bluuebunny/crossref_metadata_2025_split huggingface dataset:
HyperCKemia in CML Patients on Imatinib Mesylate.
Authors: Hewitt Joanne D. , Rusnak Deborah A. , Cox-Kennett Nanette , Larratt Loree M. , Turner Robert 
Published: October 2019

Abstract
Imatinib mesylate (IM) is the standard therapy for Philadelphia chromosome positive chronic myelogenous leukemia (CML). It is generally well tolerated with most non-hematologic toxicities being mild to moderate in severity. Muscle cramps and/or myalgia may occur in up to half of patients (pts) treated, particularly with doses of IM > 400 mg/day. Prompted by a case of rhabdomyolysis, we began to monitor creatine kinase (CK) levels in CML patients on IM in 2005. 71 patients with chronic phase CML (diagnosed between 1994 and 2007 and treated with IM between 2000 and 2007) had CK levels done every 3 months. Elevated CK occurred in 33/71 (47%) of patients (30% grade 1; 11% grade 2; 4% grade 3 and 2% grade 4); the majority (91%) (including those with ≥ grade 3 toxicity) were taking ≤ 400 mg/day of IM. Of these 33 patients, 21 had a normal baseline CK. The mean and median duration of IM exposure at the time of first documented CK elevation in these 21 patients was 82.5 weeks and 53 weeks respectively (range 4 – 300 weeks). 36% (12/33) of the patients with elevated CK levels reported associated symptoms (muscle cramps, muscle spasms and/or myalgia): the majority of the adverse events were ≤ grade 2 in severity, with some pts reporting more than 1 symptom. CK elevation was documented once in 8 patients, continuously in 9 patients and intermittently in 16 patients. 7 patients required dose modification; all subsequently had a reduction in CK levels to ≤ grade 1. Of the 38/71 who had normal CK levels, 24% (9/38) reported either grade 1 or 2 muscle cramps and/or myalgia: only 1 of these pts required dose reduction due to muscle related toxicity. Possible factors contributing to CK elevation included hypothyroidism (9 pts), vigorous physical activity (7 pts), antipsychotics (7 pts), cholesterol lowering agents (6 pts), alcohol use (2 pts), beta blockers and infection (1 pt each).
Conclusions: hyperCKemia is common in patients on IM for CML (1);hyperCKemia is not correlated with myalgia or muscle cramps;many patients had multiple potential etiologies for increased serum CK;hyperCKemia responds to IM dose modification.
Absence of Residual Vein Thrombosis after an Episode of Idiopathic Deep Vein Thrombosis: Short-Term Anticoagulation Is Safe. The “Extended Dacus Study”.
Authors: Siragusa Sergio M. , Malato Alessandra , Bellisi Mario , Attanzio Maria Teresa , Cigna Valeria , Caramazza Domenica , Lo Coco Lucio , Milio Glauco , Bajardi Guido 
Published: October 2019

Abstract
Background. The optimal duration of Oral Anticoagulant Therapy (OAT) for Deep Vein Thrombosis (DVT) can be tailored by Residual Vein Thrombosis (RVT) (Siragusa S et al. Blood2003;102(11):OC183), a marker able to assess the individual risk for recurrent thrombosis. However, in patients with idiopathic DVT the safety of early interruption of OAT, because of absence of RVT, is still debated.
Objective of the study. In the present study, we evaluated the safety of withholding OAT, in patients with idiopathic DVT and without RVT, three months after the index thrombotic episode.
Study design. Prospective controlled study with two groups: patients without RVT stopped OAT after 3 months while those with RVT continued for additional 3 months.
Materials and Methods. Consecutive patients with a first episode of idiopathic DVT of the lower limbs; patients with cancer or known thrombophilia were excluded. At the third months of OAT, RVT was assessed as previously described; briefly, RVT was considered absent when a clot occupying less than 40% of the vein lumen was detected by compression ultrasonography. Events, classified as recurrent DVT and/or Pulmonary Embolism (PE) and/or major and minor bleeding were evaluated; all patients were followed-up for at least 12 months after OAT discontinuation.
Results. During the period 1999–2006, 518 patients were included in the study. In 206 (39.7%) RVT was considered absent (RVT negative group) and they stopped OAT; the remaining 312 patients continued anticoagulants for additional 3 months (RVT positive group). Total duration of follow-up (FU) was 184.7 years for RVT negative group (with a mean FU of 3.0 ± 0.83 years) and 191.3 years for RVT positive group (with a mean FU of 3.1 ± 0.89 years). The rate and type of events during FU is reported in table and figure.
