bluuebunny/crossref_metadata_2025 huggingface dataset:
Clofarabine (CLO) Is Active in Patients (pts) with Refractory and/or Relapsed Non-Hodgkin’s Lymphoma (NHL): A Phase I/II Study.
Authors: Nabhan Chadi , Fried Walter , Galvez Angel G. , Venugopal Parameswaran , Gozun Phillip , Bitran Jacob D.
Published: October 2019

There is no known standard of care for pts with relapsed and/or refractory NHL who cannot undergo stem cell transplantation (SCT) or have relapsed after SCT. Such pts are candidates for new therapies. CLO is a novel nucleoside analogue with known activity in acute leukemia and myelodysplasia. Previous clinical trials with CLO have established safety and potential activity in a variety of tumors. We performed a phase I/II study of CLO in a heavily pretreated pt population with refractory and/or relapsed NHL regardless of cell type, histology, or grade. Eligible pts were adults over 18 years of age who have relapsed and/or refractory NHL with measurable disease. Pts were required to have adequate performance status, bone marrow function (unless cytopenias were related to disease involvement), renal, cardiac, and liver functions. Pts with bulky disease (>10 cm at any site), known HIV, or immune-related cytopenias were excluded. CLO was given as a 1-hour intravenous infusion for 5 consecutive days every 28 days for a maximum of 6-cycles. All enrolled pts received anti-viral and anti-pneumocystis carinii prophylaxis. Growth factors were administered at the investigator’s discretion. Pts were divided into cohorts of 3 each. CLO was given at 4 mg/m2 to the first cohort with escalated doses by 2 mg/m2 increments for each cohort. Once the dose-limiting toxicity (DLT) was reached, the phase II portion of this study was initiated at the dose below the DLT level. All pts were followed until disease progression. To date, 13 pts have been enrolled with 7 on the phase I portion and 6 on the phase II portion. For the phase I portion, the median age was 79 (range: 27–81); the median number of prior therapies was 5 (range: 2–6) with 3 pts having relapsed after prior SCT. The median number of given CLO cycles in the phase I portion was 2 (range: 1–5). The DLT at 6 mg/m2 was thrombocytpenia establishing 4 mg/m2 as the appropriate dose for phase II. For the phase II portion, the median age was 78 (range: 50–83), median number of prior therapies was 2 (range: 1–8). Taken all together (phase I and II pts), 9 out of 13 pts are evaluable for response. (All received at least 1 cycle). There was 1 complete response (CR) and 4 partial responses (PR) for an overall response rate (OR) of 55%. Four patients demonstrated stable disease (SD) with one of them progressing shortly after 2 months. Eight patients remain alive (overall survival: 61%) at a median follow up of 4 months (range: 1–13). Median times to progression and duration of response have not been reached in responding pts.

CLO is active in heavily pretreated refractory and/or relapsed NHL. The drug has an acceptable toxicity profile. Myelosuppresion is the major adverse event in this heavily pretreated population. The study continues to accrue patients and will be updated at the meeting.
Quality of Life in Patients with B-Cell Lymphoma during Maintenance Therapy with the Anti-CD20 Antibody Rituximab.
Authors: Witzens-Harig Mathias , Heiss Christiane , Benner Axel , Hensel Manfred , Neben Kai , Dreger Peter , Kraemer Alwin , Ho Anthony D.
Published: October 2019

The introduction of rituximab into the treatment of malignant lymphomas of the B-cell lineage has had a major impact on the management of these diseases. In diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) several multicenter prospective randomized trials consistently demonstrated an improved outcome when rituximab was added to chemotherapy. In addition, prolonged exposure to rituximab as maintenance therapy has been benefical in patients with FL and mantle cell lymphoma (MCL). For patients, the effect of any prolonged antitumor therapy on the quality of life (QoL) is a very important question. However, so far the question whether rituximab maintenance therapy may impair QoL in patients with Non-Hodgkins-lymphoma remains unanswered. To investigate this subject, we have performed a prospective randomized trial of rituximab maintenance therapy (8 cycles rituximab 375 mg/m2 every 3 months) versus observation in patients with CD20+ B-cell Non-Hodgkins-Lymphoma in our institution. Between July 2002 and December 2005, 106 patients (pts) were included into the trial. QoL was assessed with the standardized questionnaires EORTC-QLQ-C30 and EuroQol-5D. After statistical analysis with the Wilcoxon signed-rank test, we found no significant differences of the QoL between the rituximab treatment group and the observation group. We conclude that rituximab maintenance therapy is safe and does not impair quality of life in this patient population.
Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions To Predict Survival.
Authors: Weisdorf Daniel J. , Spellman Stephen , Klein John , Haagenson Michael D. , Horowitz Mary , Lee Stephanie , Anasetti Claudio , Setterholm Michelle , Drexler Rebecca , Maiers Martin , King Roberta , Confer Dennis
Published: October 2019

