bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged Hematologic Toxicity from the Hyper-CVAD Regimen; Manifestations, Frequency, and Natural History in a Cohort of 125 Consecutive Patients.
Authors: Gill Saar , Lane Steven , Crawford Julie , Mollee Peter , Marlton Paula , Cull Gavin , Prince Miles , Seymour John Francis 
Published: October 2019

Abstract
Hyper-CVAD is a dose-intensive regimen which has been employed in the last decade to treat patients with a range of hematologic malignancies, with impressive efficacy. This regimen has been associated with considerable short-term hematologic toxicity, which has been mostly described as transient and reversible. However, recent reports have highlighted a concerning early rate of MDS or AML on medium-term follow-up. While cases of MDS/AML may be the most extreme end of the spectrum of hematopoietic stem cell damage, in the current retrospective study we describe other prolonged hematologic sequelae of this regimen. All patients were previously untreated and received Hyper-CVAD for the treatment of NHL or ALL. 125 patients (pts) with a median age of 47 (range, 15–76) were followed up for a median of 23 months (range, 1–84). The median number of Hyper-CVAD cycles was 6 (range, 2–9). Follow-up for blood counts was censored at the next cytotoxic therapy. At 3 months post therapy, 78 patients were evaluable. Thirty-two (41%) had achieved full blood count recovery and 45 (59%) had persisting cytopenias. Dose intensity delivered was significantly associated with persisting cytopenias (p = 0.028), but age (p = 0.61), underlying disease (0.49) and bone marrow involvement at diagnosis (p = 0.81) were not. Of the patients who had not normalised all counts by 3 months, anemia was present in 56% (median 106 g/L, range 76–119), neutropenia in 47% (median 1.27 × 109/L, range 0.03–1.75) and thrombocytopenia in 76% (median 96 × 109/L, range 9–120). One, two and three lineage cytopenias were present in 42%, 42% and 16% of pts, respectively. The median time to normalisation of counts for those with post-treatment cytopenias in the respective lineages was 9 months (range, 6–12) for Hb, 6 months (range, 6–30) for neutrophils, and 6 months (range, 6–30) for platelets. The median time to normalisation of the lowered counts was 9 months (n = 18) in those with multi-lineage cytopenias and 6 months (n = 12) in those with one lineage cytopenia. At 1 year following Hyper-CVAD with no further therapy, 49 patients were evaluable and 3 (6%), 7 (14%), and 9 (18%) still had anemia, neutropenia or thrombocytopenia respectively. MDS/AML was diagnosed in 3 patients at 4, 21, and 21 months after therapy. Of these patients, one received an autologous stem cell transplant 2 months after Hyper-CVAD, one was cytopenic at 3 months, and one was lost to follow-up until re-presenting with AML. These results indicate a considerable rate of prolonged hematologic toxicity after Hyper-CVAD, and a minor rate of MDS at this limited follow-up. These findings likely reflect cumulative damage to hematopoietic stem cells.
Improvement of Overall Survival in Mantle Cell Lymphoma during the Last Decades.
Authors: Herrmann Annina , Hoster Eva , Dreyling Martin , Unterhalt Michael , Brittinger Günter , Hiddemann Wolfgang 
Published: October 2019

Abstract
Purpose: Mantle cell lymphomas (MCL) represent a lymphoma subtype with an especially poor long term prognosis. Although various therapy strategies have been applied within the last 30 years, MCL is still considered incurable by conventional chemotherapy.
Patients and methods: To determine whether patient outcome has improved during the last decades, we compared data from the “Kiel lymphoma group” (KLG) collected in the years 1975–1986 with data from the “German lymphoma study group” (GLSG) of the years 1996–2004. To minimize potential heterogeneity of risk profiles of the two patient populations, frequency matching was pursued. Additionally, the effects of other potential prognostic parameters were adjusted by a Cox proportional hazard model.
