bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II, Randomized, MultiCenter, Dose-Ascension Study of the p38MAPK Inhibitor Scio-469 in Patients with Myelodysplastic Syndrome (MDS).
Authors: Sokol Lubomir , Cripe Larry , Kantarjian Hagop , Sekeres Mikkael A. , Parmar Simrit , Greenberg Peter , Goldberg Stuart , Bhushan Vikas , Shammo Jamile , Hohl Raymond , Li Yu-Ping , Lowe Ann , Zhu Joy , List Alan 
Published: October 2019

Abstract
Pro-apoptotic cytokines generated in the medullary microenvironment potentiate ineffective hematopoiesis in MDS. Preclinical investigations indicate that inhibition of p38α mitogen-activated protein kinase (MAPK) suppresses inflammatory, angiogenic and pro-apoptotic cytokine induction from marrow stromal cells. SCIO-469, is a novel highly selective p38αMAPK inhibitor. SCIO-469 was studied in a phase I/II, multicenter trial in patients (pts) with IPSS low and intermediate-1 risk MDS. The primary objective was to determine the safety and tolerability (NCI CTCAE) of the agent; secondary objectives were to evaluate erythroid response rate, hematologic improvement, bone marrow and cytogenetic response according to IWG MDS response criteria and the relation to biological correlates. Between 2005–2006, 62 pts were enrolled. At the time of abstract submission, 29 pts had preliminary response assessment. Demographic features include IPSS Low (45%) or Int-1 (55%) risk MDS, median age 71.5 years (range 48–88); WHO phenotype: RA 9%, 5q- syndrome 8%, RCMD 32%, RARS 13%, RCDM-RS 13%, RAEB-I 11%, MDS-u 9%, MDS/MPD 4%. Among these, 91% failed erythropoietin treatment (tx) and 11% had prior chemotherapy; 79% received RBC transfusions within 8 wks prior to study tx. Pts were randomly assigned to one of two lower dose levels: 30 mg TID (15 pts) and 60 mg TID (15 pts) and later to a 3rd dose level of 90 mg TID (15 pts) after initial confirmation of drug tolerance. Since maximal tolerated dose (MTD) was not achieved, a 4th dose level (120mg TID) was added with 17 pts accrued, none of whom are included in the response data. Responses were evaluated after 16 weeks of tx, with responders continuing SCIO-469 for up to 78 weeks. Fifteen grade 3 or 4 adverse events were observed in 10 pts: 1 jaundice, 1 hyperamylasemia, 1 hyponatremia, 1 atrial FIB, 1 hypotension, 2 cancer (melanoma, colon), 2 pneumonia, 3 neutropenia, 1 lower extremity edema, 1 pyrexia, and 1 abdominal pain. Other than three grade 3 or 4 neutropenia, no significant hematologic toxicities were observed. The MTD for SCIO-469 was not reached. Preliminary response was analyzed in pts completing &gt;16 weeks of treatment [N=29]: Erythroid: major 1, minor 2; Platelet: major 1, minor 0; Neutrophils: major 3, minor 0, with no relation to dose. BM responses evaluated in 25 pts yielded only 1 partial response. Progression occurred in 4 pts. Tx is ongoing with pending analysis of correlative biological studies. Our preliminary analysis indicates that SCIO-469 is generally well tolerated and modestly active as monotherapy in low/int-1 risk MDS at dose levels 30–90 mg po TID.
Clinical Relevance of Cardiac Iron Overload Estimated by MRI T2* in Regularly Transfused Low Risk MDS.
Authors: Ferte C. , Ernst O. , Beyne-Rauzy O. , Chaury M.P. , Brechignac S. , Brauner M. , Mirault T. , Kanaan K. , Bourgeois E. , Cambier N. , Quesnel Bruno , Fenaux Pierre , Rose Christian 
Published: October 2019

Abstract
Background: Cardiac iron overload is the first cause of mortality in thalassemia. In MDS, a causal relationship between cardiac iron overload and death is not as well established and heart complication may be of intricate origins in these elderly pts. Cardiac MRI T2* allows accurate measurement of heart iron and is influenced by iron content only (and not by other cardiac diseases). T2* value < 20ms is clearly associated with cardiac iron overload. A few reports (Winder et al ASH 2005, Chacko J BJH2006;133: supp1) showed no cardiac iron overload by T2* in small numbers of multitransfused MDS. We performed a similar analysis in our transfused low risk MDS pts.
