bluuebunny/crossref_metadata_2025_split huggingface dataset:
TKI258 (CHIR-258) Selectively Inhibits FGFR1 Fusion Genes Associated with the 8p11 Myeloproliferative Syndrome.
Authors: Chase Andrew , Grand Francis H. , Cross Nicholas C.P. 
Published: October 2019

Abstract
The 8p11 myeloproliferative syndrome (EMS) is an atypical stem-cell myeloproliferative disorder typically characterised by eosinophilia and associated T- or B-cell lymphoma. The disease is aggressive with transformation to acute leukemia usually occurring within 1–2 years from diagnosis and stem cell transplantation remains the only curative treatment. EMS is caused by constitutive activation of the receptor tyrosine kinase FGFR1 by fusion to unrelated partner genes, the most common being ZNF198. The partner protein promotes dimerisation and ligand-independent activation of the FGFR1 kinase in a manner analogous to BCR-ABL. To investigate the possibility of targeted therapy for EMS, we have studied the effects of TKI258 (formerly CHIR-258) on transformed cell lines and primary cells from patients with FGFR1 translocation fusion genes. TKI258 is an ATP-competitive inhibitor with activity against class III-IV receptor tyrosine kinases (which includes FGFR, VEGFR and PDGFR families) that is currently being assessed for treatment of a variety of malignancies. The growth, as assessed by the MTS assay, of Ba/F3 cells transformed to IL3 independence by the ZNF198-FGFR1 fusion gene was inhibited by TKI258 with an IC50 of 160 nM, compared to an IC50 of 995 nM for Ba/F3 cells transfected with vector only. Western blotting demonstrated dose-dependent inhibition of phosphorylation by TKI258 of ZNF198-FGFR1 and downstream signaling molecules ERK and STAT5. Primary cells from four MPD patients with FGFR1 translocations (ZNF198-FGFR1, FGFR1OP1-FGFR1, MYO18A-FGFR1 and BCR-FGFR1) and three control MPD patients without FGFR1 translocations were exposed to 0, 20 and 100 nM TKI258 in liquid culture for two weeks. All four FGFR1 patients demonstrated substantial reductions in cell numbers in both 20 and 100 nM cultures relative to control whereas no differential cell loss was seen in cells from non-FGFR1 patients. The response of colony growth to inhibition by 20 nM and 100 nM TKI258 was measured in four FGFR1-translocation patients (with and without cytokines) and in ten normal peripheral blood (NPB) controls (with cytokines). To allow sample comparison an inhibition index was calculated as the mean reduction in colony numbers at 20 nM and 100 nM TKI258 at days 7 and 14 relative to control. Four FGFR1-translocation patients showed a significant reduction in colony growth (mean inhibition index = 0.48, range = 0.24–0.60) compared with normal controls (mean index = 0.73, range = 0.48–0.87) (p < 0.01). In summary TKI258 shows significant selective activity against ZNF198-FGFR1-transformed Ba/F3 cells and against primary cells from patients with FGFR1 translocations in both liquid culture and colony assays. TKI258 is therefore a good candidate for targeted therapy for EMS patients, who currently have a poor prognosis and few treatment options.
An Inhibitor of Uroporphyrinogen Decarboxylase (URO-D) Causes Porphyria Cutanea Tarda (PCT).
Authors: Kushner James P. , Franklin Michael R. , Reilly Christopher P. , Bergonia Hector A. , Phillips John D. 
Published: October 2019

