bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma.
Authors: Leleu Xavier , Touzeau Cyrille , Benboubker Lotfi , Facon Thierry , Delain Martine , Fourneau Nele , Phelps Charles , Forslund Ann , Hellemans Peter , Smit Johan , Badamo-Dotzis Julie , Moreau Philippe 
Published: March 2020

8530 Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age = 69 (range 50-82) years; multiple myeloma stage: IA = 11% and IIIA = 89%; prior lines of therapy: 1 = 100%, 2 = 55.6%, and 3 = 11.1%; prior VELCADE treatment = 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q+V+D regimen. The most common adverse events (≥ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.
Long-term follow-up of the GELA LNH 03-7B study: A prospective phase II study of 150 patients over 80 years with diffuse large B-cell lymphoma (DLBCL) treated with RminiCHOP.
Authors: Peyrade Frederic , Fain Olivier , Fabiani Bettina , Bauduer Frederic , Van Den Neste Eric , Macro Margaret , Devidas Alain , Collignon Joelle , Rose Christian , Bonnet Sophie , Maerevoet Marie , Demuynck Hilde , Casasnovas Rene-Olivier 
Published: March 2020

8536 Background: We report the outcome of patients included in the LNH 03-7B prospective phase II study of the GELA group which evaluated the tolerance and efficacy of a reduced dosage chemotherapy regimen (miniCHOP) associated with full dose rituximab in patients aged over 80 years with DLBCL. Methods: Patients were between 80 and 95 years (median 83 years), had disease stage I Bulky to IV and 65% had poor risk lymphoma according to IPI. Perfomance status was 0-2 in all cases. The majority of deaths and grade III/IV toxicity occurred during cycle 1 and 2. Response to treatment and early survival analyses were previously presented with 20 months median follow-up (Lancet oncol 2011;12:460-468). Results: At the time of this analysis, The median follow-up time was 41 months and 75 (50%) patients were alive. The 4-year estimated overall survival (OS) was 49.3% [95% CI: 40.8-57.3%] and the median OS was 38 months. The 4-year estimated PFS, EFS and DFS were 41.4% [95% CI: 33.1-49.5%], 39.4% [95% CI : 31.2-47.5%] and 57.9% [95% CI : 47.3-67.2%] respectively.]. During the additional follow-up, 8 patients relapsed (10% of CR patients) and 17 died. No long term toxicity was recorded. In a multivariate analysis an albumin level >35 g/l remained significantly associated with a longer survival. Conclusions: These results show that very old patients with DLBCL treated with RminiCHOP could express long-term survival and probably be cured. Regarding the DFS and despite the early toxicity, it seems crucial to obtain the best possible response. This long term analysis confirm that in patient aged over 80y with DLBCL and with PS from 0 to 2, RminiCHOP is the treatment cornerstone. Clinical trial information: NCT01087424.
Beneficial effect of complete response and type of therapy in multiple myeloma.
Authors: Pandey Shivlal , Rajkumar S. Vincent , Dispenzieri Angela , Lacy Martha , Gertz Morie , Buadi Francis , Dingli David , Hayman Suzanne R. , Russell Stephen J. , Lust John Anthony , Zeldenrust Steven R. , Kapoor Prashant , McCurdy Arleigh Robertson , Kyle Robert A. , Kumar Shaji 
Published: March 2020

