bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Higher Ratio of Dose to Actual Weight of Conditioning Chemotherapy Leads to More Toxicity without Improvement in Outcome in Autologous HSC Transplant for DLBCL.
Authors: Costa Luciano J. , Micallef Ivana N. , Inward David J. , Johnston Patrick B. , Porrata Luis F. , Litzow Mark R. , Ansell Stephen M. 
Published: October 2019

Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU, etoposide, cytarabine and melphalan (BEAM) is a standard widely used DLBCL conditioning regimen. Chemotherapy doses, both standard and high dose, are traditionally based in body surface area (BSA) and are often calculated using the corrected ideal body weight. However, this practice is empirical and the best way to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlate the BEAM dose/actual weight ratio with toxicity and overall outcome in a uniform cohort of patients receiving HSC transplant for relapsed DLBCL
Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a HSC transplant following BEAM conditioning was performed. All doses were based on BSA calculated using the corrected ideal body weight. Weight-based dose intensity was retrospectively calculated utilizing the melphalan dose/Kg as a surrogate for the entire regimen. Weight-based dose intensity was correlated with toxicity in the first 30 days after transplant and survival outcome.
Results: Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77); 65% were males; median number of prior chemotherapy regimens was 2. Median dose of melphalan was 3.2 mg/Kg (interquartile range 2.9–3.6; range 2.2–4.5). Only one patient died within 30 days of the transplant. Patients who received > 3.6 mg/Kg of melphalan were more likely to have Grade 3 or 4 mucositis (44.4% v. 9.8%, P=0.001) than the remaining patients. Median numbers of days spent in the hospital in the first 30 days after transplant was 13 (3–18) for melphalan dose >3.6 mg/kg vs. 7 (0.5–10.5) for the remaining patients (P=0.043). Weight based dose intensity did not correlate with survival (P=0.8) or disease-free survival (P=0.3).
Conclusion: Weight based dose intensity of BEAM correlates with toxicity post autologous HSC transplant. Patients receiving doses corresponding to >3.6 mg/kg of melphalan are at increased risk of high-grade mucositis and prolonged hospitalization.
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Current Models for Predicting Warfarin Maintenance Dose Do Not Work in an Ambulatory Venous Thromboembolism Patient Population.
Authors: Wells Philip , Rodger Marc , Fleming Jennifer , Kassem Sarah 
Published: October 2019

Abstract
Warfarin is the most widely used anticoagulant for the treatment of conditions such as deep vein thrombosis and pulmonary embolism. Warfarin has a narrow therapeutic index, and individual patient response to the drug is highly variable. Models to predict the maintenance dose have been published but not validated in independent populations (Kamali et al, Sconce et al, and Gage et al). Most of the prior data was derived in patients with atrial fibrillation and these may not be applicable to our predominantly ambulatory VTE population. The prior models incorporate a variety of factors that have been predicted to have an effect on warfarin dosing, such as age, height, and polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP450) 2C9 enzyme. We enrolled 51 consecutive VTE patients on stable doses of warfarin as defined in the prior studies. As in those studies we excluded patients with known or suspected non-compliance, known liver disease and known congestive heart failure. All previously suggested predictive variables were collected. Mean warfarin dose, mean INRs, and gene polymorphisms were determined by previously described standard methods. In addition we are testing the recently identified coding VKORC1 Asp36Tyr polymorphism which predisposes to warfarin resistance. This study aimed to examine the accuracy of three previous models to predict individual warfarin dosing in pursuit of the development of a more accurate regression model. Preliminary results with the first 51 patients, through correlation analysis, indicate that none of the previous models provide an accurate prediction of warfarin maintenance dose. The mean maintenance dose of the patient population was 6.23mg. The doses predicted by the previous models were significantly lower at 4.4mg, 5.3mg, and 4.5mg for Kamali, Gage, and Sconce, respectively. The Pearson correlation coefficients were 0.047, 0.27, and 0.50, respectively. A preliminary model has been developed with a Pearson correlation coefficient of r=0.78, and a p-value <0.0001. The R2 value for the model was 61.5%. We have now recruited over 290 patients and are analysing the data. We will report more precise data on correlations with the other models and if a new model with a higher R2 can be determined it will be reported.
Allogeneic Stem Cell Transplantation in Multiple Myeloma: One Center Experience of 86 Patients.
Authors: Volin Liisa , Uotinen Heli , Juvonen Eeva , Nihtinen Anne , Ruutu Tapani 
Published: October 2019

