bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dexamethasone+Thalidomide (Dex/Thal) Compared to VAD as a Pre-Transplant Treatment in Newly Diagnosed Multiple Myeloma (MM): A Randomized Trial.
Authors: Macro Margaret , Divine Marine , Uzunhan Yurdagul , Jaccard Arnaud , Bouscary Didier , Leblond Veronique , Janvier Maud , Genet Philippe , Castaigne Sylvie , Royer Bruno , Allard Christian , Chevret Sylvie , Fermand Jean-Paul 
Published: October 2019

Abstract
Since 2003, 204 patients (pts) younger than 66 yrs with untreated active MM were randomly assigned to receive a 4 month treatment with Dex/Thal (n=100) or with a VAD-like regimen (n=104). Then, all pts were intended to proceed to peripheral blood stem cell (PBSC) mobilization using cytoxan 4 g/m2 + G-CSF 5 μg/kg and to receive high dose therapy (HDT) with melphalan 200 mg/m2 and autologous PBSC support. Pts in the Dex/Thal arm received orally Thal for 3 mths at a fixed dose of 200 mg/d combined with Dex, 40 mg/d for 4 days every other wk for 2 mths and then monthly for 2 mths. Pts in the VAD arm received the same Dex regimen plus 3 courses of 4 days continuous infusions of Doxorubicin (9 mg/m2/d for 4 days) and Vincristine (0.4 mg/d for 4 days), 4 wk apart. Anticoagulation prophylaxis wasn’t systematically given.
Main characteristics of pts included in both arms were similar, including age (mean 55.1 yr in the Dex/Thal arm vs 56.4 yr in the VAD arm), MM stage (stage III 78% vs 85%), isotype (IgA: 21% vs 32%, p=.55), serumβ2m (mean 5.2 mg/L vs 3.9 mg/L, p=.24) serum creatinine (≤300 μmol/L in all pts) and albumin levels. Data were analyzed in an intent to treat basis. Primary objective was the achievement of at least a very good partial response (VGPR), defined as a decrease in serum and urine monoclonal immunoglobulin by 90% or greater.
In both arms, 91% of pts proceeded to PBSC mobilization, PBSC harvests were similarly successful and 83% of pts received HDT and autotransplant. Before PBSC collection, 24.7% and 7.3% of pts were in VGPR in the Dex/Thal arm and in the VAD arm, respectively (p=.0027). Before HDT, VGPR rate was 34.7% in the Dex/Thal arm as compared to 12.6% in the VAD arm (p=.002). At 6 mths post transplant, the benefit of Dex/Thal wasn’t further observed with VGPR rates of 44.4% in the Dex/Thal arm and 41.7% in the VAD arm (p=.87). Six pts died in the Thal/Dex arm (including 4 early deaths, within 4 mths post randomization) as compared to 9 pts in the VAD arm (including 3 early deaths).
Venous thrombosis or pulmonary embolism were recorded in 22.8% of pts in the Dex/Thal arm and in 7.5% in the VAD arm (p=.004). A symptomatic peripheral neuropathy was observed in 17.4 % and 12.9% of pts, respectively (p=.42). Otherwise, toxicity profile were similar in both groups. Before PBSC mobilization, mean duration of hospitalization, whatever the cause, was 8.3 days in the Dex/Thal arm as compared to 20 days in the VAD arm (p=.0001).
This randomized study confirms that oral Dex/Thal is an effective first line treatment for symptomatic MM, and supports its use as an induction regimen which could be preferred to infusional VAD in candidates for HDT.
Memory B Cells Protect from CMV Infection in the Absence of T Cells.
Authors: Winkler Thomas H. , Weisel Florian , Klenovsek Karin , Mach Michael 
Published: October 2019

