bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ruxolitinib (RUX) in combination with azacytidine (AZA) in patients (pts) with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).
Authors: Assi Rita , Cortes Jorge E. , Pemmaraju Naveen , Jabbour Elias , Bose Prithviraj , Kadia Tapan M. , Dinardo Courtney Denton , Zhou Lingsha , Pierce Sherry , Van Derbur Stephanie , Tuttle Carla , Borthakur Gautam , Estrov Zeev , Garcia-Manero Guillermo , Kantarjian Hagop M. , Verstovsek Srdan , Daver Naval Guastad 
Published: September 2018

7064 Background: Clinical trials exclusively focusing on pts with MDS/MPNs are lacking. Combining RUX and AZA may target distinct manifestations of MDS/MPNs. Methods: Pts were treated with single-agent RUX 15 mg or 25 mg (based on platelets count) orally twice daily continuously in 28-day cycles for the first 3 cycles. AZA 25 mg/m2 (day 1-5) was added on each cycle starting cycle 4 and could be increased to 75 mg/m2 (maximum) or started earlier than cycle 4 and/or at higher dose in pts with proliferative features or high blasts. Results: 35 pts with med age 70 years (range, 43-79) were enrolled (MDS/MPN-U, n = 14; CMML, n = 17; atypical CM (aCML), n = 4), 28 (80%) were Int-2/High per MF DIPSS, 14 (41%) had splenomegaly > 5 cm, and 12 (34%) had EUMNET MF-2/MF-3 fibrosis. Common mutations on a 28-gene sequencing panel included JAK2 (29%), RAS (27%), ASXL1 (21%), TET2 (18%), and DNMT3A (12%). All 35 pts were evaluable for response per MDS/MPN IWG criteria and 17 (49%) responded. 6/17 (35%) IWG responses occurred after the addition of AZA (med time after AZA = 1.8 months). JAK2 mutated pts had a trend to higher responses vs those with non-mutated pts (8/10 vs 9/25, P = 0.19). Ten pts had > 5% pretreatment BM blasts and 7 achieved a reduction in blasts to < 5% (70%). A > 50% reduction in palpable spleen length reduction at 24 weeks was seen in 9/12 (75%) pts. New grade 3/4 anemia and thrombocytopenia occurred in 18 pts (51%) and 19 (54%) pts but were manageable with dose modifications. Only one pt discontinued therapy due to cytopenias. At a med follow-up of 17.4 mo (range, 1.2-36.8+), 14 (40%) pts died: pneumonia (n = 4), sepsis (n = 4), progression to AML (n = 4), and cardiac arrest (n = 1). The med survival for all pts was 16.6 mo (1.0 - 36.8). Compared to CMML and aCML, MDS/MPN-U pts had significantly better med survival (26.4+ vs 15.0+ vs 1.5+ mo, respectively; p = 0.01). Conclusions: The combination of RUX and AZA showed an IWG-response rate of 49% in pts with MDS/MPNs, and was well-tolerated. The benefit appears more profound in pts with MDS/MPN-U. This study is ongoing. (ClinicalTrials.gov Identifier: NCT01787487).
Results of a phase II multicenter study of obinutuzumab plus bendamustine in pts with previously untreated chronic lymphocytic leukemia (CLL).
Authors: Sharman Jeff Porter , Yimer Habte Aragaw , Boxer Michael , DiBella Nicholas , Babu Sunil , Li Jia , Mun Yong Jun , Skettino Sandra L. , Danilov Alexey Valeryevich 
Published: September 2018