Abstract
The role of allogeneic stem cell transplantation (SCT) in the treatment of multiple myeloma (MM) is unclear. High transplant-related mortality has been regarded as a particular problem. At the Helsinki University Central Hospital 86 patients with MM have been treated with allogeneic SCT since 1995. The conditioning was at first myeloablative (MA). Since 1999 reduced intensity conditioning (RIC) after autologous SCT has been used in most cases, but a number of young patients with aggressive disease have been transplanted with MA conditioning. Of the patients 42 were male and 44 female. The median age at SCT was 50 (27–64) years. The median number of chemotherapy lines before allogeneic SCT was 1 (range 1–7). Prior autologous SCT had been performed to 55 patients. The median time from diagnosis to allogeneic SCT was 12 (4–168) months, and the time between autologous and allogeneic SCT 6 (2–146) months. At the time of allogeneic SCT 9 patients were in CR, 63 in PR, 4 had stable disease, and 10 progressive disease. 72 patients had a sibling donor: 68 were HLA-identical, one 1 antigen mismatch, 3 identical twins. 14 patients had an HLA-matched unrelated donor. The conditioning was MA in 32 and RIC in 54 patients. The MA conditioning consisted of Cy/TBI in 22, Mel/TBI in 3, and Treosulfan/Fld in 7 patients. RIC was the Seattle protocol (Fld/TBI 2 Gy) in 45, reduced Treosulfan/Fld in 8, and Fld/Cy in 1 patient. 26 patients received a BM graft and 60 patients a PB graft. As GVHD prophylaxis, 18 patients were given CsA/Mtx, 20 CsA/Mtx/MP, 45 CsA/MMF, and 3 nothing (identical twins). The median follow-up time from allogeneic SCT was 39 (2–136) months, 46 (7–136) months for the MA patients and 34 (2–92) months for the RIC patients, respectively. The OS was 50% at 61 months post SCT and there have been no deaths after this time-point. The median PFS was 31 months. After this time-point the disease has progressed in one case, at 90 months. Of the 32 MA patients 16 (50%) and of the 54 RIC patients 22 (41%) have achieved CR after SCT. The cumulative incidence of acute GVHD grade II-IV was 28%. The cumulative incidence of chronic GVHD was 72%, 58% in the MA and 83% in the RIC patients (p=0.074). The incidence of extensive chronic GVHD was significantly (p=0.012) higher in RIC than MA patients, 66% vs. 23%. There were no statistical differences in the incidence of acute or chronic GVHD by donor type (72 siblings/14 unrelated). The cumulative 100-day transplant related mortality was 4.5% and that of the whole follow-up time 14%. 26 patients have died. The cause of death was myeloma in 15, GVHD in 7, and infection in 4 patients. In conclusion, in the present material transplant-related mortality was low and the survival encouraging, supporting the use of allogeneic transplantation with curative aim in selected cases. Developing chemotherapy, given prior to transplantation, may improve the results.
Allogeneic Stem Cell Transplantation with Dose-Reduced Conditioning in Relapsed Follicular and Mantle Cell Lymphoma - A Prospective Phase II Trial of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Dreyling Martin H. , Beelen D.-W. , Schleuning Michael , Ho Anthony D. , Gramatzki Martin , Glas B. , Pfreundschuh Michael , Wilhelm Martin , Schmitz Norbert , Kolb Hans-Jochem , Unterhalt Michael , Hiddemann Wolfgang 
Published: October 2019

Abstract
Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach.
Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes >3 cm, elevated LDH, >20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma.
Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%).
Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.
Disparities of Minor Histocompatibility Antigens in Unrelated Allo-HCT.
Authors: Markiewicz Miroslaw , Siekiera Urszula , Wojnar Jerzy , Wylezol Iwona , Giebel Sebastian , Dzierzak Monika , Karolczyk Agnieszka , Holowiecki Jerzy 
Published: October 2019