Results: A total of 520 patients were evaluable for analysis. The median overall survival significantly increased from 2.7 years up to 4.8 years (p<0.0001; hazard ratio (HR) 0.44) and 5-year-survival of advanced MCL more than doubled from 22% [95% CI, 13% to 31%] to 47% [95% CI, 38% to 55%]. Multivariate analysis identified a poor performance status (HR 2.26), a high LDH level (HR 1.75), and age (HR 1.38) as additional prognostic variables.
Conclusion: Patients with advanced MCL benefit from the progress of medical treatment resulting in almost doubling of overall survival during the last 3 decades, even though relapses are regularly observed.
Phase II Trial of the Bonn Polychemotherapy Protocol with Deferred Radiotherapy in Patients with Primary Central Nervous System Lymphoma.
Authors: Schmidt-Wolf Ingo G.H. , Juergens Annika , Pels Hendrik , Glasmacher Axel , Schulz Holger , Engert Andreas , Linnebank Michael , Reichmann Heinz , Kroschinsky Frank , Vogt-Schaden Marlies , Egerer Gerlinde , Fliessbach Klaus , Schlegel Uwe 
Published: October 2019

Abstract
Objectives: The trial was performed to evaluate response rate, response duration, overall survival, and toxicity in primary central nervous system lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy.
Patients and Methods: From 09/1995 to 12/2002, 88 patients with PCNSL (median age 62 years) were enrolled onto a pilot/phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX) (cycles 1,2,4,5) and cytarabine (ara-C) (cycles 3,6) based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide) was combined with intraventricular MTX, prednisolone and ara-C. Primary endpoint was time to treatment failure (TTF), secondary endpoints were response, overall survival, response duration, 5-year-survival fraction and (neuro)toxicity.
Results: Eighty-four of 88 patients were evaluable for response. Of these, 46 (54%) achieved complete response (CR), 4 (5%) complete response/unconfirmed, 8 (10%) partial response (PR), and 14 (17%) progressed under therapy. Seven (8%) out of 84 patients died due to treatment-related complications. In five (6%) of 84 patients therapy had do be discontinued due to severe treatment related complications. Follow-up is one to 124 months (median 42 months). Kaplan Meier estimates for median time to treatment failure (TTF), median overall survival and median response duration are 19 months, 55 months and 37 months respectively. For patients aged 60 years or older, the respective numbers were 9 months, 34 months and 24 months; in patients younger than 60 years Kaplan Meier estimate for TTF is 49 months, median overall survival and median response duration have not been reached yet. The 5-year survival fraction is 72% in patients < 60 years and 24% in older patients. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 20 (23%) patients. In a subgroup of patients (n=23) treated with chemotherapy alone serial neuropsychological testing showed no chemotherapy related cognitive decline in any patient. However, 8 out of 13 documented elderly patients treated with cranial irradiation as salvage therapy developed severe cognitive deficits.
Conclusions: Primary chemotherapy based on high-dose MTX and ara-C is highly efficient in PCNSL. A substantial fraction of patients < 60 years can obviously be cured with this regimen.
SGN-70, a Humanized Anti-CD70 Antibody, Targets CD70-Expressing Hematologic Tumors.