7523 Background: Bendamustine (B) + rituximab (R; BR) is a commonly used 1L treatment for CLL. The CLL10 study reported an ORR of 96% and CR of 31% with BR. Obinutuzumab (GA101; G) is a glycoengineered, type II anti-CD20 monoclonal antibody. A randomized Phase III trial in 1L CLL pts showed that G significantly improved PFS and CR rate compared with R, when used in combination with chlorambucil (Goede 2014). B + G (BG) was evaluated in a subgroup of CLL pts in the GREEN study (Stilgenbauer 2015). We present results of a Phase II study (NCT02320487) evaluating the efficacy and safety of BG as 1L treatment for CLL pts. Methods: 102 pts with previously untreated CLL received BG, consisting of 6 cycles of G (cycle [C] 1: 100mg day (D) 1, 900mg D2, 1000mg D8 and D15; C2–6: 1000mg D1) and B (90mg/m2: C1, D2 and D3; C2–6, D1 and D2). Each cycle was 28 days. Primary endpoint was CR assessed using iwCLL criteria. Secondary endpoints included ORR, PFS, OS, and MRD. Median follow-up at the time of analysis was 11.0 months. Results: Median pt age was 61 yrs (range 35–90); 68.6% were male; 44.1% had Rai stage 3–4. For evaluated pts, IgVH status was 32.9% mutated and 67.1% unmutated. The incidences of trisomy 12, normal cytogenetics, and deletions of 13q, 11q, and 17p were 23.4%, 37.5%, 17.2%, 15.6%, and 6.3%, respectively. Investigator-assessed CR rate was 49.0% (95% CI 39.0–59.1) and ORR was 89.2% (95% CI 81.5–94.5) after 6 cycles. MRD negativity (MRD-) in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of pts at the end of induction response assessment and in 75.5% of pts at any time following treatment. MRD- in bone marrow (BM) was 60.8% in pts with BM samples. The most common AEs (all grades [Gr]) were infusion reactions (72.5%), nausea (52.0%), pyrexia (36.3%), neutropenia (34.3%), fatigue (34.3%), constipation (26.5%), and rash (26.5%). The most common Gr 3–4 AE was neutropenia (26.5%). Incidence of Gr 3–4 infections was 11.8%. Incidence of TLS was 4.9% (all Gr 3). Three pts died; none were deemed related to study treatment or CLL by investigators. Conclusions: BG is an effective regimen for 1L treatment of CLL pts, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed. Clinical trial information: NCT02320487.
Single institution experience of allogeneic stem cell transplantation for Hodgkin lymphoma.
Authors: Pineda-Roman Mauricio , Afshar Solmaz F. , Galitzeck Zachary , Steinberg Amir 
Published: September 2018

7529 Background: Hodgkin lymphoma (HL) is curable in the majority of cases without stem cell transplantation (SCT). However, patients(pts) who relapse after chemotherapy require autologousSCT, and about half of those pts relapse. For over 3 decades, allogeneic SCT has been implemented in more refractory HL pts. We present the long term follow up of a group of pts from a our institution who underwent alloSCT for HL. Methods: 21 pts with HL transplanted from 2008 to 2015 and disease characteristics (HL type, status at SCT, chemosensitivity), treatment( graft source, donor type, auto and allo SCTdates, GVHD prophylaxis ) and outcomes (maximum grade of acute and chronic GVHD, survival (OS) and causes of death) were analyzed. Results: 13 males and 8 females received an alloSCT from 2008 to 2015, 11 pts had Nodular sclerosis HL, 6 NOS, 2 mixed cellularity, 1 lymphocyte predominant and 1 lymphocyte depleted. Performance status was 60 to 100, median of 90. 16 grafts were unrelated and 5 HLA identical. 18 pts received PBSC, 2 bone marrow and one double cord transplant. Most pts, 19, had a prior autoSCT, one had 2 prior autoSCT and for one , the allo was the first SCT. One patient was transplanted in unconfirmed first CR, 2 in confirmed CR, 4 in PR without prior CR, 3 in 1strelapse, 5 in 2nd relapse, 5 in 3rd relapse, and one in primary induction failure. All patients had a reduce intensity conditioning: 14 Flu/Mel, 4 Flu/Mel ATG, and one each Flu/TBI/ATG, Flu/TBI, Flu/Cy. Acute GVHD happened in 11 pts: max grade I in 1 , II in 7, III in 1 and IV in 2. 6 pts had extensive chronic GVHD. 12 pts (57.1%) have died (survival range 0.65-43.45 months, mean 13.1, median 6.12). Causes of death were primary disease in 4, infection in 3 pts, GVHD and infection in 2, ARDS, organ failure, pulmonary toxicity in 1 each. 9 pts (42.8%) are alive (survival range 1.63-8.44 years, mean 4.97, median 4.47) Conclusions: AlloSCT for pts with relapsed HL is a feasible treatment modality that can lead to long term OS in a significant proportion of pts. Our data is comparable with other published studies for HL alloSCT. The utility of alloSCT should not be dismissed even in the age of Brentuximab and checkpoint inhibitors.
Double-blind, randomized phase 3 study to compare efficacy and safety of the biosimilar CT-P10 to rituximab combined with CVP therapy in patients with previously untreated advanced-stage follicular lymphoma.
Authors: Kim Won Seog , Jurczak Wojciech , Sancho Juan-Manuel , Javrid Edvard , Kim Jin Seok , Hernandez Rivas Jose Angel , Prokharau Aliaksandr , Vasilica Mariana , Nagarkar Rajnish , Osmanov Dzhelil , Buske Christian , Kwak Larry , Ogura Michinori , Lee Sang Joon , Lee Sung Young , Bae Yunju , Coiffier Bertrand 
Published: September 2018