Conclusions. This investigation shows that in patients without RVT, three months of OAT are safe even after an episode of idiopathic DVT. This hold for at least 30% of the entire DVT population and has an important clinical impact; in fact, it is possible to select a group of patients with a very low risk for recurrences over a period of 3 years. This approach carries also a negligible risk for bleeding.
Events between RVT Negative and Positive Groups Outcomes RVT Neg. group (206) RVT Pos. group (312) "p" value *After OAT discontinuation, **During OAT Recurrences, n/total (%)* 2/206 (0.9) 63/312 (20.2) <0.0005 Recurrences, n/100 person-year (%)* 2/184.7 (1.1) 63/191.3 (32.9) <0.0005 Type of recurrent VTE DVT 1 43 DVT + PE 0 6 Isolated PE 0 3 Controlateral 1 11 Major bleeding, n/total (%)** 0/206 3/312 (0.9) Major bleeding, n/100 person-Yr (%)** 0/184.7 3/191.3 (1.5) Figure Figure
Outpatient Management of Both Myeloablative and Reduced-Intensity Allogeneic HCT Results in Low Non-Relapse Mortality Irrespective of HCT-CI.
Authors: Bashey Asad , Manion Karen , Morris Lawrence E. , Holland Kent , Conaghan Gerard , Matthews Rebekkah , Dooley Amy , Sizemore Connie , Kerns Leslie , Solomon Scott R. 
Published: October 2019

Abstract
Myeloablative allogeneic hematopoietic transplantation continues to be performed as an inpatient procedure from the start of the preparative regimen until neutrophil recovery in most centers. Advances in supportive care and improved remission status pre-transplant may enable predominantly outpatient management of such patients during their transplant. We have analyzed transplant outcomes for consecutive unselected allogeneic transplants performed at our center between February 2005 and June 2006. Patients were scheduled to be admitted to the inpatient unit for less than one day for the stem cell infusion. The remainder of the transplant procedure including the preparative regimen and the period of pancytopenia prior to hematopoietic recovery were managed in the outpatient setting. Patients were admitted to the inpatient BMT unit for the management of complications only. Outpatient care was performed in a dedicated, fully HEPA-filtered facility with detailed infection control measures. If necessary, patients were admitted directly to the inpatient unit and use of the emergency department of the hospital was avoided. Patients were assessed daily for a minimum of 28d post HCT. Fifty-nine patients underwent first allogeneic HCT using non-cord blood donors during the period (median age 41 (21–63); 41 M, 18F; diagnoses - AML=17, ALL=11, NHL=8, MDS/MPS=7, MM=6, HD=2, OTH=7; Myeloablative=35, RIC =24; Related donors=38, MUD=21; ASBMT disease risk score - high=39, intermediate=4, low=16. Median inpatient stay from start of preparative regimen to d100 was 18d (1–63d). With a median follow-up of 565d (383–873d) for all patients, estimated probability of overall survival (OS) at 100d, 12m and 24m are 95%, 80% and 58% respectively. Corresponding probabilities of non-relapse mortality (NRM) are 3.5%, 14% and 23%. For patients undergoing myeloabative HCT, OS and NRM probabilities were 96%, 78%, 58% and 5%, 16%, 22% respectively. The HCT-comorbidity index (HCT-CI, Sorror et al Blood106:2912 [2005]) was used to assess co-existing morbidities. Probabilities of OS and NRM by HCT-CI risk group are shown in the Table. These data suggest that planned outpatient management of allogeneic HCT including myeloblative HCT can be performed without compromising OS and NRM if the appropriate facilities are provided.
HCT-CI 0 1–2 ≥3 Overall Survival d100 100% 97% 83% p=NS 12m 87% 81% 67% Non-Relapse Mortality d100 0% 3% 9% p=NS 12m 10% 14% 20%
A Non-Myeloablative Regimen of Fludarabine and Melphalan Is Safe and Well Tolerated for Allogeneic Transplantation in Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Saliba Rima M. , Parikh Gaurav C. , Hosing Chitra , Mendoza Floralyn , Weber Donna M. , Wang Michael , Thomas Sheeba K. , Flosser Thuy S. , Kebriaei Partow , Popat Uday , Alousi Amin M. , de Lima Marcos , Champlin Richard E. , Giralt Sergio A. 
