bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective Analysis of Weekly Administration of Bortezomib in Multiple Myeloma.
Authors: Sayar Hamid , Lee Fa-Chyi 
Published: October 2019

Abstract
Background: Currently the standard treatment of multiple myeloma (MM) with the proteasome inhibitor bortezomib (Velcade) is by twice weekly administration of the drug. We present a retrospective study of bortezomib therapy by weekly dosing in MM patients unable to tolerate the standard regimen.
Methods: Since January 2004, five patients (3 male and 2 female, age 47 – 81) have been treated at our center by weekly, and one (male, 86) by every-two-week administration of bortezomib. This approach was selected primarily due to low performance status and/or comorbidities. All patients had failed at least one prior treatment modality. Each cycle of the weekly schedule consisted of one dose every week for two weeks, followed by two weeks of rest. Mainly for convenience purposes, two patients while stable on weekly treatment, were switched to even less frequent treatment of once every-three-weeks. Furthermore, five patients received a plain dose of 2.0 mg rather than regular dose calculation per body surface area.
Results: All 5 patients on weekly schedule had an initial moderate to major response, followed by a stable course. None of them, however, achieved a complete remission. 2/5 demonstrated progression of disease after they were switched to every-three-week dosing. The patient on every-two-week treatment had an initial favorable response, and is currently being switched to the weekly schedule due to excellent tolerance.
Conclusion: Our retrospective analysis indicates that weekly bortezomib therapy is a promising alternative approach to the treatment of MM in those patients intolerant to standard regimen. It seems reasonable, therefore, to attempt a larger prospective study of bortezomib administration with less frequent dosing, mainly in this group of MM patients.
A Phase I Study of Talvesta® (Talotrexin) in Relapsed or Refractory Leukemia or Myelodysplastic Syndrome.
Authors: Giles Francis , Rizzieri David A. , George Solly , Stock Wendy , Fontanilla Jeannie , Choy Gavin S. , Berk Gregory I. 
Published: October 2019

Abstract
Talvesta® is a novel, nonpolyglutamatable antifolate drug which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talvesta binds more tightly to DHFR than methotrexate (MTX), with a Ki of 0.35 pM, which is 15-fold lower than MTX. Talvesta enters cells by the reduced folate carrier (RFC) pathway. In CCRF-CEM leukemia cell lines, Talvesta compared to MTX exhibited an IC50 of 1.1 nM and 11 nM, respectively. An open-label, dose escalation study of Talvesta administered as a 5–10 minute infusion on Days 1–5 on a 21-day cycle to patients with relapsed or refractory leukemias is ongoing. The primary objectives of this study are to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT), and evaluate the pharmacokinetics, safety and efficacy. Patients with AML, ALL, CLL, CML-BP, MDS, RAEB or RAEBT and CMML for whom no standard therapy resulting in a durable remission is available and with an ECOG PS 0–2, were enrolled. The starting dose was 0.2 mg/m2 (1 mg/m2 per cycle) based on preclinical data with dose escalation based on a modified Fibonacci sequence. Three patients were treated at each dose level in the absence of a DLT. All patients received folic acid and B12 vitamin supplementation. Plasma Talvesta concentrations were analyzed by a validated LC/MS/MS method during cycle 1. To date, twenty-two (22) (16 male) heavily pre-treated patients (11 AML, 7 ALL, 1 CML-BP, 2 CLL, 1 Hairy Cell) median age 52 years (range, 19–84) have been enrolled and received a total of 29 cycles of Talvesta (median 1, range 1–4) at doses of 1 mg/m2 to 4 mg/m2 per cycle. Two patients experienced neutropenic fevers possibly/probably related to talvesta administration. Dose escalation continues in an attempt to identify a DLT with subsequent initiation of a Phase II study in patients with refractory ALL. One major response has been observed in a patient with refractory ALL. Pharmacokinetic parameters are pending analysis. Talvesta at the tested doses in this heavily pretreated leukemia patient population has been well tolerated.
Reduced-Intesity Allogeneic HSCT in Hematologic Malignancies: Influence of Underlying Diagnosis and Prior Autograft on Outcome.
Authors: Mehta Jayesh , Gordon Leo , Tallman Martin , Winter Jane , Williams Stephanie , Frankfurt Olga , Evens Andrew , Grinblatt David , Kaminer Lynne , Meagher Richard , Rashid Kamran , Grabowski Donna , Singhal Seema 
Published: October 2019