7532 Background: CT-P10 is a biosimilar candidate to the innovator rituximab (RTX). In patients with rheumatoid arthritis, CT-P10 has demonstrated equivalence in pharmacokinetics (PK) and efficacy (Yoo, ACR 2016). This study aimed to demonstrate non-inferiority of efficacy and PK equivalence between CT-P10 and RTX in patients with newly diagnosed advanced follicular lymphoma (AFL) (NCT02162771). PK equivalence was confirmed (Coiffier, ASH 2016). Methods: A total of 140 patients were randomized in a 1:1 ratio to receive CT-P10 or RTX (375 mg/m2 i.v) plus CVP (cyclophosphamide, vincristine, and prednisone) every 3 weeks over 8 cycles. Overall response rate (ORR) according to the 1999 IWG criteria over 24 weeks was assessed by the independent review committee. Results: Noninferiority of CT-P10 to RTX was shown for the primary efficacy endpoint of ORR. The ORR difference was 4.3% (Table) and the lower bound of the 95% confidence interval was -4.25%. B-cell depleted after the 1st infusion and remained as depleted over 8 cycles in both groups. Overall safety profile of CT-P10 was consistent with that of RTX and the proportion of patients with positive anti-drug antibody was similar in both groups (4.3% and 2.9%) for 24 weeks. Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in each group. Conclusions: This study demonstrates noninferiority of efficacy of CT-P10 to RTX combined with CVP in previously untreated AFL. CT-P10 was well-tolerated and the safety profile including immunogenicity of CT-P10 was comparable to that of RTX over 8 cycles of induction period. Clinical trial information: NCT02162771. [Table: see text]
Copanlisib in patients with relapsed or refractory follicular lymphoma.
Authors: Dreyling Martin H. , Santoro Armando , Leppa Sirpa , Demeter Judit , Follows George , Lenz Georg , Kim Won Seog , Mollica Luigina , Nagler Arnon , Diong Colin Phipps , Provencio Mariano , Stevens Don A. , Trevarthen David , Magagnoli Massimo , Cupit Lisa , Yin Shuxin , Hiemeyer Florian , Garcia-Vargas Jose E. , Childs Barrett H. , Zinzani Pier Luigi 
Published: September 2018

7535 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (iNHL) subtype, yet treatment options in the relapsed/refractory (r/r) setting are limited. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity. We report results from the FL subset of a large phase II study (n=141) in iNHL patients (pts) (NCT01660451, part B). Methods: A total of 104 pts with indolent FL (grade 1-3a) relapsed/refractory to ≥2 prior lines of treatment were treated with copanlisib (60 mg IV infusion) administered on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: Of the 104 pts treated, 62% were refractory; median prior lines 3 (range 2-8), median time from progression 8 wks (range 1-73 wks). 52% were male, 83% white, median age 62 yrs, and 62% ECOG 0. At the time of primary analysis the ORR was 58.7%, comprising 15 pts (14.4%) with complete response (CR) and 46 (44.2%) with partial response. Stable disease was observed in 35 (33.7%) pts and progression of disease as best response in 2 pts. The median duration of response was 370 days (range 0-687), with 43 responders censored at data cut-off. Median duration of treatment was 22 wks (range 1-105); 33 (32%) pts remained on treatment. For all pts, the most common treatment-emergent AEs occurring in >25% of pts included (all grade/grade 3+): diarrhea (34%/5%), reduced neutrophil count (30%/24%), fatigue (30%/2%), and fever (25%/4%). Hyperglycemia (50%/41%) and hypertension (30%/24%) were transient. The incidence of pneumonitis (8%/1.4%), hepatic enzymopathy (AST 28%/1.4%; ALT 23%/1.4%), opportunistic infection (1.4%) and colitis (0.7%) were low. Six deaths were observed, 3 of which were attributed to copanlisib: one lung infection, one respiratory failure, and one thromboembolic event. Conclusions: Copanlisib was highly active as a single agent in heavily pretreated r/r FL pts and resulted in durable responses in the majority of pts. Toxicities were manageable, with a low incidence of severe AEs associated with other PI3K inhibitors, especially hepatic enzymopathy, opportunistic infections, and colitis. Clinical trial information: NCT01660451.
Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma.
Authors: Flowers Christopher , Isufi Iris , Herrera Alex Francisco , Okada Craig , Cull Elizabeth H. , Kis Bela , Chaves Jorge , Bartlett Nancy L. , Bryan Locke Johnson , Houot Roch , Ai Weiyun Z. , Chau Ian , Linton Kim , Briones Javier , de la Cruz Merino Luis , Panizo Carlos , Von Keudell Gottfried Raffael , Lu Hailing , Hsu Frank J. , Halwani Ahmad Sami 
Published: September 2018