Methods: We prospectively evaluated by MRI both cardiac T2* according to Anderson (Eur Heart J 2001) and liver iron content (LIC ) according to Gandon (Lancet 2004) and cardiac function by echocardiography in multitransfused low risk MDS pts. Cardiac MRI T2* was also assessed in 33 controls.
Results: 21 MDS were analyzed, 9M/12F. Median age: 75 years ( 50–83); FAB : RA= 3, RAS=13, RAEB = 3, CMML n=1, unclassified n=1. Karyotype: fav n= 1, Int n= 18, failure n=1. IPSS: low n= 10, Int I n= 10, unavailable n=1. Median interval from MDS diagnosis and first transfusion was 40 and 24 months respectively. At inclusion, median number of RBC units transfused was 81 (range 6–282, and greater than 100 in 8 pts). Median serum ferritin level was 2152 ng/ml and 11 patients were on chelation therapy (CT). 9/21 pts had cardiac symptoms and were on cardiac therapy. LVEF was below normal (55%) in 3/21 cases. Left ventricular telediastolic diameter LVTD was above normal (normal 53 mm) in 6/14 pts evaluated. Median LIC was 350 micromoles/g/dw (95–898 ). Median Cardiac T2* was 27 ms (8–74) and did not differ significantly from controls (T2*=27ms+/−6.4). No correlation was found between cardiac T2* and ferritin, LIC, LVEF, time from MDS diagnosis. However 3/21 pts had cardiac iron overload with T2* < 20 (18ms,15ms,8ms respectively). LVEF and number of RBC units transfused of these pts was respectively 69%,51%,33% and 119,150,282 RBC units. Two of them were on iron CT, one of them since 8 years. The last 2 pts had clinical signs of cardiac failure unexplained by other causes and both had increased LVTD.
Conclusions: Although cardiac T2* did not differ significantly in transfused MDS and in controls, 3 heavily transfused (all in the 8 patients who had received >100 RBC units) had clear cardiac iron overload, clinically relevant in 2 of them and not correlated with higher liver iron overload. Differences between our study and previous studies could be due to the higher number of transfused RBC units in our pts with abnormal T2*, as compared to a median of 50 in the study of Winder, but further studies are required to confirm this finding.
Immunosuppressive Therapy in Children with Refractory Anemia: Results of Japanese Childhood MDS Study Group Trial (MDS99).
Authors: Hasegawa Daisuke , Yagasaki Hiroshi , Ohtsuka Yoshitoshi , Inoue Masami , Kikuchi Akira , Ohara Akira , Tsuchida Masahiro , Kojima Seiji , Manabe Atsushi , Nakahata Tatsutoshi 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder and uncommon in childhood. Especially, refractory anemia (RA), which is a subgroup of MDS without an increased number of blasts, is quite rare in this age group. Although hematopoietic stem cell transplantation (HSCT) is thought to be a curative therapy for pediatric MDS, it may cause severe complications and mortality. Several reports have shown encouraging results with immunosuppressive therapy (IST) in adult patients with RA. We report the outcome of 12 children with RA enrolled on a prospective multicenter trial conducted by Japanese childhood MDS study group. In this study, a child who was suspected of having RA required repetitive bone marrow aspiration at 6–8 weeks intervals. If the disease was stable and blood transfusion was not urgent, the patient could be monitored closely without any therapy. If physicians decided to start therapy due to progression of cytopenia, the patient received IST consisting antithymocyte globulin (ATG), cyclosporine (CyA) and methylprednisolone (mPSL). Of the 12 children, 9 received IST (IST group), 2 were followed without treatment (observation group) and one underwent HSCT without IST. Seven children showed hematological response in the IST group, and a response rate was 77.8%. Of note, 1 patient with monosomy 7 showed complete cytogenetic response after IST and remained in remission. One patient became refractory to IST after relapse and underwent bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) 1-antigen mismatch relative, and she is alive without disease on 351 days after HSCT. One patient received BMT from an HLA-matched unrelated donor without IST because he had monosomy 7, but he relapsed and died from disease progression. Neither of 2 patients in the observation group experienced disease progression. There were 8 children who showed chromosomal abnormalities, including monosomy 7 and trisomy 8, 7 of whom received IST and 6 children showed hematological response. No severe adverse events related to IST were reported in this study. Eleven of the 12 patients are alive after a median follow-up of 1,319 days. The probability of survival at 5 years was 88.9%, which was superior to our previous retrospective analysis of children with RA. We conclude that IST for children with RA seems an effective modality and warrants an international clinical trial.