Abstract
RI-HSCT is now accepted practice in a number of clinical scenarios. However, two circumstances in which it is still often not covered by insurance carriers is a diagnosis of acute leukemia (AL) and relapse following an autograft. The aim of this analysis was to specifically study the influence of these 2 factors in the context of known prognostic variables in a series of 91 uniformly-treated patients with hematologic malignancies (19–71 years; median 53; 22% >60 years). 41 had relapsed after a prior autograft (6/29 AL, 20/38 lymphoma, 15/24 myeloma; P=0.005). 62% had refractory disease. Performance status (PS) was 0 in 31%, 1 in 47%, and 2/3 in 22%. Donors (55% >45 years) were HLA-matched siblings (n=51), 10/10 allele-matched unrelated (n=29), or 9/10 allele-matched (n=11). The conditioning comprised 100 mg/m2 melphalan with (no prior auto) or without (prior auto) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibs) or tacrolimus-mycophenolate (others). G/GM-CSF were not given routinely. Supportive care was uniform. As the table below shows, the 2-year cumulative incidence of relapse and non-relapse mortality (NRM) and 2-year disease-free (DFS) and overall (OS) survival rates were not significantly influenced by the diagnosis or prior autograft.
Relapse NRM DFS OS Acute leukemia 55% 22% 23% 37% NHL/Hodgkin 42% 29% 28% 47% Myeloma 66% 18% 16% 36% P 0.35 0.49 0.89 0.51 No prior autograft 48% 26% 25% 39% Prior autograft 60% 21% 19% 42% P 0.82 0.55 0.88 0.52
Next, diagnosis and prior autograft were entered into a Cox model with chemosensitivity, donor age, LDH and PS; variables known to influence outcome significantly in this group of patients. The 4 known variables retained their significance in influencing OS (LDH P=0.001, chemosensitivity P=0.003, PS P=0.003, donor age P=0.01) and DFS (chemosensitivity P=0.002, PS P=0.02, donor age P=0.02, LDH P=0.03). Prior autograft did not influence OS (P=0.77) or DFS (P=0.57) as shown in the figure below (derived from the Cox model; adjusted for the 4 significant variables).
Figure Figure
Diagnosis did not influence DFS (P=0.49). However, it did affect OS (overall P=0.04; AL vs myeloma P=0.23; AL vs lymphoma P=0.01; myeloma vs lymphoma P=0.25) as shown in the figure below (derived from the Cox model; adjusted for the 4 significant variables.
Figure Figure
The difference in OS likely reflects the fact that unlike for lymphoma and myeloma, salvage therapy is of limited benefit for AL relapsing after HSCT. However, comparable DFS suggests that the extent of benefit provided by the RI-HSCT procedure itself is independent of diagnosis. We conclude that prior autograft or the underlying diagnosis should not be used to determine eligibility for RI-HSCT.
The Proteasome Inhibitor NPI-0052 in Combination with Bortezomib Induces Antitumor Activity in Waldenstrom Macroglobulinemia.
Authors: Jia Xiaoying , Leleu Xavier , Moreau Anne-Sophie , Hatjiharisi Evdoxia , Ngo Hai , O’Sullivan Garrett , McMillin Douglas , Treon Steven , Mitsiades Constantine , Hideshima Teru , Palladino Michael , Anderson Kenneth , Chauhan Dharminder , Ghobrial Irene 
Published: October 2019

