic evaluation of the bone marrow revealed lymphoid follicles with regressed germinal centers in 1 patient. Another patient showed tumorlike but bland polyclonal plasmacytosis with large perivascular plasma cell clusters. The HHV8-positive patient revealed interstitial HHV8-positive cells accompanied by a mild plasmacytosis. The atypical lymphoid follicles could be regarded as a bone …

CHOP Improves Response Rates but Not Overall Survival in Follicular and Mantle Cell Lymphoma (MCL)- Results of a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Abstract In advanced stage follicular lymphoma conventional chemotherapy is non-curative and no major improvement in overall survival has been achieved by different regimens. Similarly, MCL, a lymphoma subtype with an especially poor clinical outcome, cannot be cured by conventional chemotherapy. In 1996, the German Low Grade Lymphoma Study Group (GLSG) started a randomized trial to evaluate the efficacy of two different anthracycline/anthrachinon containing regimens comparing CHOP (cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 2, adriamycine 50 mg/m2 day 1, prednisone 100 mg/m2 days 1–5) and MCP (mitoxantrone 8 mg/m2 days 1–2, chlorambucil 3x3 mg/m2 days 1–5; prednisone 25 mg…

Modification of Hepatitis B Virus Infection by Recombinant Leukocyte Alpha A Interferon

A defect in alpha interferon production in patients with chronic type B hepatitis offers a rationale principle for treating this disease with interferon. Two trials with interferon in chronic type B hepatitis indicate that this therapy achieves an elimination of HBsAg and HBeAg significantly higher than spontaneous. Our study and that of others indicate, however, that the response to interferon therapy is dependent on many variables including: the type of interferon, the interferon dose, duration of interferon treatment, sex, sexual preference in men and coinfection with other viruses. As of the multiple modes of action of interferon, a better understanding of viral replication, of the anti…

Effects of bortezomib on pro-inflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman Disease

Corynebacterium parvum (Propionibacterium acnes): an inducer of tumor necrosis factor-alpha in human peripheral blood mononuclear cells and monocytes in vitro.

The present study investigates the potential capacity of the immunostimulant Corynebacterium parvum (C.p.) to induce tumor necrosis factor-alpha (TNF-alpha) in human peripheral blood mononuclear cells (PBMC) and blood monocytes (BMo) in vitro. Both at the mRNA and protein level, stimulation of PBMC and BMo upon C.p. induces TNF-alpha. Compared to the hitherto used TNF-alpha inducers in vitro such as Sendai virus, phytohemagglutinin or lipopolysaccharide the C.p. stimulus displayed a threefold stronger induction of TNF-alpha production (p less than 0.001). Using C.p. as an inducer it was possible to demonstrate that TNF-alpha production is regulated by prostaglandin E2; preincubation of the …

Active immunization of homosexual men using a recombinant hepatitis B vaccine

Twenty homosexual men [13 anti-human immunodeficiency virus (HIV)-positive, seven anti-HIV negative] without HBsAg, anti-HBs, and anti-HBc were vaccinated with three 20 micrograms doses of a recombinant hepatitis B vaccine. All anti-HIV-positive homosexuals were nonresponders independent of the initial number of CD4-positive cells. Among seven anti-HIV-negative individuals, five responded. After three doses of the vaccine, CD4-positive cells fell in anti-HIV positive individuals by 22.4%. A similar fall in CD4-positive cells of an average 24.9% was noted in 17 matching, but nonvaccinated, anti-HIV-positive homosexuals. The study indicates that the efficacy of vaccination in anti-HIV-positiv…

Urinary adiponectin excretion rises with increasing albuminuria in type 1 diabetes

Urinary adiponectin (u-adiponectin) excretion has been suggested to reflect early glomerular damage. Inspired by this, we studied the levels of u-adiponectin in type 1 diabetic patients with different levels of urinary albumin excretion (UAE).U-adiponectin was analysed by ELISA in type 1 diabetic patients: Fifty-eight with normoalbuminuria (30mg albumin/24h), 43 with persistent microalbuminuria (30-300mg/24h) and 44 with persistent macroalbuminuria (300mg/24h). For comparison, a control group of 55 healthy individuals was included.U-adiponectin increased with increasing levels of UAE (p0.01). U-adiponectin median (interquartile range): Normoalbuminuria 0.38 (0.14-1.31), microalbuminuria 1.1…

A phase II study of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas

The clinical course of peripheral T-cell lymphoma (PTCL) is usually aggressive and the prognosis unfavorable. Therefore, there is a need for improvement of treatment options. Patients with newly diagnosed (n = 27) or refractory/relapsed (n = 11) PTCL received a combination of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin. The overall response rate (ORR) was 61%, with a complete response rate of 39%. In newly diagnosed patients the ORR was 63%, the median overall survival 25.9 months, and progression-free survival 11.8 months. In relapsed/refractory patients the median OS was 6.1 months. The most frequent grade 3/4 toxicities were leukopenia (95% of patients) and thrombocytopen…

The effect of recombinant alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins in man.