Abstract
Hepatic iron content is increased in patients with PCT and phlebotomy-induced iron depletion corrects the clinical and biochemical phenotype. Approximately 20 percent of patients with PCT are homozygous for mutations of the hemochromatosis gene (HFE) but the cause of iron overload in most patients is unknown. Hepatic URO-D activity is markedly reduced when PCT is manifest and URO-D activity improves following iron depletion. Most patients with PCT have no mutations of the URO-D gene (sporadic PCT) but approximately 1/3 of cases are heterozygous for URO-D mutations (familial PCT) (BLOOD. 2000; 95:1565–71). To determine the mechanism by which iron overload causes PCT we created 3 murine models: Mice with one null allele of Uro-d (Uro-d+/−) and 2 null Hfe alleles (Hfe−/ −) (PNAS.2001; 98:259–64); Uro-d+/− mice treated with iron-dextran, aminolevulinic acid (ALA) and polychlorinated biphenyls (PCB) and; wild type mice treated with iron, ALA and PCB (J. Biochem. Mol. Toxicol.2001; 15:287–93). All models accumulate uroporphyrin in the liver and all have hepatic URO-D activity of 25% or less but Western blots revealed no change in URO-D protein. An iron deficient diet prevented the PCT phenotype in Uro-d+/−, Hfe−/ − animals and greatly attenuated the phenotype in animals treated with ALA and PCB (Env. Toxicol. Pharmacol.2005; 417–23). Liver homogenates from all porphyric models were heat denatured and clarified by centrifugation. The supernatants inhibited the activity of purified recombinant human URO-D (rhURO-D) by approximately 60%. The inhibitory activity was further purified by solid phase extraction and HPLC. The fraction containing the inhibitory activity did not fluoresce. Mass spectrometry of this fraction demonstrated a dominant peak with a mass of 835 Da and an absorption maximum of approximately 500 nM, the optical signature of a porphomethene. An inhibitor with identical properties was generated by partially oxidizing the uroporphyrinogen (837 Da) substrate of URO-D under UV light. Full oxidation of either the inhibitor purified from porphyric mouse liver or from partially oxidized, enzymatically generated uroporphyrinogen (either isomer I or III) yielded a compound with a mass of 831 Da and an absorption maximum of approximately 400 nM, indicating that the fully oxidized inhibitor was uroporphyrin. Tandem mass spectrometry of the 835 Da inhibitor indicated that the inhibitor was a tetrapyrrole. Collectively these data indicate that the inhibitor is a porphomethene derived form uroporphyrinogen through oxidation of a single bridge carbon between adjacent pyrrole rings. An inhibitor of rhURO-D was also identified in heat-denatured cytosol from liver biopsy samples obtained from four humans with PCT. We conclude that clinical expression of PCT requires an iron dependant oxidation reaction that generates a porphomethene inhibitor of URO-D.
Tissue Factor and Soluble Markers of Platelet and Endothelial Activation in Essential Thrombocythemia: Relationship with Thrombosis and JAK2 V617F Mutation Status.
Authors: Cervantes Francisco , Arellano-Rodrigo Eduardo , Alvarez-Larran Alberto , Reverter Juan-Carlos , Villamor Neus , Colomer Dolors 
Published: October 2019

Abstract
There is increasing evidence that platelet and leukocyte activation plays an important role in the thrombotic complications of patients with essential thrombocythemia (ET), but the relationship of both thrombosis occurrence and JAK2 V617F mutation status with the levels of circulating tissue factor (TF) and of soluble markers of platelet and endothelial activation is not known. In 53 ET patients (26 of whom had a previous history of thrombosis), platelet TF expression and plasma levels of TF, soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), von Willebrand factor antigen (VWF:Ag), soluble thrombomodulin (sTM), D-dimer, and prothrombin fragment 1+2 (F1+2), measured by ELISA, were compared with those in matched healthy individuals and correlated with thrombosis occurrence and JAK2 V617F mutation status. ET patients with thrombosis had significantly higher levels of sP-selectin than patients without thrombosis and the controls, whereas ET patients without thrombosis had significantly higher levels than the controls (99.8 ± 47.1 ng/mL versus 70.6 ± 37.8 ng/mL versus 32.4 ± 11.9 ng/mL; p= 0.0001 for all comparisons). The same applied to sCD40L levels (226.7 ± 104.7 pg/mL in patients with thrombosis, 186.4 ± 92.1 pg/mL in patients without thrombosis, and 81.3 ± 22.0 pg/mL in controls; p= 0.0001 for all comparisons). Circulating VWF:Ag and F1+2 levels were higher in ET patients than in controls, but no significant difference was observed between patients with and without thrombosis. No differences in TF platelet expression, TF and sTM plasma concentrations were found between patients and controls. A positive correlation was observed between sP-selectin and F1+2, a marker of thrombin generation (r= 0.378, p= 0.01). Patients with the JAK2 mutation (22 out of 52 assessable patients), as compared with those with the wild-type allele, had significantly higher levels of sP-selectin (p= 0.002), sCD40L (p= 0.03), TF (p= 0.016), VWF:Ag (p= 0.0001), and sTM (p= 0.032). These results support a role for soluble markers of platelet activation in the thrombosis of ET as well as their potential to identify ET patients at greater risk of thrombosis. The association between JAK2 mutation and increased levels of TF and soluble markers of platelet and endothelial activation would suggest that the mutation could promote an enhanced prethrombotic state in ET.
SGN-30 (Anti-CD30 mAb) Has a Single-Agent Response Rate of 21% in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).
Authors: Forero-Torres Andres , Bernstein STeven H. , Gopal Ajay , Foss Francine , Leonard John P. , Rosenblatt Joseph D. , Bartlett Nancy L. , Cheson Bruce D. , Epner Elliot , Hernandez-Ilizaliturri Francisco J. , Proctor STephen J. , Brice Pauline , Tilly Herve , Haioun Corinne , Jerkeman Mats , Bosly Andre , Gianni Alessandro M. , Holte Harald , Mahendra Premini , Uharek Lutz , Lorenz Jennie , Barton Jeremy , Sievers Eric 
Published: October 2019