Abstract
Background: Waldenstrom’s Macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. Recently, Bortezomib has demonstrated clinical activity in patients with relapsed WM. The purpose of this study was to investigate the in vitro effect of the new proteasome inhibitor NPI-0052 (Nereus Pharmaceuticals, CA), alone and in combination with Bortezomib, in WM.
Methods: WM cell lines (BCWM1 and WSU-WM) and IgM secreting low-grade lymphoma cell lines (MEK1, RL, Namalwa) were used. Bone marrow primary CD19+ malignant cells were obtained from WM patients after informed consent. Inhibition of growth was measured using MTT assays. DNA synthesis was measured using the thymidine incorporation assay. Apoptosis was determined using Apo2.7 staining, followed by flow cytometric analysis. Determination of the additive or synergistic effect of the combination was calculated using the CalcuSyn software (Biosoft, MO) based on the Chou-Talalay method with the combination index (CI)<1.0 indicating synergism.
Results: NPI-0052 induced cytotoxicity and inhibition of DNA synthesis, with an IC50 of 20–30nM in all cell lines tested at 24 hrs. NPI-0052 induces 50% apoptosis at 48 hrs. Similar effects were demonstrated in primary CD19+ WM cells. Bortezomib induced cytotoxicity and inhibition of DNA synthesis with an IC50 of 20–30nM in all cell lines tested. Importantly, the combination of NPI-0052 and Bortezomib induced significant inhibition of proliferation compared to each agent alone, specifically at the combination of 2.5nM and 5nM of Bortezomib and 10nM of NPI-0052. For example, Bortezomib single agent at 2.5nM and 5 nM induced 8% and 13% cytotoxicity in BCWM.1 in vitro, respectively, while the combination Bortezomib and NPI-0052 10nM induced a synergistic cytotoxic effect, 44% (CI=0.7) and 58% (CI=0.47), respectively. The combination effect of NPI-0052 20 nM with Bortezomib 2.5nM and 5nM was also synergistic, with 61% (CI=0.7) and 66% (CI=0.7) cytotoxicity, respectively. Similar effects were observed in 3 primary CD19+ WM cells obtained from patients’ bone marrow.
Conclusion: NPI-0052 has significant anti-tumor activity against WM in vitro, especially in combination with Bortezomib. These results provide the framework to further study the potential therapeutic role of NPI-0052 in WM. *XJ and XL are co-first authors.
Bortezomib Once Weekly Is Well Tolerated as Maintenance Therapy after Less Than a Complete Response to High-Dose Melphalan in Patients with Multiple Myeloma.
Authors: Knop Stefan , Hebart Holger , Kunzmann Volker , Angermund Ralf , Einsele Hermann 
Published: October 2019

Abstract
Background: Despite intensive treatment strategies in multiple myeloma (MM) consisting of one or two cycles of high-dose melphalan (HD-Mel) with autologous stem cell support only a minority of patients (pts) achieves molecular complete remission leading to an event free survival (EFS) of eight to ten years. The median EFS for all patients following HD-Mel, however, is no more than 30 to 35 months. Several agents have been evaluated as a part of maintenance strategies in order to eradicate minimal residual disease and thus extending the period until salvage treatment is required. Interferon alpha, that has been most widely used in this setting showed a significant prolongation of EFS and a trend to better overall survival in a large meta-analysis. Bortezomib (VELCADE® [Vel]), a proteasome inhibitor, has substantial anti-myeloma activity in relapsed and refractory disease and was shown to induce exceptional response rates, including consistently high CR rates in up-front treatment.
Patients and methods: We decided to set up a phase II trial in patients up to 70 years with less than CR (SD, PR, or VGPR) after one or two cycles of HD-Mel using a less dose-intense schedule than the standard protocol for monotherapy. The first eleven pts were to receive four cycles of Vel 1.0 mg/m2 once weekly for four weeks followed by a two-week rest period. Since no dose limiting toxicity occurred, the dose was increased as per protocol to 1.3 mg/m2 for the subsequent pts.
Results: Up to now, 20 subjects were included with a median age of 60.5 (range, 46 – 69) years, 3 of whom had previously received single, and 17 tandem HD-Mel. Two cases of moderately severe herpes zoster prompted us to generally administer acyclovir prophylaxis throughout the treatment. Five pts experienced symptoms of peripheral neuropathy all of which were of grade I. WBC nadir occurred during cycles 2 and 3 with a median of 3.7 × 109/l while median PLT and HB values did not decline below normal values. Three patients progressed while on the study and received salvage treatment while all other patients enrolled completed all four scheduled cycles of treatment. To date, two patients showed improvement of response by conversion of VGPR into CR with confirmed negative immunofixation.
Conclusion: We are currently continuing patient accrual on the once-weekly 1.3 mg/m2 schedule since treatment is considered to be safe. Data on the efficacy (i.e. median EFS, OS as compared to historic controls on interferon alpha), however, will require significantly longer follow up.
N-Acetylcysteine Mildly Inhibits the Graft vs Leukemia Effect but Not the Lymphokine Activated Cells (LAK) Activity.
Authors: Shapira Michael Y. , Weiss Lola , Reich Shoshana , Zeira Michael , Slavin Shimon 
Published: October 2019