A Phase II Study of Nilotinib, a Novel Inhibitor of c-Kit, PDGFR, and Bcr-Abl, Administered to Patients with Systemic Mastocytosis.
Authors: Hochhaus Andreas , Ottmann Oliver G. , Lauber STephanie , Hughes Timothy , Verhoef Gregor , Schwarer Anthony P. , Gratwohl Alois , Rafferty Teresa , Resta Debra , Gattermann Norbert 
Published: October 2019

Abstract
Systemic mastocytosis is a clonal disorder associated with a constitutive activation of the c-kit tyrosine kinase based on point mutations and is characterized by mast cell infiltration of extracutaneous organs. Nilotinib is a novel aminopyrimidine which potently inhibits Bcr-Abl, as well as the PDGF-R, and c-kit tyrosine kinases. Preclinical data demonstrated the activity of nilotinib against D816V mutated c-kit in biochemical and cellular assays. This Phase II study was designed to evaluate the safety and efficacy of nilotinib administered at an oral dose of 400 mg twice daily to patients with systemic mastocytosis defined by specific disease criteria and with a clinical indication for treatment. Data are available for 60 patients (34 male, 26 female). The median age is 51 years (range, 29 to 79). Of the 60 patients 31 (52%) had extramedullary involvement at baseline. In 30/36 patients investigated (83%) D816V c-kit mutation was found by D-HPLC and/or conventional sequencing in bone marrow or extracutaneous organs. Two patients showed the c-kit I798I polymorphism. Treatment is ongoing for 38 (63%) patients; 22 (37%) have discontinued; ten (17%) for adverse events, seven (12%) withdrew consent, and one (2%) each for disease progression and lost to follow-up. There were two (3%) deaths related to disease progression. Based on investigators’ assessment of serum tryptase, bone marrow mast cell counts and improvement of clinical symptoms 12 patients (20%) had a documented clinical response including two (3%) complete, five (8%) incomplete, four (7%) minor, and one partial response. Adverse events occurring in >15% of patients included nausea in 28 (47%), headache in 26 (43%), fatigue in 25 (42%), vomiting in 22 (37%), diarrhea in 21 (35%), pruritis in 16 (27%), and rash in 15 (25%) patients, dizziness and muscle spasms in 14 (23%) patients each, bone pain in 12 (20%), pyrexia and myalgias in 11 (18%) patients each, and dyspnea, constipation, increased ALAT, and arthralgias in ten (17%) patients each. Most side effects occurred early after initiation of nilotinib therapy and were successfully treated with H1- and H2-blockers and/or corticosteroids, indicating a mast cell degranulation syndrome. Overall the most frequent Grade 3/4 adverse events included diarrhea in four (7%) patients, and thrombocytopenia and headache in three (5%) patients each. The data suggest that nilotinib has clinical activity and an acceptable safety and tolerability profile in patients with systemic mastocytosis with constitutive c-kit activation. Individual molecular characterization will help to guide targeted therapy in this disease.
Phase II Preliminary Results of SGN-30 (Anti-CD30 mAb) in Patients with CD30+ Lymphoproliferative Disorders.
Authors: Duvic Madeleine , Kim Youn , Reddy Sunil , Forero-Torres Andres , Pinter-Brown Lauren C. , Rarick Mark U. , Zic John , Worobec Sophie , Korman Neil , Kuzel Timothy , Bohjanen Kimberly , Flessland Karen , Barton Jeremy , Sievers Eric 
Published: October 2019

Abstract
SGN-30 is a monoclonal antibody directed against the CD30 antigen, a member of the TNF receptor super-family. It has been evaluated in phase II clinical trials in patients with systemic Anaplastic Large Cell Lymphoma (ALCL) and Hodgkin’s lymphoma (HL). SGN-30 has shown good tolerability and objective tumor responses in patients with systemic ALCL. This multicenter, single arm phase II study, originally designed to evaluate the tolerability and activity of SGN-30 in patients with relapsed/refractory primary cutaneous ALCL (pcALCL), was expanded to include other symptomatic CD30-positive lymphoproliferative disorders: CD30+ Lymphomatoid Papulosis (LyP) or CD30+ Large Cell Transformation of Mycosis Fungoides (t-MF) without systemic involvement. Seventeen patients (14 male, 3 female) with median age of 63 years (range 33–79) have been enrolled. The median number of prior therapies was 3 (range 1–4). All patients had received at least 1 prior systemic therapy. SGN-30 was administered at a dose of 12 mg/kg by 2-hour infusion every 2–3 weeks. Up to 3 cycles (each comprised of 6 doses of SGN-30) were given. Evaluation of response was determined by Physician’s Global Assessment (PGA) which was performed 2–3 weeks after each infusion. The best response assessment per indication is shown below:
One Grade 3 pruritis and one Grade 3 increase in the number of neoplastic lesions were reported; both were considered to be unlikely related to SGN-30. There was one SAE in which an 80 year-old male died from complications of pneumonia, MI and aortic stenosis. This SAE was considered unrelated to the study drug. Preliminary data from this phase II study indicates that SGN-30 is well tolerated and demonstrates clinical antitumor activity.