Published: October 2019

Abstract
Background: Allogeneic transplantation is a potentially curative approach in patients with myeloma. The potential benefit is offset by a higher risk of transplant-related mortality (TRM), graft-vs.host disease (GVHD) and opportunistic infections. The success of reduced intensity conditioning approaches has renewed interest in allogeneic transplantation. In this randomized phase II trial we evaluated whether lowering the dose of melphalan in a nonablative preparative regimen can lower the toxicity and TRM. Two reduced intensity regimens:
fludarabine + melphalan 140 mg/m2 (FM 140) and fludarabine + melphalan 100 mg/m2 (FM 100) were compared in patients undergoing allogeneic stem cell transplantation.
Methods: We enrolled 22 patients, 11 in each arm, who were 70 years of age or younger and had an HLA-identical sibling donor. Patients underwent allogeneic transplantation between April 2002 and January 2007. Median age was 52.5 years (Range: 32–63). GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on days 1, 3, 6 and 11. Median interval between diagnosis and transplant was 28 months (9–232). Only 6 patients (27%) received transplant for the consolidation of first remission, the rest had relapsed or refractory disease (73%). Twenty-one patients had a prior autotransplant; 3 of these had 2 prior autotransplants. Median number of prior treatment regimens was 5 (1–10). Cytogenetic abnormalities were observed in 8/22 patients (36%).
Results: The 2 groups were comparable in terms of age, disease status, prior therapy and other prognostic factors. Median time to neutrophil engraftment in both arms was 12 days. TRM in the first 100 days was zero in both arms. Response rate (CR 18% + PR 64%) was 82%, with no significant difference between the 2 arms. After a median follow up of 25 months (26 months in FM 100, 21 months in FM 140), Kaplan-Meier estimates of 2-year PFS in FM 100 vs. FM 140 were 41% vs. 42%, respectively. Kaplan-Meier estimates of 2-year OS in FM 100 vs. FM 140 were 60 vs. 36%, (p=0.4), respectively. There was no significant difference in the incidence of grade II-IV acute GVHD (27 vs. 36%) or chronic GVHD (50 vs. 43%) between the 2 arms. There was a decrease in overall grade II-IV toxicity in the FM 100 arm (45% vs. 73%) that did not reach statistical significance (p=0.2) Patients transplanted in relapse had shorter PFS (0.09).
Conclusions: The dose of melphalan in preparative regimen can be safely reduced without adversely impacting the engraftment in this heavily pretreated patient population. There was a trend towards lower grade II-IV toxicity and prolonged OS in the FM 100 arm. This approach may be more beneficial when used early in the course of treatment.
Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct Study.
Authors: Douketis James , Cook Deborah , Zytaruks Nicole , Heels-Ansdell Diane , Crowther Mark 
Published: October 2019

Abstract
Background: Critically ill patients with renal insufficiency are at high risk for deep vein thrombosis (DVT). Low-molecular-weight heparins (LMWHs) effectively prevent DVT but are avoided in patients with renal insufficiency because of potential bioaccumulation and potential bleeding risk. However, evidence is lacking that LMWHs bioaccumulate in such patients.
Objectives: The objectives of DIRECT were, in critically ill patients with severe renal insufficiency, to determine if dalteparin prophylaxis leads to bioaccumulation and bleeding from excessive anticoagulation and to determine the pharmacodynamic profile of dalteparin.
Methods: Multi-center, open-label, prospective cohort study of critically ill patients with a creatinine clearance <30 mL/min who receive dalteparin, 5000 IU once-daily, subcutaneously for up to 30 days. Dalteparin bioaccumulation in a patient was defined by a trough anti-Xa level >0.40 IU/mL, measured twice-weekly 20 hours after the prior dalteparin dose. The pharmacodynamic profile of dalteparin was assessed by anti-Xa levels measured at 0, 1, 2, 4, 8, 12, 20, and 24 hours after the prior dose on days 3, 10, and 17 of treatment.