Abstract
N-acetylcysteine (NAC) is a known antioxidant and induces modulation of glutathione cellular content effects. It has been suggested that in the context of stem cell transplantation (SCT), NAC was suggested as a possible agent in order to prevent and treat graft-vs.-host disease, veno-occlusive disease and idiopathic pneumonia syndrome. We investigated the possible effect of NAC on graft-vs.-leukemia effect (GVL) and lymphokine activated cells (LAK) activity in murine models. After 10 days of either oral or intraperitoneal NAC treatment, the cytotoxic activity of the LAK cells against Yac cells (H-2a, NK sensitive tumor cell line)did not significantly differ from LAK activity generated from spleen cells obtained from untreated controls. However, NAC mildly suppressed GVL (appearance of BCL1 leukemia in 8/36 animals treated with NAC as compared to 0/20 in the transplantation control group, p=0.023, figure 1). In spite of this mild suppression of GVL, no negative effect on engraftment, judged by achievement of donor chimerism, was seen.
We conclude that NAC usage in SCT maybe relatively safe in regard to the GVL effect, yet further clinical studies are warranted.
Figure Figure
B Cells Suppress IL-2, IFN-γ and TNF-α Production from Alloaggressive CD8+ T Cells in a Mismatched Murine Model of Bone Marrow Transplant.
Authors: Ritchie David S. , Watt Victoria 
Published: October 2019

Abstract
B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells in models of autoimmunity and tumor immunology. We have previously shown that resting B cells also inhibit anti-tumor T cell function and suppress graft versus host disease (GVHD) in a mismatched mouse model. We have extended these findings to reveal that B cell depletion of the donor graft results in more rapid T cell engraftment and higher IL-2, IFN-γ and TNF-α production by engrafting alloagressive T cells. In turn the degree of cytokine production was highly correlated with the degree of weight loss in mice developing GVHD underscoring the importance of T cell derived inflammatory cytokines in the development of GVHD. Conversely, those mice treated with additional resting B cells at the time of marrow infusion showed lower levels of cytokine production from engrafting T cells and subsequently less GVHD. Further, the amount of INF-γ and TNF-α production from alloaggressive T cells post transplant was substantially greater when a donor splenocytes we used to supplement bone marrow. The clinical score and histological examination of mice undergoing splenocyte + bone marrow transplant showed substantially differences compared to that observed in the bone marrow only model The post splenocyte transplant model reflected a hyperacute GVHD syndrome as opposed to clinically relevant, histologically proven acute GVHD derived from the transplant of bone marrow and furhet indicate that rapid disregulated T cells engraftmnet of central to the onset of devastaing GVHD. These findings indicate that resting B cells may regulate T cell engraftment and activation through regulating T cell homeostasis and suppression of inflammatory cytokines. B cells therefore may potentially be used therapeutically to limit GVHD mediated by alloaggressive T cells, whilst profound pre-transplant depletion of B cells may be detrimental to transplant outcome due to the promotion of GVHD.
The Comparison of In Vitro and In Vivo Anti-Host Responses as a Predictor of T Cell Reactivity after Allogeneic-BMT as Determined by TCR Vb Spectratype Analysis.
Authors: Friedman Thea M. , Azhipa Olga Y. , Filicko Joanne , Mookerjee Bijoyish , Flomenberg Neal , Donato Michele L. , Rowley Scott D. , Korngold Robert 
Published: October 2019

Abstract
Immunotherapeutic strategies have gained recognition as viable alternatives to more conventional therapeutic modalities for the treatment of cancer. In this regard, adoptive T cell therapy through allogeneic blood and marrow transplantation (BMT) has offered the first evidence to demonstrate that anti-tumor effects could be achieved against hematological malignancies. However, complications which include graft failure, opportunistic infections, leukemic relapse and graft-versus-host disease (GVHD) underscore the importance for the development of more targeted strategies in order to promote the successful implementation of allogeneic-BMT as a long term curative approach. It is well understood that mature donor T cells present in the donor inoculum must be an integral part of any such strategy as they play a pivotal role in all of the above mentioned complications. The incidence of the first three complications is diminished by the presence of mature donor T cells while, unfortunately, the transplantation of mature alloreactive donor T cells also directly induces the latter complication of acute GVHD, which can be directed against either HLA or minor histocompatibility antigen (miHA) disparities. Efforts to pan deplete donor marrow inoculum of T cells have been successful in minimizing the development of disease but have been associated with increased leukemic relapse. Thus, one approach to solve this problem would be to identify and then selectively deplete alloreactive donor T cells while allowing the residual T cells to provide protection against infection and to mediate a leukemia-specific GVL response. We hypothesized that an in vitro culture system using a one-way mixed lymphocyte reaction generated between a potential allogeneic BMT donor and their respective recipient could give rise to many of the alloreactive T cell responses that would be predictive of those that would be generated in vivo, following BMT. We proceeded to test the predictive value of the in vitro culture system through the use of TCR CDR3 Vβ spectratype analysis in the clinical BMT setting. To this end we compared, by spectratype analysis, the in vitro and post-transplant in vivo responses of nine donor patient pairs. The results indicated a high association of overlapping Vβ CDR3-size skewing as defined by the reactive Vβ families in the patient post-transplant also found to be reactive in the in vitro culture system (range of overlap 50–100%, median 72.5%). Thus, in vitro spectratyping analysis may be useful in guiding the manipulation of the donor T cell inoculum in order to provide improved BMT outcomes.
In Vitro Methotrexate: A Practical Approach to Selective Allodepletion.
Authors: Sathe Atul , Ortega Sterling , Mundy Dorothy , Collins Robert H. , Karandikar Nitin J. 
Published: October 2019