Abstract
Infections with cytomegalovirus are still a major clinical problem in immunosuppressed patients e.g. after bone marrow or stem cell transplantation. To prevent clinical overt disease resulting from disseminated virus infection, immunoprophylaxis and/or -therapy are considered a major goal. The humoral immune response contributes to immune protection against CMV by providing neutralizing antibodies. However, in the early phase after transplantation a primary immune response is not possible. Humoral anti-CMV immune effector functions can only be provided by memory B cells. The activation requirements for resting memory B cells are unclear. Using non-infectious hCMV particles in mice we have recently shown that activation of virus-specific memory B cells to secrete IgG is independent of cognate or bystander T cell help. To analyze whether transfer of memory B cells into immunodeficient mice can protect from lethal infection we switched to an infectious animal model using mCMV. When memory B cells from mCMV-infected mice were adoptively transferred into RAG-1−/− mice, a strong IgG anti-mCMV titer developed within 4–6 days after infection with mCMV. Virus dissemination and subsequent disease was inhibited. A 100–1000 fold decrease of virus titers and a 1.000–10.000 fold decrease of viral DNA load in spleen and lung was observed in mice that received mCMV specific memory B cells. Even in an established mCMV infection virus dissemination and subsequent disease could be prevented by means of adoptive memory B cell transfer. In further experiments we also used a virus mutant that cannot be controlled by NK cells in C57Bl/6 mice. Even in this experimental system we could demonstrate that adoptive transfer of memory B cells in the absence CD4 and CD8 cells is sufficient to protect from viral dissemination and rapid lethality. Our results show that memory B cells can mediate protection against mCMV in the absence of cognate or bystander T cell help. Similar regimens might be a therapeutic option for CMV reactivation after bone marrow transplantation in patients.
Cost-Effectiveness of Rituximab Post CVP Induction for the Treatment of Low-Grade NHL.
Authors: Hornberger John C. , Reyes Carolina , Shewade Ashwini , Loecke David , Valente Nancy 
Published: October 2019

Abstract
Background: Extended Rituximab (R) therapy after CVP (cyclophosphamide, vincristine, prednisone) induction in the first-line treatment of low-grade, CD20-positive, B-cell NHL significantly prolongs progression-free survival (PFS). A societal cost-effectiveness analysis is performed to estimate projected lifetime clinical and economic implications of this treatment.
Methods: A Markov model with 3 health states (progression-free, post-progression, and death) was developed to estimate the direct medical costs and quality-adjusted life-years (QALYs) for a representative patient cohort with low-grade, CD20-positive, B-cell NHL. Kaplan-Meier estimates of PFS and overall survival (OS) up to 4 years are obtained from the ECOG/CALGB intergroup E1496 trial. After 4 years, transition rates are assumed to be the same in both arms. Costs include drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Incremental costs associated with R are based on Medicare reimbursement rates and published drug prices. Utilities are derived from the literature and a 3% discount rate is employed.
Results: Projected mean OS is 1.2-yrs longer for patients assigned to extended R therapy versus observation alone (15.2 v 14.0 yrs). Extended R therapy is estimated to cost $42,822 on average, with an expected gain of 0.85 years of quality-adjusted survival. Over a lifetime, the cost per QALY gained is $57,515. Sensitivity analyses performed on all variables contributing to the model results showed that utility for follicular NHL patients (range: 0.68–1) and number of R infusions (range: 8–17) most influence the incremental cost-effectiveness ratio (ICER).
Conclusion: The ICER of extended R dosing following CVP induction remains well below the threshold considered acceptable for oncology in the United States. Additional analysis of long term follow-up data will be useful for further evaluation of clinical and economic implications of this treatment for low-grade, CD20-positive, B-cell NHL patients.
Pre Transplantation MGUS and Transformation to Multiple Myeloma in Kidney Transplantation: A Single Center Experience.
Authors: Naina Harris V.K. , Kyle Robert , Habermann Thomas M. , Harris Samar , Cosio Fernando G. , Stegall Mark D. , Leung Nelson 
Published: October 2019