Abstract
Disparities of minor Histocompatibility antigens (mHag) have been considered as an important immunogenetic factor influencing immune responses following transplantation despite fully matched HLA of donor and recipient. The aim of our study was to answer whether mHag incompatibility may influence the outcome of allo-HCT. DNA samples from 92 unrelated donor/recipient pairs completely matched in HLA-A*,B*,C*,DRB1*,DQB1* alleles were collected in order to define minor Histocompatibility HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY genotypes with use of Dynal AllSet kits by PCR-SSP method. Unrelated allo-HCTs were performed in the Department of Hematology and BMT in Katowice, Poland, with use the same standard operating procedure from January 2004 until December 2006. Host versus Graft or Graft versus Host direction of immune responses in donor/recipient pairs was analyzed with use of the minor Histocompatibility Database of Leiden University Medical Center. We observed the impact of mHAg mismatches upon chronic GVHD, incidence of leukemia relapse and graft failure. Patients transplanted from donors with mHAg’s incompatibility in GVH direction had higher probability of chronic GVHD in comparison to other pairs (54% vs 31%, p=0.07). This impact was most prominent for mismatched mHAgs with broad tissue distribution (62% vs 36%, p=0.04), especially HY (66% vs 38%, p=0.02). Opposite influence of HY mismatches in GVH direction was observed upon the probability of relapse, which was lower in the HY-mismatched than in HY-matched group (6% vs 23%, p=0.046). Two mHAgs with tissue distribution restricted to hematopoietic cells mismatched in HVG direction were associated with higher incidence of graft failure than in matched pairs: HA-1 (38% vs 12%, p=0.09) and HA-2 (50% vs 13%, p=0.09). Minor Histocompatibility typing of completely HLA matched patients helps to identify individuals who are at higher risk of cGVHD, leukemia relapse and graft failure, and thus supports precise matching of donor/recipient pairs for unrelated allo-HCT.
High CD49d Protein Expression Predicts Short Overall Survival and Early Progression in Chronic Lymphocytic Leukemia Patients.
Authors: Gattei Valter , Bulian Pietro , Del-Principe Maria Ilaria , Zucchetto Antonella , Maurillo Luca , Buccisano Francesco , Bomben Riccardo , Dal-Bo Michele , Luciano Fabrizio , Rossi Francesca M. , Degan Massimo , Amadori Sergio , Del-Poeta Giovanni 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is a heterogeneous disease with highly variable clinical courses which can be at least in part foreseen by investigating the expression of known prognosticators, including the IGHV gene mutational status or CD38/ZAP-70 expression. By analysing the coordinated expression of several surface antigens in a series of CLL with known clinical courses, we identified the simultaneous over-expression of CD38 and CD49d as part of the signature characterizing the subgroup with the worst outcome. The aim of the present study was to investigate the relationship between CD49d and other well-established biologic prognosticators (CD38 and ZAP-70 expression, IGHV gene mutational status), or markers of tumor burden (Rai clinical stage, beta2-M, sCD23), and to define the independent prognostic impact of CD49d in predicting overall survival (OS) and disease progression (evaluated as time-to-treatment, TTT) in CLL patients. The study includes samples from 303 patients affected by CLL according to the current diagnostic criteria (median age: 63.5 years, range 32–97). The entire cohort of patients was utilized to investigate the impact of CD49d and other prognosticators (CD38, ZAP-70, IGHV gene mutational status) on OS. TTT information and additional laboratory parameters (beta2-M, sCD23) were available for 232/303 patients, whose therapies were established according to NCI-WG criteria. CD49d expression was determined by three-color flow cytometry combining anti-CD49d, anti-CD19 and anti-CD5 mAbs; its expression was demonstrated to be stable over-time and the 30% of positive CD5+CD19+CLL cells was chosen as cut-off to discriminate CD49dlow from CD49dhigh cases. CD49d, whose expression was strongly associated with that of CD38 (p=2.2×10exp-16) and ZAP-70 (p=2.6×10exp-5), or with IGHV gene status (p=1.1×10exp-6), was independent predictor for OS (HR=4.39; p=0.0081) along with IGHV status (HR=5.54; p=0.0005) or, if this parameter was omitted, with ZAP-70 (HR=2.90; p=0.0092). CD49d also effectively predicted TTT and refined the prognostic relevance of all the investigated prognosticators. Notably, a CD49dhigh phenotype, while not changing the outcome of good prognosis (ZAP-70low, mutated-IGHV) CLL, was necessary to correctly predict the bad clinical courses of ZAP-70high (HR=3.12; p=0.023) or unmutated-IGHV (HR=2.95; p=0.002) cases. These findings support the introduction of CD49d detection in routine prognostic assessment of CLL patients, and suggest both pathogenetic and therapeutic implications for CD49d expression in CLL, e.g. envisioning the use of a humanized anti-CD49d monoclonal antibody, currently employed in multiple sclerosis (Natalizumab), for selcted CLL patients.
Clinical Efficacy of Lenalidomide in Fludarabine-Refractory Chronic Lymphocytic Leukemia Patients.
Authors: Chanan-Khan Asher A. , Czuczman Myron S. , Padmanabhan Swaminathan , Keating Michael J. , O’Brien Susan M. , Wierda William G. , Ferrajoli Alessandra 
Published: October 2019