Unrelated donor (URD) hematopoietic cell transplantation (HCT) is best performed using a donor who is allele-matched with the recipient at HLA-A,B,C and DR. Earlier reports analyzing outcomes of HCT have been limited by incomplete or lower resolution typing at some HLA loci. Excluding these incompletely typed pairs from studies decreases the power of analyses because of smaller sample size. If adjustment for known and unknown HLA-matching status could be accomplished, these patients could be retained in most analyses where HLA-matching is not the primary research focus. To understand the impact of incompletely characterized major histocompatibility antigens on the success of HCT, we analyzed 15,867 URD HCT using multivariable regression modeling adjusting for HLA and non-HLA factors affecting 1 year and 5 year survival. Of 26 independent matching groups defined by the completeness and resolution of donor:recipient pair matching we identified 3 distinct groups with significantly different outcomes: well matched, partially matched, and mismatched. Well-matched cases had no identified HLA mismatch and informative, though not necessary high-resolution data at all 4 loci or allele matching at HLA-A,B & DRB1 (n=7,753, 49% of the study population). Partially matched pairs had a defined, single locus mismatch at any of the 4 loci and/or missing HLA-C data [including 6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] (n=5,396, 34%). Mismatched cases had 2 or more identified allele or antigen mismatches (n=2,692, 17%). Multiple-variable-adjusted one- and five-year survival estimates are shown in the Table. Using these HLA matching categories, we identified independently significant, 7–8% better 5 year survival using a better matched donor (between these 3 categories) stratified across patient subgroups of recipient age, disease stage, and using either myeloablative or non-ablative conditioning. Notably, the common term “6/6 antigen matched” [6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] had survival outcomes within the partial matched cohort. We suggest that these HLA subgroups should be used in analyses of URD HCT outcomes when complete HLA typing is not available. This improved categorization of HLA matching status allows adequate adjustment for HLA donor-recipient HLA compatibility in retrospective studies and will help standardize interpretations of prior URD HCT experience.

HLA Matching Group 1 Year Survival (95% CI)* 5 Year Survival (95% CI)* Well Matched 53.5 (52.3–54.7) 34.9 (33.5–36.3) Partially Matched 41.5 (40.1–42.9) 27.0 (25.7–28.5) Mismatched 31.0 (29.3–32.9) 18.3 (16.7–19.9) * p<0.001
Biscoclaurine Alkaloid Cepharanthine Inhibits the Growth of Primary Effusion Lymphoma In Vitro and In Vivo and Induce Apoptosis Via Suppressing the NK-κB Pathway.
Authors: Okada Seiji , Makise Naoko , Hiyoshi Masateru , Suzu Shinya
Published: October 2019

Primary effusion lymphoma (PEL) is a unique recently identified non-Hodgkin’s lymphoma which was originally identified in AIDS patients. PEL is characteristically infected by the Kaposi sarcoma-associated herpesvirus (KSHV) and shows a peculiar presentation involving liquid growth in the serous body cavity with generally poor prognosis. As the NK-κB pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of biscoclaurine alkaloid, Cepharanthine, on PEL derived cell lines (BCBL-1, TY-1, and RM-P1) in vitro and in vivo. MTT assay revealed the cell proliferation of PEL cell lines was significantly suppressed by the addition of Cepahranthine (1–10μg/ml). Cepharanthine also inhibited NK-κB acitivation and induced apoptotic cell death in PEL cell lines. We established PEL animal model by intraperitoneal injection of BCBL-1 into the nobel immunodeficient NOD/Scid/Jak3null mice. Intraperitoneal injection led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, resembling the diffuse nature of human PEL. Intraperitoneal administration of Cepharanthine inhibited the ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NK-κB could be an ideal molecular target of PEL and Cepharanthine could a unique therapeutic agent for PEL.
Concomitant Diagnosis of Chronic Myeloid Leukemia and B-Cell Chronic Lymphocytic Leukemia in a 57-Year-Old Female Patient, with Good Therapeutic Response Exclusively to Imatinib in Both Myeloid and Lymphoid Clones.
Authors: Moellmann-Coelho Arthur , Otero Luise , Bigni Ricardo S. , Azambuja Denise , Stefanoff Claudio G. , Dobbin Jane A. , Zalczberg Ilana
Published: October 2019