Lymphoproliferative Disorders CR PR SD PD Pending Evaluation *Duration of CR: 256+ days **Duration of PRs: 56, 72, 84, and 271 days ***One patient with concurrent LyP received a single dose of SGN-30, 9 days after discontinuing methotrexate, experienced a worsening of his disease, and came off the study with PD. pcALCL (n=10) 5** 3 2 pcALCL/t-MF(n=1) 1* t-MF(n=2) 2 t-MF/LyP(n=3) 1 1 1 LyP(n=1) 1***
Natural Course of the Subsequent Pregnancy after a Single Loss in Women with and without the Factor V Leiden or Prothrombin 20210A Mutations.
Authors: Coppens Michiel , Folkeringa Nienke , Teune Margreet , Hamulyak Karly , van der Meer Jan , Prins Martin H. , Büller Harry R. , Middeldorp Saskia 
Published: October 2019

Abstract
In previous case control studies factor V Leiden and the prothrombin 20210A mutation have been associated with pregnancy loss, in particular recurrent and late (>12 weeks of gestation) losses in women carriers1. The prognosis of a second pregnancy after an initial late pregnancy loss in women with inherited thrombophilia is uncertain; the live birth rate reported in different cohort studies varied from 11 to 98%2–4. This has led to a debate about whether low-molecular-weight heparin should be prescribed to women with thrombophilia and pregnancy loss, despite the absence of evidence about its effectiveness from placebo-controlled trials.
We determined the live birth rate of the 2nd pregnancy following a first loss in a large family study that included patients with documented venous thromboembolism or premature atherosclerosis and carriership of the factor V Leiden or prothrombin 20210A mutations and their 1st degree relatives. Ectopic or terminated pregnancies and pregnancies lost due to known chromosomal abnormalities were excluded, as well as pregnancies during which anticoagulants were used. A total of 993 women (498 carriers) who had had 2809 pregnancies (1420 in carriers) were analyzed. After an early pregnancy loss in the 1st pregnancy, the live birth rate of the 2nd pregnancy was 77% (95%CI 62–87) in carriers and 76% (95%CI 57–89) in non-carriers. After a late pregnancy loss in the 1st pregnancy, the live birth rate of the 2nd pregnancy was 68% (95%CI 46–85) in carriers and 80% (95%CI 49–94) in non-carriers (OR 0.9, 95%CI 0.5–1.3).
We conclude that the pregnancy outcome in women with either factor V Leiden or the prothrombin 20210A mutation is fairly similar to the outcome in women without these mutations. After a late pregnancy loss in the first pregnancy, the live birth rate in the second pregnancy tended to be somewhat lower for carriers than for non-carriers. The live birth rates for both carriers and non-carriers in this study was substantially higher than in some other cohorts, which may be due to the fact that the cohort was not selected based on obstetric indications. Given the observed favourable prognosis after a first pregnancy loss even in women with known thrombophilia and a late loss, low-molecular-weight heparin to improve pregnancy outcome should not be used before results from ongoing randomized placebo controlled trials have shown its effectiveness and safety.
Marked Activity of Bortezomib, Rituximab, and Dexamethason in Relapsed and Refractory Mantle Cell Lymphoma.
Authors: Drach Johannes , Kaufmann Hannes , Pichelmayer Oskar , Sagaster Verena , Seidl Sonja , Chott Andreas , Zielinski Christoph , Raderer Markus 
Published: October 2019

Abstract
Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. We have now enrolled 14 pts at a median age of 69 years (range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 12 pts, high-dose therapy in 4 pts, and thalidomide in 7 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts), vasculitic skin infiltrates in 3 pts, and hyponatremia in 1 pt. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 12 pts evaluable for efficacy, 9 have achieved a response (3 CR, 6 PR), and 2 pts experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. All 3 pts who achieved a CR are still progression-free at 12 months after treatment initiation. Among pts in PR, 3 pts have relapsed (progression-free survival 14, 11, and 6 months, respectively), and 3 pts are still progression-free beyond 6 months from initiation of treatment. In summary, the BORID treatment regimen has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable and durable response.