Abstract
SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below:
CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of >365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21%
Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.
Penetration of Yttrium-90-Labeled Ibritumomab Tiuxetan (Zevalin™) into Primary CNS Lymphoma.
Authors: Kiewe Philipp , Korfel Agnieszka , Maza Sofiane , Jahnke Kristoph , Munz Dieter L. , Thiel Eckhard 
Published: October 2019

Abstract
Background: Salvage treatment has not yet been established in primary CNS lymphoma (PCNSL). The introduction of anti-CD20 monoclonal antibody rituximab expanded treatment options in systemic B-cell lymphoma. Due to its large molecular size, rituximab poorly penetrates the blood-brain-barrier (BBB) limiting its use in PCNSL. According to FDG-PET investigations, however, the BBB is initially leaky in PCNSL and reconstitutes after therapy-induced tumor shrinkage. We treated patients with relapsed/resistant PCNSL with a single course of Y-90 anti-CD20 antibody ibritumomab tiuxetan and evaluated the penetration of the antibody into the tumor.
Methods: Immunocompetent patients with histologically confirmed, therapy resistant or recurrent PCNSL after at least one pretreatment, and adequate cardiac and bone marrow function were treated with rituximab 250 mg/m2 on day -7 and day 0, followed by Y-90-ibritumomab tiuxetan 15 MBq/kg IV. In three patients single photon emission computed tomography (SPECT) target imaging with gamma-emitting 111-Indium-ibritumomab tiuxetan was performed repeatedly 4 - 168 hours after Y-90-ibritumomab tiuxetan. Response evaluation by contrast-enhanced magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) was scheduled before, one month and two months after treatment as well as every three months thereafter in responders.
Results: Seven patients with a median age of 46 years (range 40–63) and a median number of 4 (range 1–6) previous therapies received antibody treatment. SPECT indicated target accumulation in the tumor starting 48 hours and still ongoing 7 days after injection of 111-Indium-ibritumomab tiuxetan. Response was observed in four of seven patients: one uncertain complete response (uCR) lasting 18+ months, two CR (0.5 and one month), and one partial response (0.5 months). Relapse usually occurred distant of target lesions. Three patients had disease progression. Toxicities were leukopenia CTC grade 3/4 (n=6), pneumonia grade 3/4 (n=2) with one fatal outcome, and thrombocytopenia grade 3/4 (n=6).
Conclusions: We provide first evidence of Y-90-ibritumomab tiuxetan penetration into PCNSL with target accumulation of the antibody in SPECT. However, responses were mostly of short duration in this heavily pretreated patient cohort with relapses occurring distant of target lesions. Hematotoxicity up to CTC grade 4 was the most common side-effect. Further investigation within a phase II study is warranted.
First Report of the HOVON 45: A Phase II Study with Rituximab, High Dose Ara-C and Autologous Stem Cell Transplantation in the Primary Treatment of Mantle Cell Lymphoma.
Authors: Van’t Veer Mars B. , Notenboom Annelise , McKenzie Marius , Kluin-Nelemans Hanneke , van Oers Rien , Zijlstra Jose , de Jong Daphne , Sonneveld Pieter , Hagenbeek Anton 
Published: October 2019