We describe the clinical, cytogenetic, hystopathologic, immunophenotypic and molecular findings of a rare case of Philadelphia positive chronic myeloid leukemia (Ph+ CML) and B-cell chronic lymphocytic leukemia (B-CLL) occurring simultaneously at diagnosis, in a 57-year-old female patient. In the present case, the patient showed at diagnosis leukocytosis (48.000/ul) with myelocytes and metamyelocytes along with well-differentiated neutrophils, but also with well differentiated lymphocytosis (28.992/ul) in peripheral blood (PB) and also in bone marrow (BM) aspirate cytology. FACS cytometry exhibited clearly two predominant separated cellular populations and the immunophenotype profile of the lymphoid component in BM and PB was CD5+, CD20+, CD23+, with light chain clonal restriction. The BM hystopathological analysis showed two distinct cellular populations, one lymphoid well differentiated CD5+/CD20+, and other myeloid, in several stages of differentiation. Cytogenetic analysis with unstimulated bone marrow culture confirmed the presence of Philadelphia chromosome but with additional translocation involving chromosomes 9, 10 and 22. Molecular studies showed the evidence of BCR-ABL positivity and the B-cell clone was documented by the presence of a clonal heavy chain immunoglobulin rearrangement. The patient was treated with imatinib mesylate 400mg/day, achieving complete cytogenetic response at the fourth month, and complete molecular response (nested PCR) of the BCR-ABL component at the sixth month of treatment. Besides, the absolute lymphocytosis was gradually reduced during the treatment exclusively with imatinib, achieving normal absolute values at the sixth month. This seldom described case of simultaneous occurrence of these two rare chronic hematological malignancies, brings interesting questions about the possible cellular origin and the correspondent mechanisms of clonal expansion. The therapeutic response of the B-cell lymphoid clone exhibited, brings also a possible relationship with the observation that the c-Abl could have enhanced expression in B-CLL cells, as described by Ke Lin et al, in which the c-Abl kinase activity could be inhibited by imatinib mesylate.
The JAK2V617F Mutation in Blood Donors with High Haematocrit.
Authors: Tagariello Giuseppe , Di Gaetano Rosanna , Sartori Roberto , Belvini Donata , Radossi Paolo , Risato Renzo , Salviato Roberta , Tassinari Cristina , Toffano Nunzio , Zanotto Daniela
Published: October 2019

By the introduction for routine tests of automated counters it has become easy and extremely common the finding of abnormal or near normal laboratory results. During blood donations haematocrit (Htc) and haemoglobin level (Hb) are regularly tested to avoid a blood donation in the case of anaemia as this is the most frequent cause of exclusion from the donation. However it is not rare to observe a level of Hb or Htc upper or close the normal highest limit. Starting from the 1st of January 2006 to the 31st December 2006, we have collected 11240 donations in total from 5636 regular blood donors (total donation index 1.99) and selected on the basis of Htc, limit upper 50% for man and 46% for women, 84 males and 19 females. In this cohort, during a 1846 years donation period, the average of donations for males was 22.2 while for females was 11.4. We collected randomly and used as control group 79 donors (59 males and 20 females) with normal Htc levels in the last blood donation. For the identification of the V617F (1848 G>T) mutation within JAK2 we used the method published by Jones ed al. in 2005 named amplification refractory mutation system (ARMS). Among the 84 men with high haematocrit level we have been able to identify 1 blood donor positive for this mutation. This blood donor had Htc equal to 50.6 in the last donation, while the average Htc in the last year was 51.7. These results account for a total prevalence of the JAK2 mutation in 1% of the blood donor population with elevated Ht (1 out of 103) while it is 0.6% (1 out of 183) of the entire population of blood donors in this study or 0.02% of the entire cohort appertaining to our transfusion service. Our results seem also in keeping with the few studies evaluating blood donors (Zanella et al., Transfusion 1987) or normal population (Ruggeri et al., Ann Int Med 2003). In both these studies the prevalence of MPD was around 3% which is not so far away from that found in our cohort (asymptomatic patients) but much higher than that supposed in hospital based cohorts in previous studies (100 fold increased). The hypothesis that the prolonged myeloid stimulus from phlebotomies can induce inhibition of the feed-back control as well as blood donations triggered the onset of a pre-existing latent primary myeloproliferative disease needs further studies to be confirmed.
Higher Sensitivity and Detection of Homozygous/Hemizygous State of JAK2 Mutation Using Plasma.
Authors: Ma Wanlong , Zhang Xi , Sun Weimin , Schwartz Joyce , Buller Arlene , Jilani Iman , Kantarjian Hagop , Giles Francis , Albitar Maher
Published: October 2019

We recently reported that analysis of plasma rather than peripheral blood cells improves detection of the JAK2 V617F mutation, the most characteristic molecular abnormality in patients with non-chronic myeloid leukemia (CML)-myeloproliferative disease (MPD). To expand on these findings, we tested 634 consecutive paired plasma and cell samples for the V617F mutation and mutations in JAK2 exon 12. All patients were clinically suspected of having a non-CML MPD. Testing was performed using direct bidirectional sequencing. The V617F mutation was detected in the plasma of 151 (24%) patients but in only 140 (22%) paired cell samples. No patients were positive by cell analysis and negative by plasma analysis while 7% of patients positive by plasma were negative by cells. Of the 151 V617F-positive samples, 58 (38%) showed homozygous/hemizygous mutation by plasma analysis; 36 (24%) were homozygous/hemizygous by cell analysis. Upon quantifying the V617F mutant peak relative to wild-type peak, plasma exhibited significantly higher relative mutant JAK2 transcript than cell samples (P<0.001). None of the 634 paired samples had exon 12 mutations, nor did an additional 130 plasma samples from patients with confirmed MPD. However, two novel mutations, C618R and V617I, were identified. These data confirm that plasma is enriched with tumor-specific nucleic acid, allowing more sensitive detection of the JAK2 V617F mutation and homozygous/hemizygous state than cell analysis.
Chronic Lymphocytic Leukemia Complicated with Paraneoplastic Pemphigus and Glomerulonephritis in a Patient and Its Treatments: Report of One Case.
Authors: Xuan Qian Si , Yong Li Jian , Ming Hong , Ruan Changgeng
Published: October 2019

Objective To study chronic lymphocytic leukemia(CLL) in association with glomerulonephritis and paraneoplastic pemphigus, and discuss the possible etiology and appropriate therapy.