Authors: McEarchern Julie A. , McDonagh Charlotte F. , Smith Leia M. , Klussman Kerry , Oflazoglu Ezogelin , Morris-Tilden Carol , Stone Ivan , McCormick Renee , Carter Paul , Gerber Hanspeter , Grewal Iqbal S. , Law Che-Leung 
Published: October 2019

Abstract
Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is restricted to activated lymphocytes but is aberrantly expressed in hematologic malignancies and solid tumors including non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, renal cell carcinoma, glioblastoma, and nasopharyngeal carcinoma. To target CD70-expressing hematologic malignancies, we have engineered a humanized IgG1 anti-CD70 antibody that mediates lysis of tumor targets via ADCC and CDC and facilitates antibody dependent cellular phagocytosis in vitro. In vivo, administration of SGN-70 prolonged survival of SCID mice bearing CD70+ disseminated human NHL or MM xenografts. Intravenous injection of the CD70+ MM cell line MM.1S resulted in disease as measured by onset of paralysis, presence of CD138+ MM cells in the bone marrow, and increasing levels of circulating human Ig lambda light chain. SGN-70 treatment of MM.1S-bearing mice significantly delayed onset of paralysis and reduced the monoclonal protein levels detected in serum approximately 4-fold compared to untreated or non-binding antibody control-treated mice. Whereas myeloma cells comprised 32±6.4 % of mononuclear cells in the long bone marrow of control mice, SGN-70 treatment reduced the myeloma cell fraction to 4.9±1.9% of mononuclear cells recovered. SGN-70 treatment also significantly extended the survival of mice bearing disseminated Raji tumors (NHL) compared to control mice. Survival benefit was absent when mice received an Fc-modified antibody deficient in effector functions, confirming that the activity of SGN-70 in these models was dependent upon Fc-FcγR interaction with host immune cells. Together, these data demonstrate that SGN-70 possesses effector cell-mediated antitumor activity and provides rationale for clinical study of SGN-70 in CD70+ hematologic malignancies.
Inhibiton of mTOR by RAD001 Restores Normal B Cell Differentiation and Prevents B Cell Lymphomas in Eμ-MYC Mice.
Authors: Wall Meaghan , Poortinga Gretchen , Cardozo Daniela , Johnstone Ricky W. , McArthur Grant A. 
Published: October 2019

Abstract
The c-Myc proto-oncogene encodes a bHLH-LZ transcription factor that regulates proliferation, differentiation and apoptosis. Deregulated expression of c-MYC is a frequent finding in a wide variety of human cancers, including B cell lymphoma. One emerging function of c-MYC is the regulation of ribosome biogenesis, protein synthesis and metabolism i.e. cell growth. mTOR, a key downstream signal transduction molecule in the PI3K/AKT growth regulatory pathway, is amenable to pharmacological inhibition by rapamycin analogues such as RAD001. We hypothesized that control of cell growth by c-MYC is important for its ability to regulate differentiation and act as an oncogene and that RAD001, by limiting cell growth, would attenuate the transforming properties of c-MYC. In Eμ-myc mice the c-myc transgene is under the control of the immunoglobulin heavy chain enhancer (Eμ). Constitutive expression of c-MYC results in a polyclonal expansion of B cell precursors followed by lymphoma development. In the current study ‘pre-lymphomatous’ Eμ-myc mice were randomized to receive RAD001 5mg/kg (n=20) or placebo (n=18) 6 days per week from 4 weeks of age. Peripheral blood B cells were analyzed by surface marker expression after 2, 4 and 8 weeks of therapy. Mice were monitored weekly for the development of lymphadenopathy. 2 weeks of treatment with RAD001 significantly reduced the numbers of B cells in the blood of Eμ-myc mice compared to placebo (1.37±0.13 ×103/μL in the RAD001 arm versus 3.41±0.64 ×103/μL in the placebo arm, p<0.05). In particular, there was preferential suppression of less mature circulating B cell precursors over mature B cells by RAD001 resulting in B cell developmental subset profiles more closely approaching those of wild-type mice (Figure 1). Treatment with RAD001 was associated with improved lymphoma-free survival; 13/14 lymphoma-free mice (92.9%) versus 6/11 (54.6%) in the placebo group in an interim analysis of mice that had received at least 60 days of therapy. These results indicate that RAD001 can firstly oppose the expansion of B cell precursors and secondly reduce the incidence of malignant transformation induced by deregulated expression of c-MYC in B lymphocytes. These findings have implications for the application of mTOR inhibitors in the treatment or prevention of malignancies associated with MYC.
Figure 1. B cell subsets after weeks of therapy Figure 1. B cell subsets after weeks of therapy
Interleukin-21-Induced Apoptosis and Cell Death of Diffuse Large B-Cell Lymphoma (DLBCL) Cell Lines and Primary Tumors Are Associated with an Induction of Bim.