Mature Results of a Prospective Trial of Rituximab in Patients (Pt) with Post Transplant Lymphoproliferative Disorder (PTLD) Unresponsive or Ineligible for Reduced Immunosuppression (RIS).
Authors: Sharman Jeff P. , Tsai Donald E. , Twist Clare J. , Horwitz Steven M. , Jones Carol D. , Horning Sandra J. 
Published: October 2019

Abstract
Background: PTLDs are typically B-cell neoplasms occurring as uncommon but serious complications of reduced T-cell immune surveillance associated with organ transplantation. RIS benefits only a subset of PTLD patients and cytotoxic therapy may be poorly tolerated. Therefore, in October 1998 we initiated a prospective study of rituximab in patients who failed or were unable to receive RIS and now report mature results.
Methods: Patients with CD20+ PTLD were eligible if they had failed to completely respond to RIS or RIS was contraindicated and had Karnofsky performance status >60, age 3–70 years (y), measurable disease, and no change in immunosuppression for at least 2 weeks and no cytotoxic therapy within 4 weeks. Rituximab was given as 375 mg/m2 weekly x 4 with disease evaluation at 1, 3, 6, 9, 12 and 18 months. Response data, survival curves, and the impact of clinical and pathological factors were evaluated.
Results: 24 of 26 enrolled pt were eligible and evaluable. Median age was 42y with 5 <17 y, 18 were male, and 14 progressed on RIS. Median time to PTLD from transplant was 47 months (m) (8 <24 m). 17/22 were EBV+, 17 were large cell or Burkitt histology, and 10 PTLD occurred in the allograft site. Response rate was 63% (46 %CR, 17% PR) and CRs were durable (1/11 progressed). With median follow-up of 65 m (range 44–82), outcomes at 5 y are: overall survival 48%, freedom from progression 41% and failure-free survival 21%. 7 pt died without progression, yielding 5 y cause-specific survival of 69%. Nine of 13 pt with disease progression were successfully salvaged with second-line therapy. In univariate analysis PTLD characteristics did not significantly correlate with outcome but 2/2 Burkitt pt quickly progressed.
Conclusions: Rituximab provided effective, durable treatment for ~40% of pt failing RIS in this series of mainly late PTLD and a majority of pt progressing after rituximab could be treated successfully. However, overall and failure-free survival reflect significant co-morbidity in this population.
Inhibition of GSK-3 Induces Apoptosis of CLL Cells by Abrogating NFkB Nuclear Activity.
Authors: Ougolkov Andrei V. , Bone Nancy , Billadeau Daniel , Lee Yean K. , Kay Neil E. 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) represents one of the most common hematological malignancies and is characterized by the expansion of a clonal B cell population. Commonly, CLL is defined as a disease of failed apoptosis of the leukemic B cells, and it is this feature that makes them refractory to common chemotherapeutic agents designed to kill CLL cells. The mechanism controlling apoptosis in CLL is complex and influenced by numerous factors, including NFkB-mediated expression of antiapoptotic proteins, such as Bcl-2 and XIAP. We recently demonstrated that glycogen synthase kinase-3 (GSK-3) b positively regulates NFkB-mediated gene transcription and cell survival in pancreatic cancer cells (Cancer Research 2005. 65:2076).
Similar to pancreatic cancer, we have found that pharmacological inhibition of GSK-3 results in decreased expression of NFkB target genes Bcl-2, Mcl-1 and XIAP in CLL B cells. In addition we noted a dose dependent increase in apoptosis levels for both the MEC1 cell line and primary CLL B cell patient samples. Using CLL blood B cells, we have found that both GSK-3b and NFkB accumulate in the nucleus of CLL cells, but not normal blood B cells. In addition, we observed that inhibition of GSK-3 leads to a decrease in NFkB-mediated gene transcription, without affecting the nuclear accumulation of NFkB. However, using chromatin immunoprecipitation, we found that NFkB binding to its target gene promoters (XIAP, Bcl-2) is significantly affected in CLL B cells treated with a GSK-3 inhibitor. These results suggest that GSK-3 regulates the nuclear activity of NFkB in CLL cells by affecting the binding of p65/p50 to the promoters of a subset of its target genes. Our results establish that inhibition of GSK-3 induces apoptosis of CLL cells and suggest GSK-3b as a potential therapeutic target in the treatment of CLL.