8541 Background: Achievement of a complete response (CR) to treatment is an important predictor of outcome for patients (pts) with myeloma (MM). The goal of the current study was to assess whether the treatment that resulted in CR has any impact on the outcomes. Methods: We identified 462 pts with MM, who fulfilled the IMWG criteria for CR, seen at Mayo Clinic between 1991 and 2011. The treatment was classified into groups by the regimen that led to CR (Table), and also based on whether an autologous stem cell transplant (ASCT) was part of the regimen. The remaining 21 pts had a variety of regimens and are not included in the Table. Results: The median age at diagnosis was 58.5 yrs (27.1–82.3 yrs) with 56% males. The overall survival (OS) from diagnosis for the entire cohort was 10.7 yrs (95% CI; 9.3, NR). The median interval from diagnosis to the recorded CR was 10.3 mos (range 1- 170), with 272 (58.4%) and 385 (82.7%) obtaining a CR in <12 mos and <24 months from diagnosis. We first compared the outcomes based on whether ASCT was part of the regimen; 328 had an ASCT while 117 pts received only chemotherapy. Median time to progression (TTP) following a CR was 5.1 yrs for the ASCT group compared with 5.5 yrs for the rest (P=0.3). Median OS from CR was 9.1 yrs for the ASCT group and 7.5 yrs for the rest (P=0.5) and OS from diagnosis was 10.1 yrs for the ASCT group and 12.6 for the rest (P=0.5). Examining the outcomes based on the regimen utilized showed that the TTP and OS from CR as well as OS from diagnosis were similar for all the groups (Table). Among pts who had a CR within a year of diagnosis, there were no differences in terms of the TTP or OS from the onset of CR or from diagnosis between the ASCT vs. chemotherapy groups or between the different regimens (P=NS for all comparisons). Conclusions: The current study highlights an important message regarding CR in MM. The results suggest that the prognostic value of CR is independent of the nature of therapy, and likely reflects the contribution of disease biology to obtaining a CR. [Table: see text]
Efficacy of radioimmunotherapy-based conditioning with high-dose chemotherapy and autologous stem cell transplantation for transformed lymphoma.
Authors: Krishnan Amrita Y. , Wondergem Marielle , Palmer Joycelynne , Shimoni Avichai , Raubitschek Andrew Antony , Nademanee Auayporn , Visser Otto , Zijlstra Jose M , Tsai Nicole , Nagler Arnon , Kogut Neil Martin , Simpson Jennifer , Forman Stephen J. 
Published: March 2020

8556 Background: Transformed non-Hodgkin lymphoma (TF NHL) has a poor prognosis with median survival of 7-20 months. Studies have suggested the benefit of HDC. The series by Eide showed 47%, 5yr OS in 47 pts treated with HDC and ASCT (Br J Hem 2011). Our multicenter experience with RIT plus HDC (Yttrium 90 ibritumomab tiuxetan plus BEAM; carmustine, etoposide, cytarabine, melphalan "ZBEAM") demonstrated the safety and efficacy of the regimen in diffuse large cell lymphoma (DLCL). Therefore, the regimen was explored in other subtypes of NHL. Herein we report the outcome of 57 pts with TF NHL treated with ZBEAM conditioning and ASCT at three centers (City of Hope USA n=20, VUMC the Netherlands n=31, Chaim Sheba Med Center, Israel n=6.) between 2003- 2011. Methods: Histological confirmation of transformation was defined as dx of DLCL in pts with either a prior history or concomitant dx of follicular NHL. Results: Median age at ASCT was 59.6 yrs (range 41-69). Median number of prior regimens 2 (range 1-6), all pts received rituximab in at least one regimen. Disease status at ASCT: 1st CR 29, 1stPR 7,1st rel 9, IF 5, 2nd CR 5, 2nd rel 1, >3CR 1. Median time from TF NHL dx to ASCT was 7.7 mo (range 2.8-116). Pts engrafted white cells at median of 12 days (range 8-33). Non relapse mortality was 3.5%. There were two second malignancies: 1 MDS and 1 SCC Skin. Median f/u for living pts was 29 mo (range 7-100). Two year PFS was 69.67% (95%CI 59.39 - 77.83) and OS 90.29% (95% CI: 79.63 - 95.52). On univariate analysis, number of prior regimens, time from TF NHL dx to ASCT and history of marrow involvement were not significant for PFS and OS. Disease status at ASCT was significant for PFS in 1st CR vs relapse disease ( p=0.03) The relapsed pts had a significant increase in risk of relapse/progression or death post ASCT compared to the 1CR patients. [HR = 2.9, (95% CI: 1.07 - 7.9)]. Conclusions: ZBEAM conditioning with ASCT is an active treatment for pts with TF NHL, and is particularly efficacious as consolidation for pts in 1st CR.
Allogeneic hematopoietic cell transplantation (alloHCT) in diffuse large B-cell lymphoma (DLBCL) after nonmyeloablative (NMA) or reduced-intensity (RIC) conditioning: Long-term outcome in 116 patients.
Authors: Poon L. M. , Saliba Rima , Rondon Gabriela , Okoroji Grace-Julia , Oki Yasuhiro , Champlin Richard E. , Hosing Chitra , Young Ken H , Turturro Francesco , Khouri Issa F. 
Published: March 2020