The effect of alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins was analyzed in eight patients with chronic type B hepatitis who participated in a pilot study of interferon therapy. Three individuals became HBsAg-negative, 4 lost HBeAg but remained HBsAg-positive and 1 remained positive for both HBsAg and HBeAg. Initiation of interferon treatment was rapidly followed by reduction or loss of hepatitis B virus DNA in the serum but by little immediate change in hepatitis B virus antigen levels. Changes in hepatitis B virus antigens were usually delayed. Loss of HBsAg from the serum was preceded by the sequential disappearance of pre-S-encoded proteins (pre-S1 and…

Efficacy of Rituximab Combined in Salvage- and High Dose-Therapy (HDT) for Patients with Relapsed NHL; Interim Analysis of a Multicenter Phase II Study.

Abstract The introduction of Rituximab (R) in the treatment of B-NHL resulted in improvement in first line therapies for indolent (ind.) and aggressive (agg.) B-NHL. However, the value of R in intensive chemotherapy relapse strategies has not definitely been demonstrated. In a phase I/II clinical trial we have demonstrated safety of R as an in vivo purging agens in salvage and high dose therapy for relapsed/refractory B-NHL. This led, with promising response rates, to the initiation of a multicenter phase II trial to further prove therapeutic efficacy. Inclusion criteria were: Pt < 65 years, ECOG < 3, relapse or progression for patients with ind. NHL and induction failure or relapse f…

Immunogenicity and safety of an inactivated hepatitis A vaccine in anti-HIV positive and negative homosexual men.

The immunogenicity, reactogenicity, and safety of an inactivated hepatitis A vaccine were assessed in anti-HIV positive homosexual men. Fourteen anti-HIV positive (group 1) and 20 anti-HIV negative (group 2) men received vaccine (containing 720 ELISA units of hepatitis A antigen per dose) intramuscularly at 0, 1, and 6 months. Twelve unvaccinated anti-HIV positive men (group 3) were included as controls to evaluate disease progression. Seroconversion (anti-hepatitis V virus (HAV ⩾20 mlU/ml) was higher in group 2 than group 1 at months 2 (100% vs. 73%) and 7 (l00%vs. 77%). Group 2 had higher antibody titres than group 1 at months 1 (201 vs. 92 mlU/ml) and 7 (1, 687 vs. 636 mlU/ml). The decli…

Failure of acyclovir to enhance the antiviral effect of α lymphoblastoid interferon on HBe-seroconversion in chronic hepatitis B

Serum HBeAg levels and HBe-seroconversion were investigated in patients with chronic HBeAg-positive hepatitis who were randomized to receive either alpha lymphoblastoid interferon (5 megaunits subcutaneously daily for 16 weeks) plus acyclovir (2 g intravenously daily during weeks 1 and 2 and weeks 9 and 10) (n = 49) or no treatment (n = 48). HBeAg levels in serial dilutions of patient serum were assessed quantitatively by radioimmunoassay and compared with the values found for negative control serum. One year after the start of therapy 44 treated patients and 43 control patients were available for follow-up. A complete response (HBe-seroconversion) occurred in 11 treated patients (25%) and …

Tumornekrosefaktor und Interferon als prognostische Marker der HIV-Infektion

Peripheral blood cells were obtained from patients at different stages of their human immunodeficiency virus (HIV) infection. It was found that the capacity to generate interferon alpha was reduced already at Walter Reed stage 2 (WR) while the interferon gamma capacity remained largely unaffected until WR stage 4. Endogenous tumor necrosis factor (TNF) alpha production increased as the HIV disease progressed. The data obtained add to our knowledge on destruction of the immune system by the HIV. Moreover TNF and acid labile interferon alpha might contribute to HIV replication and disease progression. Nevertheless the tests performed are too time-consuming to be introduced into routine analys…

Polatuzumab Vedotin in Relapsed and Refractory (r/r) Large B-Cell Lymphoma (LBCL): Real-World Data of the German National Compassionate Use Program (CUP)

Introduction The antibody-drug conjugate polatuzumab vedotin (Pola) has recently been approved in combination with bendamustine and rituximab (Pola-BR) for patients with r/r diffuse LBCL (DLBCL). Methods To characterize the efficacy of Pola-BR in a real-world setting, we retrospectively analyzed data from 97 patients with r/r LBCL who were treated with Pola in 24 German centers within the national CUP. Clinical baseline and follow-up (FU) data were collected by chart review and summarized descriptively. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods. Fisher's exact test was used to compare categorical factors between gro…

Comparison of 2 Doses of Intravenous (IV) Temsirolimus (Temsr) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Abstract Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75…

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.

BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 …

Efficacy and safety of yttrium 90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem cell transplantation.

A prospective, multicenter, nonrandomized phase 2 trial was conducted to evaluate the efficacy and safety of a single dose of yttrium-90 (90Y) ibritumomab tiuxetan in elderly patients in first relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem-cell transplantation. Patients had been previously treated with chemotherapy (group A, n = 76) or chemotherapy plus rituximab (group B, n = 28). Patients in group A were further divided into patients in whom induction therapy had failed (stratum AI, n = 33) and patients who had relapsed after achieving complete response (CR; stratum AII, n = 43). The overall response rate (ORR) was 52% and 53% in strata AI and AII…

Treatment of hepatitis B surface antigen (HBsAg)-positive chronic hepatitis with recombinant leucocyte α-A interferon

A total of 32 individuals with HBsAg-positive and anti-delta-negative chronic hepatitis were treated with recombinant alpha-A interferon in phase I and phase II studies. In 5/32 patients HBsAg could be eliminated and in 19/32 individuals HBeAg became negative including all those who also eliminated HBsAg. Side-effects were tolerable in most patients and were readily reversible upon discontinuation of interferon therapy. In conclusion, treatment of HBsAg-positive chronic hepatitis with interferon seems to be a promising therapeutic approach. Future studies will have to establish the optimal dose, duration of treatment and factors predicting a favourable outcome of the treatment.

Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma : Final Results From a Phase I Study

Purpose Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m2/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results B…

Safety and Clinical Activity of the Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) in Combination with Rituximab in Follicular Lymphoma or Diffuse Large B-Cell Lymphoma: Preliminary Report of a Phase 1/2 Study

Abstract Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Inotuzumab ozogamicin targets B-cell malignancies since they often express CD22. In a previously reported phase 1 dose-escalation trial in patients with CD22-positive B-cell non-Hodgkin’s lymphoma (NHL), the maximum tolerated dose (MTD) was determined to be 1.8 mg/m2 every 4 weeks. Responses were seen in patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). This ongoing study consisted of a limited dose escalation (DE) portion to confirm the MTD of inotuzumab ozogamicin whe…

Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial.

8507 Background: Therapies approved in US for R/R PTCL have overall response rates (ORR) of 25%-27%. The need for new therapies persists. BELIEF is a pivotal, single-arm study of belinostat in patients with R/R PTCL after failure of ≥1 prior systemic therapies. Methods: Entry criteria were measurable PTCL, platelets ≥ 50,000/µL, no prior HDACi therapy, and adequate organ function. PTCL was confirmed by central pathology review (CPRG). Belinostat 30 min IV infusion at 1000 mg/m2was administered on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. Tumor response was assessed by Cheson 2007 criteria. The primary endpoint was ORR. Results: Patients with R/R PTCL (N=129, 53…

High Anti-Lymphoma Activity of Bendamustine/Mitoxantrone/Rituximab (BMR) in Rituximab Pretreated Relapsed or Refractory Indolent Lymphomas. A Multicentre Phase II Study of the German Low Grade Lymphoma Study Group (GLSG).

Abstract Purpose: Bendamustine is a new anti-lymphoma agent with promising activity. Based on a preceeding phase I study the current trial explored Bendamustine in combination with Mitoxantrone and Rituximab (BMR) in patients with relapsed or refractory indolent lymphomas. Patients and Methods: Patients with relapsed or refractory symptomatic stage III/IV indolent lymphomas with or without prior treatment with Rituximab were eligible. Therapy consisted of Bendamustine 90 mg/m2 days 1+2, Mitoxantrone 10 mg/m2 day 1, Rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of 4 cycles. Results: Between 04/03 and 07/04 62 patients were recruited from 24 participating institution…

Tubular markers are associated with decline in kidney function in proteinuric type 2 diabetic patients.