Introduction: Fludarabine treatment has been shown to be beneficial for patients with Chronic Lymphocytic Leukemia (CLL), and fludarabine-based combinations may even further improve outcomes in patients with CLL. However, most CLL patients eventually become fludarabine refractory, a state which is associated with a relatively short survival. Treatment of fludarabine-refractory patients is challenging, with a median survival of about 10 months. Recently, 2 phase II clinical trials (Chanan-Khan et al. JCO 2006 and Ferrajoli et al. ASH 2006) demonstrated the clinical efficacy of lenalidomide, an immunomodulatory agent, in relapsed/refractory CLL patients. We conducted a subset analysis to examine the efficacy of lenalidomide in patients who are fludarabine refractory.
Methods: All patients enrolled on the 2 phase II single agent lenalidomide clinical trials were evaluated and patients with fludarabine-refractory disease (progressed while on or within 6 months of fludarabine-based therapy) were assessed for clinical efficacy of lenalidomide. Lenalidomide was given orally either at 10 mg daily for 28 days followed by 5 mg increments every 28 days to a maximum dose of 25 mg or given at 25 mg on days 1–21 of each 28-day cycle. Response was assessed using the NCI-WG 1996 criteria.
Results: A total of 80 patients were collectively enrolled in these clinical studies. Among these, 29 were identified to have fludarabine-refractory disease. Important clinical characteristics of these patients are reported in Table 1. The overall response rate in fludarabine-refractory patients was 34.5% (10/29). Complete remission was observed in 2 (6.8%) patients.
Conclusion: Lenalidomide is a novel agent with immunomodulating properties demonstrating clinical efficacy in relapsed or refractory CLL patients. Interestingly, clinical responses to single agent lenalidomide were noted despite refractoriness to fludarabine (a subset of CLL patients with poor survival and limited therapeutic options). This observation of the clinical benefit of lenalidomide independent of responsiveness to prior fludarabine is encouraging and warrants further evaluation.
Table 1 Ferrajoli et al. Chanan-Khan et al. Fludarabine-refractory (N=12) Fludarabine-refractory (N=17) ORR, overall response rate; PFS, progression-free survival; OS, overall survival. Median age, years (range) 62 (51–82) 68 (53–75) Sex, female/male 4/8 4/13 Median no. prior therapies (range) 4 (3–15) 4 (1–10) Median beta microglobulin (range) 5 (3–10) 5 (2–10) Advance Rai Stage (III/IV), n (%) 7 (58.3) 13 (76.4) ORR, n (%) 3 (25.0) 7 (41.2) Median PFS, months 12 14.9 Median OS, months All alive (range, 7–19) 23
AVE5026, a New Anticoagulant for the Prevention of Venous Thromboembolism in Total Knee Replacement Surgery - TREK: A Dose Ranging Study.
Authors: Lassen Michael R. , Dahl Ola E. , Mismetti Patrick , Destrée Dominique 
Published: October 2019

Abstract
Introduction: AVE5026 is a new extractive heparinoid, with predominantly anti-Xa activity (anti-Xa/anti-IIa ratio &gt;30). TREK (a multicenter, randomized, double-blind, double-dummy, parallel group, dose response study of subcutaneous AVE5026 with an enoxaparin calibrator arm in the prevention of venous thromboembolism in patients undergoing elective total knee replacement surgery) evaluated the efficacy and safety of AVE5026 for primary prophylaxis of venous thromboembolism (VTE)
Methods: TREK was a stratified (pre-operative injection/no pre-operative injection) dose-ranging study. Patients were randomized to receive subcutaneously and once daily AVE5026 (5, 10, 20, 40 or 60mg) or enoxaparin 40 mg for up to 10 days after surgery. Depending of the stratum, the first dose was administered 11-13h before or 7–9h after surgery. A mandatory bilateral venography was performed 5–11 days after surgery. The primary efficacy endpoint was the composite outcome of
any deep vein thrombosis (DVT) identified on mandatory venography; symptomatic VTE and VTE-related deaths. The primary safety endpoint was major bleeding.
Results: Of 678 treated patients, 464 were eligible for the primary efficacy analysis with evaluable venous thromboembolism (VTE) assessment. The primary efficacy endpoint rates were at 40.0%, 44.1%, 15.6%, 13.6% and 5.3% for the AVE5026 doses of 5, 10, 20, 40 and 60 mg, respectively demonstrating a highly significant dose response (p&lt;0.0001). The rate in the enoxaparin calibrator arm was 35.8%. A significant dose response was also observed for proximal deep vein thrombosis (DVT) with rates decreasing from 7.7% to 0% (p=0.0002). A statistically significant dose response was found for major bleeding with rates increasing from 0% to 3.4% (p=0.02) and any bleeding ranging from 3.8% to 20.5% (p= 0.0003) for the AVE 5026 dosing arms, compared with 0% and 5.0%, respectively, in the enoxaparin group.
Conclusions: In TREK, AVE5026, a novel anticoagulant, showed a significant dose response in prevention of venous thromboembolic events and a reverse dose-response for bleeding. These data suggest that AVE5026 may be a valuable addition to the armamentarium of antithrombotic agents and support further clinical development.