Abstract
The Dutch Hemato-Oncology Study Group (HOVON) evaluated in a phase II trial the efficacy of the addition of rituximab, high dose Ara-C and autologous stem cell transplantation after BEAM conditioning to conventional CHOP in 88 previously untreated patients with mantle cell lymphoma, with respect to remission rate, failure free survival (FFS) and overall survival (OS). From 2002 to 2005, 86 eligible patients were included and evaluated. The male : female ratio was: 4 and the median age 55 years (32–66). Median follow-up of all patients still alive was 25.5 months. Patients were treated with R-CHOP21 x 3 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 day 1 and prednisone 100 mg days 1 – 5). Stem cells were harvested after high dose Ara-C x 1 (2g/m2 BID days 1 – 4), followed by rituximab on day 11 for in vivo purging and G- CSF. After haematological recovery BEAM conditioning (carmustine 300mg/m2 day 1, Ara-C 200mg/m2 and etoposide 200 mg/m2 days 2 – 5 and melphalan 2 x 100 mg/m2 day 6) was given with autologous stem cell support day 8). After 3 x R-CHOP 17 patients did not reach PR and went off study, according to the protocol, and 5 patients were excluded for other reasons. Sixty four patients received HD Ara-C and 63 patients proceeded to BEAM. Haematological toxicity was as follows: the median time of recovery of leukocytes (> 1,0 x 109/l) from start of high dose Ara-C was 17 days (range: 0 – 59 days), from start of BEAM 26 days (range: 17 – 55). For platelets the median time to recovery (> 50 x 109/l) from start of high dose Ara-C was 23 days (range: 0 – 44 days) and from start of BEAM 25 days (range: 16 – 364). Non-hematological toxicity grade 3–4 was seen during CHOP in 13%, after HD Ara-C in 20%, mainly gastro-intestinal, and after BEAM in 51%, mainly gastro-intestinal and liver, of the patients. Grade 3–4 infections were seen during CHOP in 17%, after HD Ara-C in 30% and after BEAM in 59% of the patients. Responses to treatment are summarised in Table 1. At two years FFS was 67%, OS was 81%. An analysis restricted to the 63 patients who completed the protocol treatment showed FFS 90% and OS 98% at two years.
We conclude that intensification of first line treatment with rituximab, HD Ara-C and BEAM is beneficial with respect to FFS and OS in younger MCL patients and that this regimen is well tolerated.
Table 1. Response to treatment N CR PR NR/PD Not yet known after 3x CHOP 83 13 (16%) 51 (61%) 17 (20%) 2 after HD Ara-C 64 22 (34%) 28 (44%) 14 after BEAM 63 43 (68%) 13 (21%) 7 died early 1
Phase II Study of Rituximab and Cladribine (2-CDA) in Newly Diagnosed Mantle Cell Lymphoma (MCL) (N0189).
Authors: Inwards David James , Hillman David W. , Fishkin Paul A. , White William L. , Morton Roscoe F. , Dakhil Shaker R. , Nikcevich Daniel A. , Wender Donald B. , Fitch Tom R. , Kurtin Paul J. 
Published: October 2019

Abstract
Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL.
Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The schedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy.
Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse events occurring more than once were neutropenia (24.1%) and leucopenia (6.9%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Fifteen (51.7%; 95% CI: 32.5–70.6%) pts achieved a CR; only one has relapsed to date (665 days after starting therapy). Four additional pts achieved a PR. Ten pts have progressed with 4 pts progressing early at 17, 45, 46, and 71 days (two of whom have died). Ten pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. Fourteen pts (48.3%) have progressed or gone on to receive additional therapy off study. At last contact, 26 (89.7%) were alive (median follow-up 14.3 months; range: 6–34). One year survival rate is 89.3% (95% CI: 78.5–100).
Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group of elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 52% achieved a complete remission. Complete remissions attained with this regimen appear to be durable, with a single relapse to date among 15 patients achieving CR.
Blastoid Mantle Cell Lymphoma (MCL): 5-yr Failure-Free Survival (FFS) Rate of 50%, without Failures after 2.5 Years Following Treatment with Rituximab (R)-HyperCVAD Alternating with R-Methotrexate/Cytarabine (M/A).
Authors: Romaguera Jorge Enrique , Fayad Luis , Rodriguez Maria Alma , Hagemeister F.B. , Pro Barbara , McLaughlin Peter , Younes Anas , Samaniego Felipe , Goy Andre , Sarris Andreas H. , Dang Nam H. , Wang Luhua , Kantarjian Hagop M. , Beasley Virginia , Medeiros L. Jeffrey , Katz Ruth L. , Cabanillas Fernando 
Published: October 2019

Abstract
Blastoid MCL has a very poor prognosis, with a median survival of 16–20 months after treatment with CHOP-like chemotherapy regimens. We recently described an intense regimen where R-HyperCVAD is alternated with R-M/A for 6–8 cycles, capable of achieving 87% complete remission (CR) rates and an overall 3-year FFS rate of 64% in a group of 97 patients with newly diagnosed aggressive MCL treated under an institutionally approved clinical trial from March 1999 to March 2001 (J Clin Oncol 23:7013–7023).
Fourteen of these patients presented with the blastoid cytologic variant and the following clinical features were compared with those without a blastoid cytology: age > 65 years, beta 2 microglobulin ≥ 3 gm/dL, elevated serum lactic dehydrogenase (LDH), and high international prognostic score (IPI). Only serum LDH was significantly different, being higher for those with blastoid presentation (p = 0.03). Rates of complete remission were lower for blastoid when compared to non-blastoid cytology (79% vs 89%, respectively) but not statistically significant (p = 0.72). With a median follow up of 57 months, there is a plateau in the FFS curve for blastoid MCL as shown below. At 57 months the median overall survival has not been reached. Contrary to what we had expected, the improved outcome in this group of patients with blastoid cytology suggests a potential for long term remission after intense, non-myeloablative chemotherapy.
Figure Figure