Our aim was to investigate u-NGAL, u-KIM1 and p-FGF23 and prediction of decline in kidney function in type 2 diabetic patients with proteinuria.We performed a follow-up study, follow-up median (range) 3.5 (1-5) years. At baseline u-NGAL, u-KIM1 and p-FGF23 (ELISA) was measured and patients were followed yearly with estimated(e)-GFR (MDRD) and u-albumin.We included 177 patients (44 women), mean age (SD) 59 (9) years. eGFR 90 (24) ml/min/1.73 m(2) at baseline, u-albumin: median (interquartile range) 104 (39-238) mg/24 h. Patients with levels of u-KIM1 in the highest quartile had a greater decline in eGFR than patients with the lowest quartile 6.0 (5.4) versus 3.2 (5.5) ml/min/1.73 m(2) per ye…

Durability of complete response after blinatumomab therapy for refractory/relapsed aggressive B-cell non-Hodgkin lymphoma.

e19041 Background: Achieving durable response in patients (pts) with relapsed/refractory (R/R) aggressive B-cell lymphoma (B-NHL) is challenging. Blinatumomab, a bispecific T-cell engager (BiTE) immunotherapy targeting CD19-expressing cancer cells, has shown promising efficacy in pts with R/R aggressive B-NHL. We report the durability of complete response (DOCR) in pts treated with blinatumomab. Methods: The DOCR in pts with R/R aggressive B-NHL responding to blinatumomab was assessed using data from two phase 2 studies (study 1 [N = 25], NCT01741792; study 2 [N = 41], NCT02910063) in pts with R/R aggressive B-NHL. CR was assessed using Cheson (study 1) and Lugano (study 2) criteria. Time-…

Immunoelectron microscopic observations on the inflammatory infiltrates and HLA antigens in hepatitis B and non-A, non-B.

The present knowledge of the inflammatory reaction occurring in situ during hepatitis B favors a T cell-dependent MHC-restricted immune response. However, the reports in the literature are primarily based on the application of monoclonal antibodies directed at different lymphocyte subsets which discern only lymphocytic phenotypes and do not reflect the actual situation adequately. Therefore, we investigated the liver biopsies of patients with hepatitis B (28 patients) and non-A, non-B (21 patients) by immunoelectron microscopy with monoclonal antibodies directed at lymphocyte subtypes (pan-B, pan-T, T8, T4 and NKH1) and at activation epitopes (IL-2 receptor, TA1 and T11/3) as well, in order…

Obinutuzumab-Based Immunochemotherapy Prolongs Progression-Free Survival and Time to Next Anti-Lymphoma Treatment in Patients with Previously Untreated Follicular Lymphoma: Four-Year Results from the Phase III GALLIUM Study

Abstract Introduction: Immunochemotherapy is standard of care treatment for previously untreated patients (pts) with advanced stage follicular lymphoma (FL). However, the majority of pts relapse, with around 20% relapsing within 2 years. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody (mAb) with increased antibody-dependent cell-mediated phagocytosis and cytotoxicity, and direct B-cell killing, compared with the type I mAb rituximab (R). The randomized Phase III GALLIUM study (NCT01332968) compared the efficacy and safety of G-chemotherapy (G-chemo) vs R-chemotherapy (R-chemo) in previously untreated pts with advanced stage FL. In the primary analysis (PA)…

Evaluation of Safety, Tolerability and Efficacy of Temsirolimus in Patients with Relapsed or Refractory Mantle Cell Lymphoma (REL/REFR MCL) in the Usual Health Care Setting

ABSTRACT Background Temsirolimus (TEMS), an mTOR-inhibitor, is approved the EU for the treatment of patients (pts) with relapsed or refractory MCL (rel/refr). A pivotal study demonstrated significantly longer progression free survival with TEMS (175mg weekly for 3 weeks followed by 75mg weekly) in rel/refr MCL pts compared to investigatoŕs choice therapy (4.8 mo vs 1.9 mo; P = .0009). To better identify safety and efficacy of TEMS in an unselected patient population during clinical routine a prospective non-interventional study with TEMS in rel/refr MCL-pts was started. Here we report on interim results of the study. Methods A registry for rel/refr MCL pts treated with TEMS was started in G…

Untersuchungen zum Verteilungsmuster von Prä S und S-kodierten viralen Hüllproteinen des Hepatitis B Virus (HBV) auf molekularer Ebene im Serum und Lebergewebe von chronischen HBsAg-Trägern

Die biologische Bedeutung der PraS-kodierten Hepatitis B Virus (HBV) — Hullproteine — insbesondere ihre Regulation innerhalb der Leberzelle — ist noch unklar. Daher war es Ziel unserer Untersuchungen, die PraS- und S-kodierten Hullproteine vergleichend im Serum und im Lebergewebe auf molekularer Ebene zu untersuchen.