Methods We presented a rare case of this disease and analyzed the clinical features and therapy. A 41-year-old male was diagnosed with CLL He received one cycle of CHOP protocol, followed by two cycles of FCM protocol, and achieved the PR. After stopped the treatment, he had progression of disease, presented high level of creatinine and urea nitrogen. Then he received two courses of high dose of methyllprednisolone before the kidney biopsy was performed. He presented paraneoplastic pemphigus while his renal inadequacy was improvement. Skin biopsy was performed. He started with oral prednisone (60mg/d) and cyclophosphamide with improvement of blisteringl eruptions, but without improvement of oral leukoplakia and dysphonia. Rituximab was given in a dose of 375mg/m2 weekly for 4 weeks, and IV immunoglobulins 0.4g/kg/d for 5 days because of intermittence fever.

Results The patient with CLL appeared the proteinuria, hematuria and intraepithelial blister formation, refractory mucosal ulceration respectively. A kidney biopsy showed focal segmental sclerosing glomerulonephritis. The histologic and immunofluorescence examinantion of a skin biopsy was compatible with PNP. Conventional protocols were unsatisfactory, but recent developments in the use of cyclophosphamide, rituximab and intravenous immunoglobulin appeared to be more successful.

Conclusions Pathogenesis of CLL in association with autoimmunity diseases was unknown, Further clinical evaluation is required to define the role of treatment of CLL-associated autoimmunity.
Aggregation of Serum Free Light Chains (FLC) Causes Overestimation of FLC Nephelometric Results as Compared to Serum Protein Electrophoresis (SPE) While Preserving Clinical Usefulness.
Authors: Émond Jean-Pierre , Harding Stephen , Lemieux Bernard
Published: October 2019

Multiple myeloma is a disease characterised by the overproduction of monoclonal proteins. Whilst concentration of FLC correlates poorly with tumour burden at diagnosis, changes during treatment are considered to be an accurate and sensitive measure of response. Aggregation of FLC presents a problem for traditional means of FLC estimation, large aggregates will not pass through the kidney making urine unreliable.

Objectives : To report follow-up of 2 patients with discrepancy between SPE M-spike and serum FLC, one with serum free lambda, the other with serum free kappa. To analyze and confirm presence of multimer FLC aggregates in these 2 patients.

Methods : Routine SPE and immunofixation were performed by capillary electrophoresis (CZE). Serum FLC was measured by nephelometry. FLC polymerisation studies were undertaken by SDS-PAGE, Western blot and Sephadex S-200 gel filtration chromatography.

Results: First patient (free lambda) is a 80 y woman with IgA lambda multiple myeloma. Upon treatment, IgA lambda peak fell from 18 g/L down to < 0,4 g/L with a serum free lambda remaining at 10 700 g/L. Monoclonal free lambda peak at CZE was estimated to 1,5 g/L, a 7x discrepancy. High dose Decadron therapy was unsuccessful, serum free lambda remaining about 2500 to 4000 g/L for the next 6 months. Polymerisation studies revealed multiple aggregates of FLC with molecular weight (MW) ranging from 24 000 Da to > 200 000 Da. Second patient (free kappa) is a 70 y old man followed since 1985 for an IgG kappa indolent multiple myeloma. Treatment with melphalan in 1998 caused disappearance of M-spike at SPE and persistant hypogammaglobulinemia. Introduction of FLC testing in August 2006 revealed an unexpected serum free kappa of 2740 g/L which remained stable in the following months. This serum free kappa is not visible by CZE. Polymerisation studies revealed multiple aggregates of FLC with MW ranging from 24 000 Da to > 200 000 Da.

Conclusion : Serum FLC measurement is a new biological parameter for investigation and follow-up of monoclonal gammopathies with added value as showed here for 2 myeloma treated patients. One should be aware of well known interferences in FLC measurement such as renal dysfunction and polyclonal hyper-gammaglobulinemia. Here we demonstrated a less well documented confounding factor creating an unexpected discrepancy between this nephelometric technique and traditional CZE/SPE. We showed highly overestimated FLC by nephelometry. We revealed a profile of multiple complexes in 2 cases of FLC (one free lambda and one free kappa) of molecular weight up to > 200 000 Da. These multimers may well impact kidney function and interfere with standard urine investigation. It appears clear to us that an interpretation from an experienced professional should accompany any FLC measurement.
A High-Throughput Arrayed Lentiviral RNAi Screen To Identify Novel Oncogenes in Multiple Myeloma.
Authors: Schinzel Anna C. , Chapman Mike , Wittner Ben , Shrestha Yashaswi , Ramaswamy Sridhar , Golub Todd R. , Hahn William C.
Published: October 2019