Results: We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; of these, 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 14) or pulmonary embolism (n = 1) within 48 hours of enrollment. Of 138 patients included, the median (inter-quartile range [IQR]) duration of dalteparin treatment was 7 days (4, 12). In 120 pa tients who had ≥1 trough anti-Xa measured (427 total), none had dalteparin bioaccumulation; the median (IQR) trough anti-Xa level was <0.1 IU/mL (<0.1, <0.1). In 138 patients who received ≥1 dose of dalteparin,10 patients (7.2%; 95% CI: 4.0, 12.8) had a major bleed, all with trough anti-Xa levels ≤0.18 IU/mL. The pharmacodynamic profile of dalteparin, shown in the Figure, was typical for drugs that do not bioaccumulate, with a typical peak and decline after 3, 10, and 17 days of treatment.
Conclusions: In critically ill patients with severe renal insufficiency, thromboprophylaxis with dalteparin did not bioaccumulate. Dalteparin, 5000 IU once-daily, appears to be a reasonable option for thromboprophylaxis of critically ill patients with severe renal insufficiency.
Figure Figure
Sirolimus as Primary Immunoprophyllaxis for Alternative Donor Allotranspplant after Non-Myeloablative Conditioning.
Authors: Karch Jon M. , Ehmann W.C. , Rybka Witold B. , Chase Gary A. , Claxton David F. 
Published: October 2019

Abstract
We have explored the immunosuppressive agent Sirolimus for immunoprophyllaxis after allogeneic hematopoietic transplant in order to exploit its favorable immunotolerance and antineoplastic properties. Where possible, co-administered tacrolimus has been tapered early so as to minimize its restraint of graft versus tumor activity. Between May 2001 and February 2007, 68 patients with matched unrelated or 5/6 antigen-matched related donors received non-ablative hematopoietic cell transplantation. Conditioning consisted of fludarabine 25mg/m2 (d-7, -6, -5, -4, -3) and cyclophosphamide 1mg/m2 (d-7, -6) followed by 5mg/m2 methotrexate days 1, 3, 6 and combination sirolimus and tacrolimus each dosed at 6–10 ng/ml levels. Median age was 55.2 (range 23.3 to 72.2). Disease diagnoses were ALL - 4, AML - 30, CLL - 7, CML - 3, HD - 1, MDS - 3, MM - 2, MPD - 4, NHL - 14. Only 22/68 patients were in remission (CR1 or CR>1) at transplant. 62/67 patients (5/6 BM and 57/61 PBSC) engrafted stably with donor cells by day 30. Donor blood chimerism was >90 percent in 35/58 by day 100 and was correlated with CD34 cells infused (R=0.263, p=0.033), but not degree of HLA match. In 19/47 patients without GVHD by day 30, tacrolimus was tapered and stopped between days 40 and 100. Sirolimus was continued in the absence of a contraindication for 8 months at least. In 6/19 patients GVHD developed within 2 months of discontinuation of tacrolimus. 2/6 patients developed grade ≥3 GVHD, and in 1/6 GVHD was the cause of death. In 4/6 grade 1–2 GVHD was controlled with steroids and/or reinstitution of tacrolimus. Toxicity was manageable. Post transplant creatinine levels >3.0mg/dl were noted at least briefly in 16/68 patients. Only 4 patients required dialysis. Tacrolimus was discontinued because of renal toxicity in 8/16. In the other 8/16 patients tacrolimus was resumed after improvement in renal function. Thrombotic microangiopathy occurred in only 1 patient. Transplant related mortality (TRM) occurred in 6/68 (9%) by 100 days, and 12/59 (20%) by year 2. The overall survival (OS) was 85% (58/68) at 100 days, and 42% (25/59) at 2 years. In 62 patients engrafting stably, median survival has not been achieved for 21/62 in CR, and was 483 days for 41/62 not in CR at transplant (see figure below.) This data suggests that non-ablative hematopoietic cell transplantation with combination sirolimus and tacrolimus therapy can be accomplished with manageable nephrotoxicity, and sirolimus-based immunosuppression provides long term survival in patients with advanced hematopoietic malignancies. In many patients without GVHD tacrolimus may be discontinued early, with immunosuppression then provided by single agent sirolimus for an extended period.
Figure Figure
Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults with CD3/CD19-Depleted Grafts after Reduced-Intensity Conditioning: A Phase I/II Study.