Abstract
Background: Monoclonal gammopathy of undetermined significance (MGUS) is reported in 3 to 5 percent of population, with the prevalence increasing with advancing age. Patients with MGUS are at increased risk for progression to multiple myeloma or other plasma cell dyscrasias. There is a paucity of information on clinical outcomes of patients with MGUS undergoing renal transplantation. A retrospective study was performed to determine wether MGUS is a contraindication to renal transplantation.
Methods: Data was collected from both the kidney transplant and MGUS database. The diagnosis of MGUS was made on the basis of either serum protein electrophoresis (SPEP) or immunofixation after excluding multiple myeloma, amyloidosis and monoclonal immunoglobulin deposition disease.
Results: Between 1977 and 2004, 3518 patients underwent kidney transplantation of whom 23 patients had a preexisting monoclonal gammopathy of undetermined significance (MGUS). Fourteen (61%) of these patients were males. The median age at the time of transplant was 59 ±12 years. Ten patients (43.5%) had IgG Kappa (GK), 7 (30.4%) had IgG Lambda (GL), 2 (8.7%) had IgA Lambda (AL), 1 (4.3%) had IgA Kappa (AK), 2 (8.7%) had IgM Lambda (ML). One patient had a biclonal gammopathy GL and ML. Patients were monitored with either SPEP or immunofixation for median duration of 1542 days after transplantation. Thirteen patients had either no change or stable monoclonal protein, 6 had a decrease in their paraprotein level. Two patients had a mild increase in their paraprotein. Two patients with GK developed into biclonal gammopathy (GK and AK). The median follow up of this cohort after the renal transplant was 1783 days. Twelve (52%) patients remained alive at the time of the study. A patient with GK prior to the transplant who underwent kidney transplantation twice developed a biclonal gammopathy and was found to have increased plasma cells (20%) in bone marrow after 14 years. On follow up for 6 years, his M-protein remained stable. Another patient was found to have 17% plasma cells around the time of kidney transplantation. He had a stable M-protein at follow-up, but underwent a stem cell transplant for recurrent immunotactoid glomerulonephritis. Two (9%) patients developed more than 15% plasma cells in their bone marrow with a stable M-protein. None of the patients with a preexisting MGUS evolved into multiple myeloma.
Conclusion: In this small study, the presence of MGUS prior to kidney transplantation did not appear to have increased the incidence of multiple myeloma post transplant. Therefore, MGUS by itself should not be considered as an absolute contraindication for renal transplantation.
Signaling Profile and Anti-Tumor Activity of the Novel HSP90 Inhibitor NVP-AUY922 in Multiple Myeloma.
Authors: Stühmer Thorsten , Zöllinger Angela , Siegmund Daniela , Chatterjee Manik , Grella Evelyn , Knop Stefan , Kortüm Martin , Unzicker Christian , Jensen Michael R. , Quadt Cornelia , Chène Patrick , Schoepfer Joseph , Garcia-Echeverria Carlos , Einsele Herrmann , Wajant Harald , Bargou Ralf C. 
Published: October 2019

Abstract
We have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumor cell survival. Pharmacologic blockade of Hsp90 has consistently been shown to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumor cells is lacking. Furthermore, these investigations have so far exclusively relied on geldanamycin derivatives. Here, we analyzed the anti-tumor effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) in a large set of primary MM samples and in MM cell lines. The majority of cell lines (n = 8), as well as most primary samples (n = 20), displayed profound apoptotic responses and steep dose-effect curves with EC50 values in the range of 5–15 nM and EC90 values between 8 and 25 nM. This effect was not attenuated in coculture with cells from the bone marrow microenvironment. Some cell lines and about a quarter of primary MM samples displayed greater resilience to drug treatment, with EC50 values but not EC90 values reached at concentrations up to 50 nM. Sensitivity of MM cells to the Hsp90 inhibitor was not correlated with TP53 mutation or Hsp70 induction levels. Western analyses of MM cell lines and flow cytometric analyses of antibody-stained Hsp90 client proteins in primary tumor cells showed that NVP-AUY922-treatment entailed molecular effects and pharmacodynamic properties consistent with abrogation of Hsp90 function. Consequently, downregulation of multiple signaling and survival pathways was detectable through, for example, decreases in the phosphorylated (activated) forms of extracellular signal-regulated kinase (ERK) 1 and 2, signal transducer and activator of transcription (STAT) 3 and glycogen synthase kinase-3beta. All samples treated displayed strong upregulation of Hsp70. Importantly, peripheral blood mononuclear cells as well as primary bone marrow stromal cells were much less affected by high (50–100 nM) concentrations of NVP-AUY922, showing that a therapeutic window might be established for the treatment of multiple myeloma. Taken together, NVP-AUY922 could be a promising new drug for the treatment of a majority of myeloma patients.
A Prospective Study of Voriconazole Therapeutic Drug Monitoring (TDM) in Patients with Acute Leukemia.
Authors: Seki Jack , Brandwein Joseph , Ward Richard , Paul Narinder , Russell Heather , Kumar Deepali 
Published: October 2019