Karyotypic complexity is one of the hallmarks of multiple myeloma, complicating efforts to identify the specific genetic alterations involved in the development of multiple myeloma. To identify genes essential for myeloma proliferation, we used a high-throughput loss-of-function approach using lentivirally delivered short hairpin RNA (shRNA) library targeting human kinases as part of a Multiple Myeloma Research Foundation sponsored pilot project. Three myeloma cell lines, MM.1S, RPMI8226 and INA6, were infected in an arrayed 384-well format. All infections were performed in quadruplicate; two replicates were treated with puromycin to select for infected cells and two were left untreated. Wells in which more than 25% of the cells survived puromycin treatment, as determined by a cell viability assay, were included in future analysis. Genes in which 2 or more hairpins scored below a defined threshold were considered as ‘hits’. To identify physiologically relevant hits, we have integrated these findings with whole genome analysis of copy number and gene expression of multiple myeloma. We have identified a number of genes that are both amplified in and required for multiple myeloma cell viability. These observations suggest potential new targets for therapeutic targeting in myeloma.
Activity of Tyrosine Kinase Inhibitors in Multiple Myeloma.
Authors: Munker Reinhold , Cordova Cory , Polk Paula , Wendling Charles V. , Sun Amanda W. , Cardelli James A.
Published: October 2019

Tyrosine kinase inhibitors (TKIs) have been successfully introduced for the treatment of cancer. Imatinib, dasatinib and nilotinib target bcr/abl and were found to induce molecular remissions in chronic myeloid leukemia. Imatinib has also been found to be active in other malignancies like gastrointestinal stromal tumors. Sunitinib and sorafenib are multi-targeted tyrosine kinase inhibitors and so far, have shown activity against renal cell carcinoma and other cancers. Gefitinib targets the tyrosine kinase of epidermal growth factor receptor and has been found to be active against some cases of non-small cell lung cancer. There is circumstantial evidence that tyrosine kinases and their receptors (e.g. VEGF, IGF-1 and FGFR3) are active in multiple myeloma. In order to develop new treatments for multiple myeloma (MM), we tested several currently available TKIs for their activity against MM cell lines.

Materials and methods: The a cell lines MC/CAR, ARH77, RPMI 8226, ARP1, JJN3, MM1S, and INA-6 were treated with various concentrations of TKIs and analyzed for cell growth in liquid culture, proliferation, apoptosis, and gene expression pattern screening 14,500 genes using U133A_2 arrays.

Results: Imatinib, nilotinib, dasatinib, gefitinib induced cytotoxicity in most cases at high concentrations (50% inhibitory concentration ≥ 100 μMol), whereas sunitinib and sorafenib were active at lower concentrations (50% IC 1– 5 μMol). The cytoxicity was observed early (within 4 to 24 hours of exposure) and involves apoptosis. Interleukin-6 did not offer protection against the cytotoxicity of sorafenib or sunitinib, however the inhibition of proliferation was more pronounced in low fetal calf serum (2.5 versus 10%). A short-term exposure of the myeloma cell line MM1S to 10 μMol sorafenib resulted in more than 2 fold changes in 283 genes or sequences (175 up, 108 down). If only 10 fold changes are considered, 21 genes or sequences were upregulated (mainly enzymes, regulators and ligands) and 11 downregulated (mainly regulatory proteins, among them IL6 signal transducer).

Conclusion: We found that the multitargeted TKIs sorafenib and sunitinib are active in vitro against multiple myeloma. We plan to investigate patient samples, and to elucidate the targets and the mechanisms of action. Our data will support clinical trials both as single agent and in combination with other drugs like bortezomib, thalidomide, alkylators and ionizing radiation.
Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial.
Authors: Eriksson Bengt I. , Borris Lars C. , Friedman Richard J. , Haas Sylvia , Huisman Menno V. , Kakkar Ajay K. , Bandel Tiemo J. , Muehlhofer Eva , Misselwitz Frank , Geerts William
Published: October 2019

Background Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA.

Methods Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively.

Results A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). Conclusions Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.

Rivaroxaban 10mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction % (95% CI) P-value for difference DVT, non-fatal PE, and all-cause mortality 1.1% (18/1595) 3.7% (58/1558) 70% (49–82%) P<0.001 Major VTE 0.2% (4/1686) 2.0% (33/1678) 88% (66–96%) P<0.001 Major bleeding 0.3% (6/2209) 0.1% (2/2224) - P=0.178 Non-major bleeding 5.8% (128/2209) 5.8% (129/2224) - P=1.000
A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).
Authors: Schuster Michael W. , Mehta J. , Waller E.K. , Rifkin R.M. , Micallef I. , Hurd D. , Parekh S. , Hari P. , Skikne B.S. , Shea T.C. , Frei-Lahr D.A. , Abonour R. , Freytes C.O. , Pineiro L. , Halvorsen Y.C. , Anaissie E.J.
Published: October 2019

Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.
Allogeneic Stem Cell Transplantation (Allo-SCT) in the Management of Advanced Waldenstrom’s Macroglobulinemia (WM).
Authors: Kyriakou Charalampia , Canals C. , Sureda A. , Taghipour G. , Cornelissen J. , Willemze R. , Socie G. , Greinix H. , Kienast J. , Hamladji R. , Kazmi M. , Jacobs P. , Schmitz N.
Published: October 2019