Authors: Sarosiek Kristopher A. , Chen Jun , Pham Dien G. , Nechushtan Hovav , Avisar E. , Kindsvogel Wayne , Lossos Izidore S. 
Published: October 2019

Abstract
IL-21, a member of the IL-2 cytokine family, is reported to have an immune-mediated anti-tumor activity against renal cell carcinoma, malignant melanoma and Non-Hodgkin’s Lymphoma (NHL) cell lines in xenograph animal models. Whether IL-21 exhibits direct anti-tumor activity against NHL cell lines and primary tumors is presently unknown.
We analyzed seven DLBCL and two Burkitt’s lymphoma cell lines for IL-21 receptor (IL-21R) expression. IL-21R was expressed at high levels in the two Burkitt’s lymphoma cell lines (RAJI and RAMOS). Out of the seven DLBCL lines, four expressed high levels of the receptor (OCI-LY-3, OCI-LY-7, OCI-LY-19, and RCK-8) while three had low receptor expression levels (OCI-LY-10, SU-DHL-4, and SU-DHL-6). IL-21 stimulation induced tyrosine phosphorylation of STAT-1, -3, and -5 as early as fifteen minutes post treatment in DLBCL lines expressing either high (OCI-LY-3 and RCK-8) or low (SU-DHL-6 and OCI-LY-10) levels of IL-21R.
In six of the seven DLBCL lines tested, IL-21 dramatically inhibited or completely abolished cellular proliferation at 25 ng/mL and 100 ng/mL concentrations, respectively. In contrast, one DLBCL cell line (OCI-LY-3) exhibited a threefold increase in cellular proliferation after stimulation with 25 ng/mL IL-21, but proliferation was effectively inhibited by 100 ng/mL IL-21.
Marked apoptosis and cell death were observed by flow cytometry at 72 hours post IL-21 exposure in all nine NHL cell lines tested with the exception of OCI-LY-3 which exhibited no significant change in cell viability. The IL-21-induced apoptosis was associated with an activation of caspases 3/7, 8, and 9, detected as early as 12 hours post IL-21 exposure. IL-21 also induced an increase in the levels of the pro-apoptotic protein Bim in all the cell lines exhibiting marked apoptosis. In contrast, Bim protein levels decreased in response to the IL-21 stimulation in the resistant OCI-LY-3 DLBCL cell line. IL-21 treatment led to a decrease in the protein levels of Bcl-2 in all the analyzed cell lines except OCI-LY-3. An increase in expression of Bcl-6 protein in three of the four tested DLBCL cell lines was observed in response to IL-21 exposure.
In primary tumors, IL-21 induced apoptosis in two of two DLBCLs, two of three follicular lymphomas, and two of six chronic lymphocytic leukemias. No apoptosis or cell death was induced in normal peripheral B-lymphocytes or in the HeLa or 293T control cells. These results suggest that IL-21 exhibits a direct anti-tumor effect on the DLBCL cell lines and primary tumors and point to a potential applicability of IL-21 in anti-DLBCL therapy. Further work interrogating the molecular mechanism of the IL-21-induced apoptosis of DLBCL cells in vitro and in animal models is in progress.
Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.
Authors: Roué Gaël , López-Guerra Mónica , Milpied Pierre , Pérez-Galán Patricia , Villamor Neus , Campo Elias , Colomer Dolors 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.
Antibody-Drug Conjugates Targeted to CD79 for the Treatment of Non-Hodgkin’s Lymphoma.