8561 Background: The role of alloHCT and conditioning intensity in DLBCL remains unclear. In this retrospective study, we determined their effectiveness in 116 patients (pts) with DLBCL (de novo, n=59, transformed, n=57) receiving alloHCT at our institution, between 1998-2011. Methods: Median age was 51years (range, 19-70); median prior therapies was 4 (range 2-12). Disease status at alloHCT was complete response (CR) (n=22), partial response (PR) (n=58), stable (SD) (n=25) or progressive disease (PD) (n=11). 41 (35%) pts had previous autografts. 74 (64%) pts received RIC of melphalan/fludarabine (Flu) or BEAM, and 42 (36%) received a NMA conditioning of Flu/cyclophosphamide or cisplatin/cytarabine/ Flu. Donor source was HLA-identical sibling (MRD) (65%), HLA-matched unrelated (MUD) (31%) or a 1-Ag mismatched donor (4%). Results: With median follow-up among survivors of 63 months (range 5-157), estimated 5-yr OS and PFS for the whole cohort was 41% and 34% respectively. On multivariate (MV) analysis, disease status was most significant predictor for OS, with chemo refractory disease (SD/PD) being associated with higher mortality rate (HR 3.7, 95% CI 1.6-8.6, p=0.002). Combined use of NMA conditioning and MRD was associated with significantly lower mortality rate (HR 0.4, 95% CI 1.6-8.6, p=0.005). OS was highest [69% (95% CI 49-82)} for pts in CR/PR after NMA with a MRD (n=29), and lowest [(12% (95% CI 3-29)] for SD/PD pts after RIC with a non MRD (n=32). Disease status was strongest predictor of PFS on MV analysis, with CR pts having improved PFS compared to SD/PD (5-year estimates of 58% and 13%, respectively (P<0.001). Pts in PR with early disease stage (< Stage 4) and negative PET at alloHCT had PFS comparable to pts in CR (56% at 5 yr HR=1.3, p=0.6), while all other PR pts had PFS comparable to SD/PD pts (PFS=20%, p 0.1). Conclusions: Our study shows disease status, donor type and conditioning intensity are predictors of outcomes after alloHCT in DLBCL. Pts with chemosensitive disease and receiving NMA, MRD had improved survival rates compared to RIC alloHCT. PR pts with low volume PR had similar outcomes to CR pts.
A matched pair analysis of conditioning BuEM versus BEAM in autologous haematopoietic cell transplantation for lymphomas in terms of toxicity and efficacy.
Authors: Sakellari Ioanna , Mallouri Despina , Batsis Ioannis , Apostolou Chryssoula , Konstantinou Varnavas , Abela Elma Maria , Douka Vassiliki , Marvaki Anastasia , Karypidis Kyriakos , Michail Iskas , Baliakas Panayiotis , Kaloyannidis Panayiotis , Yannaki Evangelia , Kouvatseas George , Smias Christos , Anagnostopoulos Achilles 
Published: March 2020

8567 Background: In autologous hematopoietic cell transplantation (AHCT) for lymphomas, the optimal conditioning regimen is currently investigated. The standard conditioning used is BEAM. During 2009-2011 a new alternative Busulphan-based conditioning regimen constructed in our unit, consisting of Busilvex (9.6 mg/Kg), Etoposide (9.6 mg/Kg) and Melphalan (140mg/m^2) (BuEM) was used. We retrospectively analysed the outcome of patients (pts) conditioned with BEAM and BuEM regimen, in terms of toxicity and efficacy, in a matched pair analysis. Methods: A matched paired analysis on a 1:2 ratio was performed. Thus, 2 control cases (receiving BEAM regimen) were matched to each patient treated with BuEM according to: phase of transplant, age, lines of previous chemotherapy. The first 50 consecutive pts treated with BuEM were matched to a random sample from the historical BEAM control population. Ninety-three BEAM pts that fulfilled the matching criteria were eventually randomly selected. Concerning pts characteristics there were no statistical significant differences except from more chemoresistant disease in the BuEM cohort (p=0.008). Thus a second matched pair analysis was conducted upon stratification by disease chemosensitivity instead of age as a risk factor. Results: Progression free survival and overall survival (OS) were 70.6% and 81.8% for the BEAM vs 68.9% and 83% for the BuEM cohort respectively (p=ns). In the BuEM cohort a borderline significantly better OS was noted in Hodgkin’s pts receiving BuEM (p=0.05). In terms of early toxicity a significantly faster neutrophil engraftment was found in the BEAM cohort, but there was a significantly less need of red blood cells, platelet transfusions and GCSF infusion in the BuEM cohort. BEAM regimen was also associated with: reduced incidence of infections (p=0.02), less severe (grade 3-4) mucositis (p=0.000) and liver toxicity (p=0.004). Conclusions: BEAM regimen was correlated with a favourable reduced early toxicity profile, ie severe mucositis and liver impairment. On the other hand, BuEM was found to be equally efficacious and moreover offered improved overall survival in Hodgkin’s lymphoma pts.
Impact of rituximab on the course of low-grade follicular lymphoma.
Authors: Krishnamurthy Jairam , Loberiza Fausto R. , Bast Martin , Tandra Pavankumar , Bhatt Vijaya Raj , Bociek Gregory , Bierman Philip Jay , Vose Julie , Armitage James O. 
Published: March 2020