Despite effectiveness of standard chemotherapy regimens, complete response is infrequent in WM patients and there is no cure. The role of Allo-SCT has not been extensively explored and the available data are limited. In this retrospective European multicenter study we report the outcome of 106 WM patients (69 male) who underwent an Allo-SCT between 1989 and 2005 and were reported to the EBMT Lymphoma Database. The median age at transplant was 49 years (21–65), and the median time from diagnosis to SCT was 34 months (5–310). The median number of treatment lines prior to allo-SCT was 3(1–10) and 19 patients had failed a prior autograft. Ten (10%) patients were in 1st maximum response (MR), 35 (33%) in PR1, 29 (27%) in PR≥2 and 32 (30%) had refractory disease at the time of transplantation. Forty-four patients were treated with conventional (CT) conditioning protocols; [Cy/TBI n=24, Melphalan/TBI, n=6, BuCy n=14] and 62 with a reduced intensity protocol (RIC); [Fludarabine based regimen n=43, Low dose TBI/Cy n=19] With a median follow up of 31 months (3 to 169) 59 (56%) patients, are alive and free of disease. Forty-eight (45%) patients developed aGVHD [Grades I-II (n=34), Grades III-IV (n=14)] with no statistically significant difference between conventional and RIC groups. Five out of nine RIC patients developed aGVHD following the administration of donor lymphocytes for either residual disease or mixed chimerism. Sixteen patients (15%) developed limited and 11 (10%) extensive chronic GVHD. Seventeen (16%) patients relapsed at a median time of 8 (1–89) months after allo-SCT. Thirty-five (33%) patients died, 5 (5%) from disease relapse or progression and 30 (28%) from regimen toxicity. Non-relapse mortality rates were estimated of 30% and 33%, at 1 and 3 years, respectively, for the CT group, and 24% and 30% for the RIC group of patients. Relapse rates at 1 and 3 years were 10%, 12% for the CT group and 14% and 25% for the RIC. Progression free survival (PFS) rates were 60%, 54% and 54% at 1, 3 and 5 years for the CT and 61%, 44% and 39% for the RIC patients. Overall survival was 65%, 59% and 59% for the CT and 71%, 66% and 66% for the RIC at 1, 3 and 5 years, respectively. Multivariate analysis showed that chemorefractory disease at allo-SCT was associated with a significantly higher relapse rate [p<0.03; 95% CI 1.1–8.9] while the use of TBI in the conditioning regimen with a significantly lower relapse rate [p<0.02; 95% CI 1.1–9.3]. There were no differences in outcome when considering the intensity of the conditioning regimen. In conclusion, allo-SCT is a feasible and well-tolerated procedure in this group of elderly patients with advanced disease. In addition, relapse rate after the allogeneic procedure is low resulting in a good long-term outcome.
Treatment Success in Cancer.
Authors: Djulbegovic Benjamin , Kumar Ambuj , Soares Heloisa , Hozo Iztok , Bepler Gerold , Clark Mike , Bennett Charles
Published: October 2019

Background: The evaluation of research output, such as an estimation of the proportion of treatments successes is of ethical, scientific, and public importance. How often experimental cancer treatments that undergo testing in randomized clinical trials (RCTs) result in discovery of successful new interventions has rarely been evaluated systematically.

Methods: We evaluated treatment success in a consecutive cohort of RCTs performed by the National Cancer Institute cooperative groups over the past five decades. We investigated therapeutic success in 3 ways:

assessing the proportion of statistically significant trials favoring new or standard treatments, determining the proportion of the trials in which new treatments were considered to be superior to standard treatments according to the original researchers, quantitatively synthesizing data for overall survival and event-free survival.

Results: Data from 624 trials (781 randomized comparisons) involving 216,451 patients were analyzed. 30% of trials had statistically significant results. Among these, new interventions were superior to established treatments in 80% of trials. The original researchers judged that the risk-benefit profile favored new treatments in 41% trials. Hazard ratio for survival and event-free survival was 0.95 (99% CI 0.93–0.98) and 0.90 (99%CI 0.87– 0.93) respectively, slightly favoring the new treatments. Breakthrough interventions were discovered in 15% of trials. The main advances have occurred in the management of gastro-intestinal cancer and hematological malignancies

Conclusions: When cancer treatments have been tested in RCTs by the NCI cooperatives groups, about one third of the trials lead to the discovery of successful new treatments. On average, the death rate in these trials has been reduced by 5% with the new treatments. Grant support: NIH/ORI (No 1R01NS044417–01; 5 R01 NS052956–02).
High-Resolution Genomic Profiles Identify Novel Genes and/or Chromosomal Regions with Prognostic and Oncogenic Significance in Myeloma Patients.
Authors: Loiseau Herve Avet , Munshi Nikhil C. , Li Cheng , Magrangeas Florence , Gouraud Wilfried , Charbonnel Catherine , Harousseau Jean-Luc , Attal Michel , Marit Gerald , Mathiot Claire , Facon Thierry , Moreau Philippe , Anderson Kenneth C. , Minvielle Stephane
Published: October 2019