Authors: Polson Andrew G. , Yu Shang-Fan , Elkins Kristi , Zheng Bing , Clark Suzanna , Ingle Gladys , Slaga Dion , Giere Lynne , Du Changchun , Stephan Jean-Philippe , Young Judy , Vandlen Richard , Chang Wesley , Scales Suzie , Ross Sarajane , Eaton Dan , Ebens Allen 
Published: October 2019

Abstract
Non-Hodgkin’s lymphoma (NHL) is an attractive indication for the use of antibody-drug conjugate (ADC) therapeutics since NHL is responsive to conventional chemotherapeutic and antibody treatments. Additionally, experience with rituximab indicates that depletion of normal B-cells can be tolerated without untoward side effects, suggesting that B-cell specific surface proteins that are also prevalent in NHL are potential ADC targets. ADCs with stable linkers have lower toxicity than ADCs containing the same drugs with less stable linkers, however, for these ADCs to be effective the antibody must be degraded to release the active drug. This limits potential targets to surface antigens that upon antibody binding are highly internalized and subsequently degraded. We hypothesized that components of the B-cell receptor (BCR) would be excellent targets for stable-linker ADCs since, when cross-linked, the BCR is targeted to the lysosomal-like compartment MIIC as part of B-cell antigen presentation. In particular, CD79, the signaling component of the B-cell receptor, comprised of two peptide chains CD79a (Igα, mb-1) and CD79b (Igβ, B29), seemed a promising target for ADC treatment of NHL. CD79’s expression is restricted to the B-cell lineage and is on the surface of almost all NHLs. Unlike surface-Ig targeted therapies, which require a new drug for each cancer clone, CD79 sequences are invariant and a single drug is appropriate for the entire population. We found that ADCs targeted to CD79b were more effective than those targeted to CD79a. Furthermore, excellent efficacy is demonstrated with ADCs containing stable linkers and our data indicate in particular, that both anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are effective at low doses in subcutaneous cell-line xenograft models of follicular lymphoma, mantle cell lymphoma, Burkitt’s lymphoma and disseminated Burkitt’s lymphoma. Mechanism-of-action experiments show that anti-CD79b antibodies down regulate surface BCR expression and internalized antibody accumulates in the lysosomal-like MIIC compartment as hypothesized. We evaluated a number of ADCs targeted to other B-cell antigens and found that they were not effective if the ADC had a stable linker, indicating that CD79 has special properties as a target for ADCs. Our results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are particularly promising therapeutics for the treatment of NHL.
Nano-Fluidic Detection of Oncoprotein Signaling in Preclinical and Patient Lymphoma Samples.
Authors: Fan Alice C. , Deb-Basu Debabrita , Horoschak Melissa , Shirer Amy , Voehringer David , O’Neill Roger , Felsher Dean W. 
Published: October 2019

Abstract
Inactivation of oncogenes can be an effective cancer therapy. Determining precise levels of oncogene expression is important in the development of drugs to target oncogenes. We have developed a novel automated nano-fluidic Western-blot-like technology to detect and quantify oncogene expression in small numbers of mouse and human hematopoietic tumor cells. To detect different levels of oncogene expression, we generated transgenic mice in which the MYC or BCL2 oncogenes are regulated conditionally via the Tetracycline Regulatory System (Tet-system). Using lymphoma- derived cell lines from these mice, we titrated the level of oncogene expression by adding different concentrations of doxycycline in vitro. We were able to distinguish among different levels of oncogene expression in cell lysates, with high sensitivity in as few as 400 cells by nano-fluidic detection. Next, lymphoma derived cell lines were injected subcutaneously into syngeneic mice. Upon tumor development, MYC or BCL2 oncogenes were inactivated in vivo. Both MYC and BCL2 levels decreased in serial fine needle aspirations (FNAs) of tumor nodules upon parallel analysis with nano-fluidic detection and Western blot. Finally, we used nano-fluidic detection to determine levels of MYC, BCL2, AKT and ERK in lymph node samples from patients with follicular, transformed DLBC, Burkitt’s, and mantle cell lymphomas. BCL2 was overexpressed in mantle cell and follicular lymphoma patients, confirmed by Western analysis, whereas MYC was found to be overexpressed in Burkitt’s lymphoma. These results demonstrate that nano-fluidic detection technology may be used both as a preclinical tool for the assessment of changes in oncoprotein signaling and as a clinical diagnostic modality on microscopic clinical specimens.