The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy: u-NGAL, u-KIM1 and u-LFABP.

Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid-binding protein (LFABP).A substudy of a double-masked, randomized, cross-over study including 52 patients with type 2 diabetes, hypertension and microalbuminuria. After 2 months washout of all antihypertensive medication except bendroflumethiazid, patients were treated in random order with irbesartan 300, 600 and 900 mg for 2 months.Urinary tubular markers at baseline and after each treatment period (ELISA),…

Tafasitamab Plus Lenalidomide Versus Pola-BR, R2, and CAR T: Comparing Outcomes from RE-MIND2, an Observational, Retrospective Cohort Study in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Abstract Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively col…

Reactivation of chronic type B hepatitis: the effect on expression of serum HBV-DNA and pre-S encoded proteins.

Hepatitis B markers were studied in seven patients with reactivated liver disease. Reactivation of chronic type B hepatitis, as indicated by the reappearance of hepatitis B e antigen (HBeAg) in the serum, was characterised by the appearance of hepatitis B virus-DNA (HBV-DNA) in the serum. The expression of pre-S 1 encoded protein remained unchanged in five of seven patients, and poly-HSA as a marker for pre-S 2 encoded protein remained detectable in six of seven patients before and after reactivation of chronic hepatitis. The level of serum HBV-DNA correlated well with the level of liver enzymes, which rose from normal to various levels after reactivation of the liver disease. The data sugg…

SAKK 36/13 ‐ IBRUTINIB PLUS BORTEZOMIB AND IBRUTINIB MAINTENANCE FOR RELAPSED AND REFRACTORY MANTLE CELL LYMPHOMA: FINAL REPORT OF A PHASE I/II TRIAL OF THE EUROPEAN MCL NETWORK

Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)

Abstract Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody.…

Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

Purpose Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. Patients and Methods In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (P…

Prognosis of patients with primary central nervous system lymphoma after high-dose chemotherapy followed by autologous stem cell transplantation

High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this retrospective multicenter study, we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first-line consolidation treated at 12 German centers between 1997 and 2011. We estimated survi…

(90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial.

Purpose We report on a multicenter phase II trial of 90yttrium-ibritumomab-tiuxetan (90YIT) as first-line stand-alone therapy for patients with follicular lymphoma (FL). Patients and Methods Fifty-nine patients with CD20+ FL grade 1 to 3a in stages II, III, or IV, age 50 years old or older requiring therapy were enrolled. They received 90YIT according to standard procedure. If complete response (CR) or unconfirmed complete response (CRu) without evidence for minimal residual disease (MRD) 6 months after application of 90YIT was achieved, patients were observed without further intervention. The same applied to patients with partial response (PR) or with stable disease (SD). Patients with CR …

FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia.

The chemoimmunotherapy FCR (fludarabine and cyclophosphamide with rituximab) is the standard first-line treatment for physically fit chronic lymphocytic leukemia (CLL) patients. To assess the risks and benefits, we investigated health-related quality of life (HRQOL). 817 untreated CLL patients received either FC or FCR within the GCLLSG CLL8 trial. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 was sent to all patients at baseline, after 3, 6, and 12 months and then yearly as follow-up. A total of 769 (94%) of 817 patients completed at least one questionnaire. Comparing HRQOL of CLL patients with the general German population, CLL patients' …

New combinations for mantle cell lymphoma: concerted action needed.

Ibrutinib Abrogates TREM-1 Mediated Neutrophil Activation

Abstract Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor on neutrophils (PMN) and important in the innate host defence against microbial pathogens. Here we examined the influence of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib on TREM-1 dependent activation of human PMNs. Firstly, ibrutinib specifically inhibited TREM-1 mediated PMN activation of the oxidative burst and CD62L shedding, whereas TLR mediated activation remained unaffected. Correspondingly, ibrutinib suppressed ERK phosphorylation after TREM-1, but not after TLR ligation. To clarify whether this TREM-1 specific effect of ibrutinib was also relevant in vivo, we treated mice with ibrut…

Bortezomib Retreatment in Relapsed Multiple Myeloma (MM): Results from a Binational, Multicenter Retrospective Survey

Abstract In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predispo…

Temsirolimus in mantle cell lymphoma and other non-Hodgkin lymphoma subtypes.