Despite major improvements in the treatment of myeloma over the last decade, disease course is variable due to genetic heterogeneity. Even though cytogenetics is a difficult art in myeloma, chromosomal abnormalities are present in 100% of the patients. In order to define the spectrum of unbalanced chromosomal abnormalities in myeloma, we studied a cohort of 200 patients ≤ 65 years of age, homogeneously treated with high dose chemotherapy in the IFM 99 trials, using the Affymetrix 500K SNP arrays. Bone marrow was obtained at diagnosis, and plasma cells were sorted using anti-CD138-coated magnetic beads. In all cases, a plasma cell suspension with a purity > 90% was obtained, and DNA was extracted using standard methods. After labeling, DNA was hybridized on the two Nsp and Sty chips, containing 260,000 SNP each. As expected, copy number variations were observed in all the cases. The most frequently involved chromosomes were chromosomes 13, 16, 1, 8 and 6. We then performed a prognostic analysis to correlate survival and chromosomal abnormalities. Many previously unreported chromosomal regions were identified; for example, 89 deleted chromosomal regions as well as 53 regions present in > 2.5 copies were associated with a survival < 3 years. Among the deleted regions with prognostic impact, the most frequent were 1p, 12p, and 4q. The most frequently gained regions associated with overall survival were 1q, 8q, and chromosomes 7 and 21. A similar analysis was performed for association with event free survival (EFS). Losses at 11q, 4q, and 12p were highly predictive of a short EFS, whereas gains of chromosome 15 predicted a longer EFS. Global analysis revealed a marked heterogeneity in the gains observed in hyperdiploid karyotypes, explaining the inconsistency in the literature regarding the prognostic value of hyperdiploidy. A more detailed analysis identified more than 80 genes presenting a double deletion, suggesting their role as putative tumor suppressor genes. This study represents the largest cohort of patients analyzed with such high-density arrays, enabling the description of a highly confident landscape of chromosomal abnormalities in myeloma. Moreover, since all the 200 patients were treated with a similar high-dose regimen, it allows powerful statistical analysis of the impact of chromosomal gains and losses on response to therapy, event free survival and overall survival. Finally, since all the patients were also annotated for other prognostic parameters such as t(4;14) or beta2-microglobulin, a multivariate prognostic model will be presented.
Serum Uric Acid Is a Novel Prognostic Factor in Patients with Primary Systemic Amyloidosis.
Authors: Kumar Shaji K. , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Leung Nelson , Zeldenrust Steven R. , Buadi Francis K. , Kyle Robert A. , Rajkumar Vincent , Gertz Morie A.
Published: October 2019

Background: Primary Systemic Amyloidosis (AL) is a fatal disorder characterized by uncontrolled deposition of light chain derived amyloid with variable survival dependent on extent of organ involvement and degree of individual organ dysfunction. We previously demonstrated that troponin T (cTnT) and N-terminal fragment of brain natriuretic peptide (NT-ProBNP) together can allow prognostic stratification in AL. Uric acid (UA) is a marker of increased mortality in congestive heart failure and we examined its prognostic value in AL.

Methods: A cohort 1977 patients with AL seen at our institution and 293 patients with AL undergoing stem cell transplant (PBSCT) were studied retrospectively to examine the value of serum UA.

Results: The median OS for those with UA>8mg/dL was 9 months from diagnosis (95% CI; 7.4, 10.6) compared to 20.3 months for those with UA<=8mg/dL (95% CI; 17.8, 22.7), P<0.001 (Figure 1). As previously demonstrated both cTnT≥0.035μg/L and NT-ProBNP≥332ng/L were prognostic for OS. The median OS for patients (n=617) with a cTnT>0.035g/L was 6.7 months (95% CI; 5.0, 8.4) compared to 35.2months (95% CI; 29.4, 41.0) for those with cTnT<=0.035μg/L, P<0.0001. Similarly, the median OS for patients with NT-ProBNP > 332ng/L was 11.8 months (95% CI; 9.4, 14.2) compared to 36.2 months (95% CI; 26.7, 45.8) for those with NT-ProBNP <=332ng/L; P<0.0001. The prognostic value of UA was independent of cTnT and NT-ProBNP and together with these allowed a novel prognostic classification. Patients with none (Stage-I), 1 (Stage-II), 2 (Stage-III) or 3 (Stage-IV) of these risk factors (UA>8mg/dl, cTnT>0.035μg/L and NT-ProBNP>332ng/L) had a median OS of 36.6, 29.2, 11.1, and 3.6 months respectively (P<0.0001) (Figure 2). We also explored various predictors of OS in this large cohort of patients. The parameters that were significant for a shorter median OS included septal thickness>15mm, ejection fraction<50%, alkaline phosphatase>upper limit of normal, serum creatinine>2.0mg/dL, serum albumin<3.0gm/dl, 24-hour urine albumin>5gm, UA>8 mg/dL, cTnT>0.035μg/L and NT-ProBNP>332ng/L. We then performed a multivariate analysis with all these variables and those predicting for shorter OS were cTnT>0.035μg/L, serum uric acid>8mg/dL, and ejection fraction<50%. The stage determined at the time of PBSCT also predicted outcome with a median OS from PBSCT not reached in stages 1 and 2, 55 months for stage 3 and 16 months for stage 4 patients.