Authors: Bethge Wolfgang A. , Bornhaeuser Martin , Beelen Dietrich W. , Stuhler Gernot , Stelljes Matthias , Schwerdtfeger Rainer , Faul Christoph , Vogel Wichard , Handgretinger Rupert , Kanz Lothar 
Published: October 2019

Abstract
Introduction: Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with a megadose of CD34-selected stem cells has been complicated by regimen related toxicities, slow engraftment and delayed immune reconstitution leading to a high treatment related mortality (TRM). A new regimen using graft CD3/CD19 depletion and reduced intensity conditioning (RIC) may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, dendritic-, natural killer- and other graft-facilitating cells which may allow stable engraftment even without the use of a megadose of CD34+ cells.
Methods: A multicenter phase I/II study of HHCT using RIC with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), OKT-3 (5 mg/day, day −5 to +14) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device has been initiated. No post grafting immunosuppression was applied if the graft contained <5×104 CD3+ cells/kg.
Results: To date, 36 patients (median age=46 [range, 21–65] years) have been enrolled in this study. Diagnosis were AML (n=20), ALL (n=7), NHL (n=3), MM (n=2), CML (n=2) and MCL (n=2). Patients were high risk with refractory disease or relapse after preceding HCT (auto=6, allo=12). The CD3/CD19 depleted haploidentical grafts contained a median of 7.5 × 106 (range, 3.4–17×106) CD34+cells/kg, 2.8×104(range, 0.4–44×104) CD3+T-cells/kg and 3.8×107 (range, 0.02–37.3 x107) CD56+cells/kg. Donor-recipient KIR-ligand-mismatch was found in 20 of 36 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Five cases of reversible peripheral neuropathy and 3 cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to >500 granulocytes/μL of 12 (range, 9–21) days, >20000 platelets/μL of 11 (range, 7–30) days and full donor chimerism after 2–4 weeks in all but one patient. Incidence of grade II-IV GVHD was 36% with grade II=9, III=2 and IV=2. TRM in the first 100 days was 10/36 (27%). Overall survival is 16/36 patients (44%) with deaths due to relapse (n=9), infection (n=9), GVHD (n=1) and PML (n=1) with a median follow-up of 194 days (range, 14–1271), resulting in a Kaplan-Meier 1 year survival estimate of 41%. We did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor.
Conclusion: This regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.
Transcription Factor NF-kB as a Biomarker for Disease Progression and Target for Treatment in Chronic Lymphocytic Leukaemia.
Authors: Hewamana Saman , Clement Mathew , Lin Thet Thet , Jenkins Chris , Fegan Chris , Rowntree Clare , Brennan Paul , Pepper Chris 
Published: October 2019

Abstract
NF-kB is part of a multi-component signalling pathway that regulates the expression of hundreds of genes involved in the control of cell proliferation, cell survival, stress responses, innate immunity and inflammation. The principal constituents of mammalian NF-kB are p65, p50, p52, c-Rel and Rel-B and in their inactive state they are bound in the cytoplasm to the inhibitor protein IKB. Phosphorylation of IKB by IKB kinase has been shown to result in the translocation of NF-kB into the nucleus where it can bind to kB responsive elements. It has been reported that NF-kB is constitutively activated in chronic lymphocytic leukaemia (CLL) cells. However, no previous studies have prospectively quantified the subunits of NF-kB in primary CLL cells or examined their relative expression between patient samples. Therefore, the aim of our study was to perform quantitative subunit analysis of NF-κB in freshly isolated CLL cells and examine their relationship with some of the well established clinical and molecular prognostic markers. NF-κB was evaluated using EMSA (n= 48), supershift assays and p65 subunit-specific ELISA (n=100). Apoptosis was measured at 24h and 48h using annexin V/propidium iodide labelling. We demonstrated a wide variation in NF-κB expression in CLL samples and p50, p65 and c-rel were consistently shown to be the predominant NF-kB subunits. Importantly, we showed a negative correlation between in vitro apoptosis and nuclear p65 NF-kB expression (r2 = −0.22) suggesting that high levels of p65 confer a cytoprotective effect on primary CLL cells. Furthermore, we found that p65 has a positive correlation (r2 = 0.3) with total white cell count (WBC) and CLL samples with a lymphocyte doubling time below 12 months have significantly higher p65 DNA binding (p= 0.02) implicating this NF-κB subunit in disease progression. Finally we have also demonstrated that the NF-κB inhibitor, LC-1, has potent in vitro apoptosis-inducing effects on primary CLL cells. Together, this work supports the use of specific inhibitors of NF-kB, particularly targeting p65, for treatment of CLL.