Abstract
Abstract 1018
Poster Board I-40

Background:
Voriconazole (VOR) is an expanded spectrum azole that is often used to treat suspected or proven invasive aspergillosis (IA). VOR plasma drug levels are not routinely monitored and their correlation with clinical response and toxicity is unclear. We sought to clarify the kinetics of levels in patients started on VOR and their relationship with CYP2C19 genotype and clinical outcomes.

Methods:
We prospectively enrolled inpatients undergoing induction or consolidation chemotherapy for AML who were able to take oral medications and started on VOR for suspected invasive aspergillosis (IA). All patients received an initial intravenous loading dose of 6mg/kg bid for two doses, then 200mg bid. VOR dose could be increased at the physician's discretion. Trough VOR levels (μg/mL) were monitored at days 0,2,4,6 and performed using HPLC. Patients also underwent genotyping for CYP2C19. Clinical and radiologic responses were graded independently by two physicians. Hepatotoxicity was correlated to peak VOR levels.

Results:
We enrolled 33 patients of which 60.6% were male and 39.4% female. Mean age was 60.2±15.4 yrs. The distribution of peak VOR levels was as follows: <2 μg/mL (n=6); 2-6 μg/mL (n=22); >6 μg/mL (n=5). Mild hepatotoxicity (liver enzymes greater than 2x baseline) was seen in 6/22 (27.2%) of patients with levels between 2-6 μg/mL and 1/5 (20%) of patients with levels >6 μg/mL. No hepatotoxicity was noted in those with peak VOR <2 μg/mL. No significant correlation was seen in mg/kg dose of VOR and levels. Of the 33 patients, 19 (57.6%) met the EORTC/MSG criteria for possible, probable, or proven invasive fungal disease. Of these 9 (47.4%) patients had a response to therapy. Mean peak VOR levels in responders vs. nonresponders was 3.78 vs. 3.12 (p=0.63). Response to therapy was 2/2 (100%) if levels were <2 μg/mL, 6/14 (42.9%) if levels were 2-6 μg/mL, and 1/3 (33%) if levels were >6 μg/mL. Breakthrough infections occurred in 5/33 (15.2%) patients given VOR, all of whom had peak levels between 2-6 μg/mL. Genotyping was performed on 11/33 (33.3%) patients and included slow metabolizers (n=5; median peak VOR 3.0), rapid metabolizers (n=5; median peak VOR 3.0) and undetermined (n=1). Genotype did not correlate with clinical outcomes.

Conclusions:
The majority of patients attained voriconazole levels > 2 μg/mL by day 6 of treatment. Voriconazole levels do not appear to predict response to therapy or breakthrough infection although mild hepatotoxicity can occur if levels are >2 μg/mL.

Disclosures:
Seki: Astellas: Honoraria; Pfizer: Honoraria; Merck: Consultancy, Honoraria, Research Funding. Kumar:Merck: Honoraria; Pfizer: Honoraria.
International Normalized Ratio (INR) Determined by Plasma-Based Methods Versus Point-of-Care Instruments in Patients with Antiphospholipid Antibody Syndrome.
Authors: Moll Stephan , McKnight Lauren , Deal Allison 
Published: October 2019

Abstract
Abstract 1067
Poster Board I-89

Background:
In some patients with antiphospholipid antibody (APLA) syndrome treated with warfarin, the International Normalized Ratios (INRs) obtained from plasma, as well as from full blood via fingerstick by older point-of-care (POC) devices, are unreliable. Reliability of newer POC devices in APLA syndrome patients is unknown and was investigated in the present study.