Interpretation: The data confirms the prognostic value of serum UA in AL and allows development of a novel and simple but powerful, reproducible staging system with applicability at all stages of AL.

Figure Figure Figure Figure
JAK2 Activation Stimulates Homologous Recombination and Genetic Instability.
Authors: Plo Isabelle , Nakadake Mayuka , Wiesmuller Lisa , Giraudier Stéphane , Villeval Jean-Luc , Vainchenker William
Published: October 2019

The JAK2 V617F mutation is a recurrent mutation frequently observed in classical myeloproliferatives syndromes such as polycythemia vera (PV) (90%), essential thrombocythemia (ET) and myelofibrosis (MF) (50%). Even if JAK2 V617F is common to these three pathologies, bi-alllic mutation of JAK2V617F have been observed in PV patients due to a loss of heterozygoty following a mitotic recombination event. Moreover, mutations in the receptor of thrombopoietin (c-mpl) have also been identified in MF and in some cases associated with the JAK2V671F mutation. These observations led us to hypothesize that initial mutation of JAK2 can stimulate others abnormalities, in particular genetic abnormalities, which could strengthen the kinase activity of JAK2. The deregulation of the DNA double-strand breaks repair mechanism, homologous recombination (HR), could be involved in the appearance of these new genetic abnormalities. Indeed, mutations in genes controlling HR lead to genomic instability, such as punctual mutation, deletion, loss of heterozygoty and chromosomal rearrangement. As a consequence, we investigated in this study the impact of JAK2 activation either by mutation (JAK2V617F) or by erythropoietin (EPO) on HR and genetic instability. First, we introduced a specific substrate of HR in the genome of Ba/F3 cell line and we measured HR after infecting cells with virus containing either JAK2wt or JAK2V617F. In the presence of EPO, JAK2V617F and at a lesser extend JAK2wt induces a 20 and 5-fold HR increase, respectively, compared to Ba/F3 control cells. In good agreement, in spontaneous condition, we observed an increase in nuclear foci of the key protein involved in this process: RAD51 and in its partner: BRCA1. A spontaneous RAD51 foci formation was also found in CD34+ cells from PV and MF patients compared with CD34+ cells from cytapheresis suggesting that an HR increase also occurs in patients. Consequently, we observed a 40% increased in sister chromatid exchange in JAK2V617F -expressing cells compared to JAK2wt-expressing cells or Ba/F3 control cells. Moreover, increases in centrosome and ploidy abnormalities were also detected in JAK2V617F-expressing cells. Finally, we found a 100-fold and 10 fold increase in mutagenesis at HPRT and Na/K ATPase loci, respectively. This result suggests that JAK2V617F induces more deletion event than punctual mutation. This work highlights a new molecular mechanism of regulation of HR by activation of JAK2 and especially by JAK2V617F. It might also give key to understand how a single mutation can give rise to different pathologies. Further works are currently under investigation to determine how JAK2V617F -induced an hyper-recombination phenotype.
Allogeneic Hemopoietic Stem Transplant for Patients with Idiopathic Myelofibrosis Using a Reduced Intensity Thiotepa Based Conditioning Regimen.
Authors: Bacigalupo Andrea , Dominietto Alida , Pozzi Sarah , Piaggio Giovanna , van Lint Maria Teresa , Zupo Simonetta , Raiola Anna Maria , Gobbi Marco , Frassoni Francesco , De Stefano Francesco , Verdiani Simonetta , Barosi Giovanni
Published: October 2019

We are reporting the outcome of 39 patients with idiopathic myelofibrosis (IMF) who received an allogeneic hemopoietic stem cell transplant (HSCT) at a single Institution. Patients. The conditioning was a thiotepa - cyclophosphamide based reduced intensity regimen, and graft versus host disease (GvHD) prophylaxis was cyclosporin and methotrexate. 30 patients received marrow, 9 peripheral blood. The donor was an HLA identical sibling (ISD) (n=22) or an alternative related or unrelatd donor (UD) (n=17). The median age was 51 (32–67), the median interval diagnosis HSCT was 1015 days (225–7178) and the Lille risk score at the time of transplant was intermediate in 23 and high in 16 patients. Splenectomy was performed in 25 patients as a preparation for transplant. Results. The overall actuarial survival is 50% with a median follow up of 823 days (221– 4356). In univariate analysis favourable factors for survival were a Karnowsky score of 100% (93% vs 37%), an interval diagnosis transplant of less than 1 year (85% vs 55%), an HLA identical sibling donor (68% vs 47%) and splenectomy pre-transplant (60% vs 50%). When combined together, 17 and 22 patients has 0–1 or 2–3 favourable factors pre-transplant: their 4 year actuarial survival is respectively 0% vs 83% (p=.0001). Patients with 0–1 favourable factors, had higher transplant related mortality (41% vs 0%; p=0.009) and higher relapse related death (35% vs 4%, p=0.01). Conclusions. We conclude that allogeneic transplantation is a curative option for patients with idiopathic myelofibrosis. We have identified factors which predict a favourable outcome and may be used to select patients for this procedure.

Figure Figure