Abstract
Graft-versus-Host Disease (GvHD) remains a major cause of transplant-related morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Selective depletion of alloreactive T-cells may alleviate GvHD, while still maintaining other advantages conferred by donor T-cells, such as graft survival, antiviral immunity and graft-versus-leukemia effect. While several strategies for in vitro allodepletion have been proposed, their transition from pre-clinical studies to clinical use is sometimes hindered due to choice of reagent or technique. In this study, we evaluated the potential use of methotrexate (MTX), an FDA-approved drug known to inhibit T-cell proliferation, as an agent for specific in vitro allodepletion. Using a sensitive, flow cytometry-based proliferation assay, we first evaluated the effect of MTX on CD4+ and CD8+ T-cell proliferation in an HLA-mismatched one-way MLR. Addition of MTX resulted in significant inhibition of both CD4+ and CD8+ T-cell proliferation in MLR as well as superantigen-stimulated control reactions (n=14; p<0.001). We next evaluated whether this exposure to MTX resulted in selective allodepletion. Thus, live cells isolated from MTX-exposed MLR cultures were re-exposed to multiple stimuli, including the same allostimulus, a third-party allostimulus, cytomegalovirus (CMV) antigen and the superantigen SEB. We observed that CD4+ and CD8+ T-cell responses to same allo-stimulus were significantly abrogated, whereas T-cell responses to third-party stimuli, CMV and SEB were all preserved (n=12; p<0.01). These results provide strong pre-clinical evidence that in vitro treatment with MTX, a practical FDA-approved agent, results in specific allodepletion and may be used as an effective approach for preventing or minimizing GvHD.
Inhibition of alloreactive T-cell proliferation by MTX Inhibition of alloreactive T-cell proliferation by MTX Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells
Outcome of Patients with Aplastic Anemia Given First Line Transplantion or Immunosuppression in the Last Decade: A Report from European Group for Blood and Marrow Transplantation (EBMT).
Authors: Locasciulli Anna , Oneto Rosi , Bacigalupo Andrea , Socié Gerard , Korthof Elisabeth , Bekassy Albert , Schrezenmeier Hubert , Passweg Jakob , Fuhrer Monika 
Published: October 2019

Abstract
Background Changes have occurred in the treatment of acquired severe aplastic anemia (SAA) over the past decade,and the optimal treatment for children and adults is often debated.
Aim of the study. Aim of this study was to assess whether the outcome of patients with SAA has improved in two sequential time periods, 1990–1995 and 1996–2002.
Patients and methods., We analyzed a total of 2479 consecutive patients with SAA classified according to first line treatment: allogeneic bone marrow transplantation (BMT) (n=1567) or immunosuppressive therapy (IS) (n=912), and stratified for age (</=> 16 years).
Transplantation. The overall actuarial 5 year survival was 74% before 1995 and has not change overall (it is currently 75%). Survival was improved in the two time periods, for patients given first line BMT (69% vs 79%, p=0.001) but not in patients given first line IS (76% vs 72%, p=0.3). In the latter patients there was a confounding effect of disease severity: patients with very severe AA (neutrophils <200) improved their autcome after IS therapy in the two time periods though not significantly (72% vs 82%, p=0.1); patients with SAA (neutrophils 200–500) had superimposable outcome (76%) and patients with non severe AA actually had worse outcome in the most recent period (77% vs 55%, p=0.01). Overall improvement was significant in children (p=0.02) but not in adults (p=0.4). In multivariate COX analysis negative predictors of survival were a long interval between diagnosis and first treatment (>50 days, RR 1.5, p=0.00001) and age > 16 (RR1.5, p=0.0001).
Interpretation and conclusions. This study shows that outcome has improved in the past decade in subsets of patients with SAA: BMT patients and IS patients if they have very severe aplasia. Early intervention should be reccommended in all patients, whathever the first line therapy, due the very strong effect of interval between diagnosis and treatment on survival.