7537 Background: Follicular lymphoma (FL) is an incurable malignancy with patients (pts) ultimately relapsing following standard therapies. Active immunotherapy has the potential to induce life-long host anti-tumor immunity and disease control. G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist in a specific formulation. Preclinically, G100 activates dendritic cells, T cells and NK cells, and triggers systemic anti-tumor immunity. In Merkel Cell carcinoma pts, G100 administered intratumorally (IT) induced tumor inflammation and responses including a CR after G100 alone. This is the first study of G100 IT in pts with NHL. Methods: Previously treated or naïve pts with FL with an injectable tumor site and distal sites of disease were eligible. In Part 1, G100 cohorts of 5 or 10µg were enrolled in a 3+3 design, followed by a large tumor ( > 4cm) cohort at 20µg. Pts received 6-9 doses of G100 IT ~qwk after radiation (RT, 2 Gy x2 doses) to the lesion. A 2nd course of G100 could be given without RT to an additional site. Results: As of 31Dec16, all 9 pts in Part 1 dose escalation (3 pts each at 5, 10, or 20 µg/dose) were evaluable for safety and efficacy. An additional 13 pts at 10µg/dose were included in the safety analysis only. No G100-related DLTs or SAEs were observed at any dose level. Of 22 safety pts, all G100 related AEs were grade 1/2 and none occurred in > 2 pts. Tumor biopsies following G100 demonstrated diffuse infiltration of CD8+ T cells in 5/5 pts and T cell repertoire analyses indicated an increased frequency of clonal tumor infiltrating lymphocytes (TILs). Best responses include: 4 PRs (45%), 3 SDs (33%) and 2 pending (22%). Of the 4 PR pts, tumor regression ranged 58-89% including up to 56% shrinkage of abscopal (distal) sites. Conclusions: G100 IT was safe, well-tolerated, induced CD8+ T cell infiltration and expansion of TIL clones. G100/RT treated and abscopal lesion regressions were observed signifying the induction or boosting of systemic anti-tumor immunity. The induction of immune responses, favorable safety profile and clinical activity indicate that G100 IT is an active agent that warrants further investigation. Part 2 enrollment continues with randomization to G100/RT ± pembrolizumab. Clinical trial information: NCT02501473.
Central line-associated complications during treatment with DA-R-EPOCH therapy for NHL.
Authors: David Rachel Julie , Baran Andrea , Kelly Jennifer , Reagan Patrick Michael , Casulo Carla , Barr Paul M. , Friedberg Jonathan W. 
Published: September 2018