8572 Background: Rituximab has revolutionized the treatment of lymphomas and has been shown to improve clinical outcomes in patients with follicular lymphoma. Our study evaluated the progression free survival (PFS) and overall survival (OS) in patients with grades I and II follicular lymphoma when rituximab was used as initial therapy, as salvage or if no rituximab was used. Methods: Patients with grades I and II follicular lymphoma treated between June 1981 and January 2010 were included. Disease and treatment related variables were compared based on type of treatment (No rituximab-Group I, rituximab as salvage-Group II, Rituximab as initial treatment-Group III) using the Kruswal Wallis or chi-square tests. Univariate probabilities of PFS and OS were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression analysis to evaluate differences in risk of treatment failure and mortality in the three groups while adjusting for covariates. Results: There were 226 patients in group I, 84 in group II and 110 in group III. Significant differences were found in some of the disease and treatment related variables. Univariate analysis is shown in the Table. The relative risk of treatment failure for group II was 0.82 (p=0.26) and 2.63 (p=0.0001) respectively in the first 10 years and after 10 years while it was 0.52 (p=0.0003) and 3.97 (p=0.001) respectively for group III in the first 10 years and after 10 years. The relative risk of mortality in group II was 0.63 (p=0.008) and group III was 0.32 (p<0.0001). Conclusions: Overall survival for patients with low grade follicular lymphoma is significantly improved when rituximab is used as initial treatment or as salvage when compared with no rituximab. [Table: see text]
Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers.
Authors: Coffey Greg , Rani Aradhana , Betz Andreas , Pak Yvonne , Pandey Anjali , Hollenbach Stanley , Gretler Daniel D. , Mant Tim , Jurcevic Stipo , Sinha Uma 
Published: March 2020

8574 Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as FcεRI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a Tmax of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC50of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of FcεRI-mediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.
Whole genome sequencing of sporadic Burkitt lymphoma in HIV-infected and uninfected patients.
Authors: Ritter Deborah , Walker Kimberly , Kwon Myoung , Lulla Premal , Bollard Catherine M. , Sheehan Andrea , Heslop Helen E. , Gibbs Richard A. , Wheeler David A. , Mims Martha P. 
Published: March 2020

8577 Background: Burkitt Lymphoma is defined by canonical translocations between MYC and immunoglobulin IgH, IgK or IgL (8:14, 8:2, 8:22, respectively), and is commonly associated with HIV. The identification of HIV from sequenced samples is critical to understanding HIV-associated Burkitt Lymphoma. While recent novel gene mutations (ID3 and TCF3) have been implicated in functional roles, concomitant genomic structural variants and the interaction of HIV with structural variation is less well defined. Methods: We sequenced the whole genomes of 15 patients with 100bp paired-end reads on Illumina Hi-Seq platform, resulting in an average insert size of 278 (+/- 63) and coverage of 60X tumor and 30X normal. We included 7 HIV-negative, and 8 HIV-positive subjects. Sequencing reads were mapped to the reference genome using BWA. Large-scale structural variation was detected by the BreakDancer and Crest programs. Functional annotation was used to prioritize structural variants for validation. Single nucleotide variants and small insertions and deletions were detected by CARNAC, a somatic variation discovery pipeline. The subset of WGS reads that failed to align to the human reference genome were tested for the presence of HIV sequences by comparing the unmapped reads to a database of viral DNA sequences which included the common subtypes of HIV defined by Los Alamos. Reads matching HIV or EBV with an expectation value of <10-4 were analyzed to determine virus coverage and viral integration sites. Results: Canonical MYC-IgH translocations were identified in 9/15 (60%) tumor samples, with 2 additional subjects harboring either a deletion or an inversion near exon1 of MYC; 4 had no MYC rearrangement. MYC translocations occurred equally in both groups. TP53 and SMARC4 point mutations were observed recurrently in the HIV uninfected group but not in the HIV infected patients. Variable levels of HIV DNA sequence were observed in normal tissue of all HIV infected patients. Conclusions: Whole genome sequencing has identified known somatic variants in HIV infected and uninfected patients. Two genes, TP53 and SMARC4, appear to be differentially mutated, but additional samples are needed to achieve statistical significance.