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has anti-tumor activity in patients with relapsed or refractory mantle cell lymphoma (MCL) and other mature lymphoid neoplasms. mTOR is an intracellular kinase that controls the mRNA translation of many proteins (eg, cyclin D1) that can act as oncogenes and contribute to lymphomagenesis. Characterized by overexpression of cyclin D1, MCL was identified as a disease that might be susceptible to mTOR inhibition. When single-agent temsirolimus was explored in two phase II studies for treatment of patients with relapsed or refractory MCL, it demonstrated anti-tumor activity, with overall response rates of 38% and 41%. Subsequent…

Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia

SummaryTreatment of relapsed or refractory autoimmune mediated haemolytic syndromes, such as autoimmune haemolytic anaemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), represents a therapeutic challenge. Here we report on our experience with the monoclonal anti-CD20 antibody rituximab (R) compared to standard treatment in these diseases. Patients with non-familialTTP orAIHA and no underlying malignancy were included in our analysis. Safety and efficacy of R-treatment were compared to results obtained in standard treatment approaches. Altogether, 27 patients were analyzed, comprising 15 patients withTTP and 12 patients with AIHA. The patients’ average age at the time of diagnosis wa…

Ibrutinib As Treatment for Chemoimmunotherapy-Resistant Patients with Follicular Lymphoma: First Results from the Open-Label, Multicenter, Phase 2 DAWN Study

Abstract Background: While first line therapy for FL with chemotherapy or chemoimmunotherapy produces durable responses, most patients (pts) with FL eventually relapse. Those who become resistant to chemoimmunotherapy have limited treatment options. Ibrutinib, an inhibitor of BTK (Bruton's tyrosine kinase) and ITK (interleukin-2-inducible T-cell kinase), has demonstrated robust clinical activity in various B-cell non-Hodgkin lymphomas. Previous Phase 1 and 2 studies have shown promising results with single-agent ibrutinib in pts with relapsed or refractory FL (Bartlett NL. Blood. 2014; 800 & Fowler N. Blood. 2015; 2706). The aim of the DAWN study was to provide additional efficacy and s…

Transplantation in follicular lymphoma: not "yes or no" but "whom and when".

After years of debate, the question as to what is the optimal use of transplantation strategies in indolent lymphoma remains controversial. In the July issue of Haematologica, a study was published by the EBMT Lymphoma Working Party that aims to define indications for hematopoietic stem cell

Treatment of Patients with Chronic Type B Hepatitis and Concurrent Human Immunodeficiency Virus Infection with a Combination of Interferon Alpha and Azidothymidine: A Pilot Study

Six patients with chronic type B hepatitis and concurrent infection with the immunodeficiency virus were treated with 600 mg azidothymidine (AZT)/day and 3 X 10(6) units of interferon-alpha (IFN-alpha) every other day for a total of 4 months. None of the patients treated lost the hepatitis B virus (HBV). HBV-DNA concentrations were not significantly influenced by this treatment. Human immunodeficiency virus (HIV) infection was also not affected except for a transient rise in CD 4-positive cells in 2 individuals, who had initially low CD 4-positive cells. Treatment did not influence the presence of HIV-Ag in the serum. In conclusion, a combination therapy of IFN and AZT does not seem to be b…

Safety of the Anti-CD19 antibody Tafasitamab in Long Term Responders from A Phase II Trial for Relapsed Lymphoma

Abstract Background: Information about the long-term tolerability of tafasitamab is still limited. Methods: 5 of 92 patients treated within a phase IIa study of single-agent tafasitamab in relapsed or refractory B NHL were followed for up to five years or longer for long-term tolerability. Results: Treatment was very well tolerated in an outpatient setting with no hospitalizations needed and mild and tolerable adverse events that occurred mostly within the first two years of treatment. Conclusions: Given the excellent tolerability and efficacy of tafasitamab this agent can be used to induce remission in relapsed or refractory lymphoma either alone or in combination with chemotherapy.

Durable Molecular Remissions in Patients with Relapsed CML Post Allogeneic Stem Cell Transplantation upon Treatment with Imatinib-Mesylate (Glivec®, STI-571). Follow-Up Results of a Phase II Open-Label Study.

Abstract Purpose: In a phase II clinical trial we have previously reported on the safety and efficacy of imatinib mesylate (IM) to induce hematologic, cytogenetic and molecular remissions in case of relapse post allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukaemia (CML). Here we report on an extended follow-up phase, which was performed to monitor stability of responses and further disease course in patients enrolled. Patients and Methods: Within the trial, patients, transplanted in chronic phase (CP) CML with molecular or cytogenetic relapse (n=37), received IM at a starting dose of 400mg. Close monitoring was performed, which, besides evaluation of sid…

A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma: Long-Term Follow-up, Final Analysis

Background: CD19 is broadly and homogeneously expressed across different B-cell malignancies and represents an attractive target antigen in patients with B-cell non-Hodgkin's lymphoma (NHL). Tafasitamab (MOR208) is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody. This ongoing study is investigating the single agent antitumor activity in adult patients with relapsed or refractory (r/r) NHL who had received at least one prior rituximab-containing therapy. Patients and Methods: The study enrolled 92 r/r NHL patients: diffuse large B-cell lymphoma (DLBCL; n=35), mantle cell lymphoma (MCL; n=12), follicular lymphoma (FL; n=34), or other indolent NHL (iNHL; n=11). The median number of pr…

Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab.

Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NH…

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly highe…

Treatment-Induced Aggravation of Vasculitis in Hairy-Cell Leukemia

Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis.

Autoantibodies to the human asialoglycoprotein receptor (anti-h-ASGPR) were studied with a solid-phase ELISA in the sera of 421 patients with inflammatory liver diseases, 288 patients with various other disorders and 31 controls. Anti-h-ASGPR were found predominantly in autoimmune chronic active hepatitis (44 of 88, 50%) and were closely related to inflammatory activity. In a subpopulation of these patients with untreated, biopsy-proven active disease or relapse, 15 of 17 were positive (88%). In contrast, only 11 of 204 patients (5.3%) with viral hepatitis were anti-h-ASGPR receptors-positive (chi 2 analysis; p less than 0.001). We also compared the occurrence of anti-h-ASGPR with antibodie…

Relationship of pre-S encoded antigens in liver and clinical manifestations of chronic hepatitis B infection.

Pre-S1 and pre-S2 encoded antigens of hepatitis B virus were localized in liver tissue using monoclonal antibodies. They were found to be exclusively expressed in the cytoplasm of liver cells. Cell bound pre-S1 encoded protein was often detected in patients with chronic liver disease and viremia. Only a small number of the HBsAg positive cells also contained pre-S1 antigen. There was no correlation with nuclear HBcAg. Livers of non-viremic HBsAg carriers contained many HBsAg expressing liver cells, that were frequently also positive for pre-S2 encoded protein but contained no detectable pre-S1 encoded protein at all. It remains open whether cell bound pre-S2 containing proteins of middle si…

ROUTES OF HIV-2 TRANSMISSION IN WESTERN EUROPE

Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma : results From the Open-Label, Multicenter, Phase II DAWN Study

Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee–assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle …

Demonstration of antibodies to the surface (anti-p41) and core proteins (anti-p24) of the human immunodeficiency virus (HIV) in individuals positive for anti-HIV.

Diagnosis of infection with the human immunodeficiency virus (HIV) relies on the demonstration of antibody to this virus. Occasionally, the combined analysis of sera using ELISA and western blot reveals false-positive results. We have compared a newly developed test to detect antibodies to the core (anti-p24) and surface (anti-p41) proteins of HIV with the established tests described above. Anti-p24 and anti-p41 were negative in three individuals positive for anti-HIV by ELISA and immunoblot; they had a low risk to acquire HIV infection and were clinically and immunologically normal and suspected false positive previously. In 62 individuals at risk, anti-p41 was always positive while anti-p…

Ofatumumab retreatment and maintenance in patients with fludarabine-refractory CLL.

6584 Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab (ofa), given as monotherapy over 6 months, showed 47% overall response rate (ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (>5cm) lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance (mt) are unknown. Methods: Pts who responded to ofa and then progressed or had stable disease (SD) in Study 406, were offered retx in Study 416 (NCT00802737; GSK/Genmab) with ofa 1 x 300 mg + 7 x 2000 mg weekly followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). Primary endpoint was OR…

Treatment of chronic hepatitis C

alpha-Interferon given subcutaneously at doses between 1-3 million units leads to responses in about 50% of patients suffering from chronic hepatitis C. A 24-week treatment is frequently (approx. 50%) followed by relapses reducing the percentage of lasting responders to approx. 20%. The patients who relapse are sensitive to retreatment with interferon-alpha. A better understanding of HCV replication and of the interferon action in this viral disease might help to further improve treatment schedules. Side effects of interferon were frequently mild and readily reversible after cessation of treatment. At present interferon treatment should not be recommended in asymptomatic patients or individ…