Methods:
60 patients on stable warfarin were enrolled: 30 with APLA syndrome, 30 without. INRs were determined using 4 POCs: CoaguChekXS®, ProTime®, the investigational ProTime®, and INRatio2®. Plasma from phlebotomy was tested for: PT, factor II activity, chromogenic factor X, anticardiolipin and anti-beta-2-glycoprotein I antibodies, lupus anticoagulant. Analysis: Data from the venipuncture INRs from the patients without APLA are used to estimate the relationship between INR and Factor II level and determine the therapeutic range of Factor II. Using the same therapeutic INR range, for each individual POC test the proportion of patients whose clinical decision based on the POC instrument is correct is estimated, along with 95% confidence intervals. This is done for patients with and without APLA. These two proportions are compared between the two groups using Fisher's Exact Tests; nominal p-values are reported. A similar analysis is done using the Factor X test as the gold standard.

Results:
Data collection has been completed; analysis of results is pending and will be available before December 2009.

Conclusions:
Data analysis will show whether the presently available POC devices give reliable INR results in patients with APLA syndrome on warfarin and can be reliably used to monitor warfarin therapy.

Disclosures:
Moll: Hemosense: research support; Roche: reserarch support; ITC: Consultancy, research support. McKnight:ITC: Honoraria. Deal:ITC: Consultancy.
Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Can Induce Durable Remission in Heavily Pretreated Relapsed Hodgkin Lymphoma. (HL).
Authors: Chen Robert , Palmer Joycelynne , Popplewell Leslie , Shen Jessica , Smith Eileen , Delioukina Maria , Kogut Neil , Rosenthal Joseph , Forman Stephen J , Nademanee Auayporn P. 
Published: October 2019

Abstract
Abstract 1192
Poster Board I-214

Background:
Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL.

Results:
Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX.
With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show:

Conclusion:
Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions.

Disclosures:
No relevant conflicts of interest to declare.
CD137/4-1BB Is Inducibly Expressed On CLL B Cells through CD40 Signaling.
Authors: Fukuda Tetsuya , Nakaima Yukana , Kasubata Aya , Watanabe Ken , Koyama Takatoshi , Rassenti Laura Z. , Kipps Thomas J. , Miura Osamu 
Published: October 2019

Abstract
Abstract 1266
Poster Board I-288
CD137/4-1BB, a TNFR family member is expressed on activated T cells as a co-stimulator. It transduces the signal for cell survival and differentiation and plays a crucial role in CD8 cytotoxic T cells. Recently, an increasing number of reports have indicated its important role on tumor immunity, and the studies of immunotherapy targeting CD137 are on going. Therefore, it is important to know the expression of CD137 and CD137L on malignant cells for the establishment of immunotherapy. As a first step, we examined CD137 expression on PBMCs from healthy donors and CLL patients. When PBMCs from healthy donors were stimulated with PMA and ionomycin, CD137 expression was induced not only on T cells but also on activated B cells. However, when PBMCs from CLL patients were stimulated in the same way, we could not detect CD137 induction on CLL B cells. Since more than 90% of lymphocytes in the patients were CLL B cells, it is conceivable that activated T cells were required to induce CD137 on B cells. To test this hypothesis we next co-cultured CLL cells with T cells activated with anti-CD3/CD28 antibody-coated beads. In this co-culture CD137 was induced on CLL B cells, and this induction was diminished by anti-CD154 blocking antibody. Furthermore, CD137 was inducibly expressed on CLL B cells after co-culture with HeLa cells transfected with CD154 gene. The induction of CD137 mRNA was also clearly detected by RT-PCR after this stimulation. This CD137 induction was more significantly observed on CLL B cells (n=14, MFIR 11.5±6.9) as compared with B cells from healthy donors (n=4, MFIR 3.7±0.6, p=0.001) or non-CLL B cell malignancies (n=9, MFIR 4.2±3.43, p=0.003). Stimulation of CD137 expressed on BJAB transfectants by co-culture with CD137L-transfected CHO cells induced a conspicuous nuclear translocation of p52, a non-canonical NF-κB factor. In agreement with this activation, the expression of survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154 stimulated CLL B cells in vitro. CD40 ligation can induce anti-CLL immunity and reduce CLL cells clinically. These data suggest that the inducibly expressed CD137 may diminish the effectiveness. It is possible that the fine adjustment of these co-stimulators can lead more effective immunotherapy.

Disclosures
No relevant conflicts of interest to declare.