Supportive Efficacy Analyses for the Phase 3 Study of Temsirolimus Versus Investigator’s Choice Therapy for the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Abstract Temsirolimus (Torisel®) is a specific inhibitor of the mTOR kinase with antitumor activity in patients with relapsed or refractory mantle cell lymphoma. In a phase 3, randomized, open-label study, patients treated with temsirolimus 175 mg weekly 3 times followed by 75 mg weekly (175/75-mg) had significantly longer progression-free survival (PFS) than those treated with investigator’s choice therapy (p-value temsirolimus: investigator’s choice = 0.0009; hazard ratio = 0.44; 97.5% CI = 0.25, 0.78; Hess et al. J Clin Oncol.2008, 28:abs 8513). Patients treated with temsirolimus 175 mg weekly 3 times followed by 25 mg weekly (175/25-mg) showed a trend towards longer PFS than those treat…

Interferon-Alpha-2-Induced Stimulation of ACTH and Cortisol Secretion in Man

Short-term effects of interferon-alpha 2 on plasma concentrations of adrenocorticotrophic hormone (ACTH) and cortisol were measured in man in relation to interferon absorption. Interferon-alpha 2 was given subcutaneously at a dose of 3 x 10(6) IU at 17.00 h to 2 female and 5 male patients who suffered from chronic hepatitis B infection and who had not previously been treated with interferon. Plasma levels of ACTH, cortisol and interferon-alpha were determined at 30-min intervals between 16.00 and 24.00 h. In each patient a similar cortisol, ACTH and interferon-alpha profile was determined on a day, when no interferon-alpha treatment was given. Interferon-alpha plasma levels peaked around 21…

High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m(2) days 1 + 2, mitoxantrone 10 mg/m(2) day 1, rituximab 375 mg/m(2) day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 - 83). Lymphoma subtypes were …

Clinicogenetic Risk Models in Patients Randomized to Receive Consolidative Autologous Stem-Cell Transplantation after Frontline R-CHOP for Advanced Follicular Lymphoma: An Analysis from the GLSG2000 Trial

Abstract Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore wheth…

Rituximab in the treatment of non-Hodgkin’s lymphoma

Beate Hauptrock, Georg HessHematology/Oncology, Johannes Gutenberg-University, Mainz, GermanyAbstract: Besides traditional cytostatic drugs the introduction of monoclonal antibodies has substantially influenced current treatment concepts of non-Hodgkin’s lymphoma (NHL).  Rituximab, a monoclonal anti-CD20 chimeric antibody, now has been widely evaluated in the various B-cell lymphatic neoplasms. Large phase III studies helped to prove the value of this drug in follicular lymphoma as part of induction or relapse treatment as well as maintenance treatment. The addition of rituximab to the well established CHOP regimens has increased achievable cure rates in diffuse large cel…

Hepatitis B virus markers among family contacts of asymptomatic HBsAg carriers.

A study was undertaken to establish the risk of family contacts of HBsAg carriers acquiring a hepatitis B virus (HBV) infection. About one-third of all household contacts of asymptomatic HBsAg carriers had signs of past or ongoing HBV infection. Family contacts of HBsAg carriers with high numbers of circulating Dane particles were shown to have a higher risk of developing HBV infection than family contacts of HBsAg carriers without serological evidence of HBV synthesis. The probability of acquiring HBV infection was not different between spouses, parents, children, and brothers and sisters, respectively of asymptomatic HBsAg carriers.

Antibodies to hepatitis B core antigen in blood donors screened for alanine aminotransferase level and hepatitis non-A, non-B in recipients.

Four-hundred and seventeen patients undergoing open-heart surgery were followed for more than 9 months after transfusion. All 2270 blood units transfused had alanine aminotransferase levels less than or equal to 30 U/l. Blood units positive for antibodies to hepatitis B core antigen (anti-HBc) were more frequently associated with recipient hepatitis non-A, non-B (HNANB) (13.7%) than anti-HBc-negative units (4.2%) (p less than 0.001). The frequency of HNANB among recipients of at least 1 anti-HBc-positive blood unit (8/79, 10.1%) was fivefold greater than among recipients of exclusively anti-HBc-negative blood units (7/338, 2.1%) (p less than 0.01). In this study the exclusion of donors posi…

Sustained remissions and low rate of BCR-ABL resistance mutations with imatinib treatment chronic myelogenous leukemia in patients treated in late chronic phase: a 5-year follow up.

The introduction of Imatinib (IM) has significantly altered the treatment for CML, although only limited follow-up results are available. As failure of Interferon-alpha had been associated with poor prognosis and results of IM-treatment in this patient group may allow earlier estimation of long-term benefits for early chronic phase patients. Therefore we prospectively analyzed the quality and duration of remissions and the rate of BCR-ABL resistance mutations occurring in patients treated with IM, if they were intolerant or refractory to interferon. Fifty-nine patients were included and median follow up is 4.75 years. Haematologic remission rate was 92% and 62% of patients achieved at least…