7543 Background: Certain non-Hodgkin lymphomas (NHL) such as primary mediastinal B-cell, Burkitt’s, and high-grade B-cell lymphoma with MYC and BCL2 rearrangements are often treated with infusional dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-R-EPOCH), which requires a central line. We have observed meaningful line-associated complications (LAC) in patients (pts) treated with DA-R-EPOCH. With the ongoing use of this regimen, we sought to identify the rates and correlates of LAC in this population. Methods: We retrospectively identified all pts treated with DA-R-EPOCH at the Wilmot Cancer Institute between 3/2011 and 10/2015. Our primary endpoint was the rate of LAC, including venous thromboembolism (VTE), extravasation, and line-associated infection (LAI) diagnosed during DA-R-EPOCH therapy. Our secondary endpoint was the rate of VTE during therapy. Rates and 95% confidence intervals (95% CI) were calculated for all endpoints. Univariate logistic regression was used to calculate odds ratios to evaluate potential predictors. Results: 43 pts received DA-R-EPOCH during the study period. 70% of pts were male; median age was 52 years. 17 pts (39.5%, 95% CI 0.25 - 0.56) experienced at least 1 LAC: 15 pts (35%, 95% CI 0.21 - 0.51) had VTE; 3 pts had LAI; and 2 pts experienced extravasations. Grade 3 toxicity was seen in 41% (7/17): 4 pts with VTE, and 3 pts with LAI. Both extravasation events were grade 2, and both occurred with mediports. In univariate analysis, BMI ≥ 35 kg/m² and receiving therapy via peripherally inserted central catheter (PICC) line were significantly associated with an increased risk of VTE (p=0.04 and p=0.02, respectively). Conclusions: 40% of pts receiving DA-R-EPOCH therapy for treatment of NHL developed LAC, almost half of whom experienced grade 3 toxicities. Clinicians need to balance these risks when selecting therapy, particularly with the lack of randomized data to support the DA-R-EPOCH approach in many circumstances. Given observed extravasations, we avoid mediports in favor of PICC lines, however this approach carries a significant risk of VTE. Future studies are needed to evaluate the role of prophylactic anticoagulation in this population.
Clinical activity, safety and tolerability of ASN002, a dual SYK/JAK inhibitor, in patients non-Hodgkin lymphoma (NHL) and solid tumors.
Authors: Rasco Drew W. , O'Rourke Timothy J. , Chen Andy I. , Wang Michael , Tolcher Anthony W. , Rao Niranjan Sathyanarayana , Denis Louis J. , Reddy Sanjeeva , Barta Stefan K. 
Published: September 2018

7545 Background: ASN002 is a novel, potent inhibitor of Spleen Tyrosine Kinase (SYK) and Janus Kinases (JAK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decreases proliferation in ibrutinib-resistant cell lines, and suppresses tumor growth in rodent xenograft models of NHL and other hematologic malignancies. Methods: This Phase 1/2 clinical trial in patients with solid tumors and hematologic malignancies evaluates escalating ASN002 oral doses of 10, 20, 30, 40, 50 and’ 75 mg BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 allows patients with solid tumors or hematologic malignancies; Phase 2 allows only patients with diffuse large B-Cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL). Endpoints include safety, tolerability, pharmacokinetics, serum markers of inflammation, and response using RECIST or Lugano Classification System. Results: Twenty-eight patients have enrolled in the DLT phase at doses of 10 mg – 75 mg BID and at 80 mg QD. All patients had multiple prior lines of treatment (range: 2 – 8). ASN002 was well tolerated. No dose limiting adverse events have been reported at these dose levels. Most drug-related adverse events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic exposure was high (Cmax, AUC (0-12h) and T1/2 at 40 mg BID were 0.7 µM, 6.3 µM.h and 18 h, respectively). High systemic exposure was also observed at 80 mg QD. Robust reduction of CRP, IL-18, MIP1β, VCAM-1, TNFR2 was observed at all doses. Stable disease (RECIST, 9+ months) in a patient with primary peritoneal cancer, about 50% reduction in target lesions at 3 months in a FL patient (Lugano, 6 prior lines) and stable disease and reduction of pruritus in a peripheral T-Cell lymphoma patient after 2 months (Lugano, 2 prior lines) of treatment were observed. ASN002 treatment continues in both lymphoma patients. Accrual of patients continues. Conclusions: ASN002 was safe and well tolerated. Encouraging preliminary evidence of efficacy in NHL patients was observed. MTD has not been reached and dose escalation continues. Updated and detailed results will be presented. Clinical trial information: NCT02440685.
Comparative double-blind randomized trial of 2 rituximab products in patients with CD20+ diffuse large B-cell lymphoma (DLBCL).
Authors: Shah Sandip , Viswabandya Auro , Mukhopadhyay Asis , Nagarkar Rajnish Vasant , Sachdeva Batra Sonica , Lopez Lazaro Luis , Kankanwadi Suresh , Srivastava Alok 
Published: September 2018

7550 Background: DRL-Rituximab (T) is a proposed biosimilar of the innovator reference rituximab (USA: Rituxan; EU: MabThera). Physicochemical analyses and nonclinical studies have shown T to be comparable with innovator Rituximab. This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity of T with EU sourced MabThera (R) in DLBCL patients. Methods: Multicentre randomized double-blind 2-arm parallel study conducted in patients aged 18-60 yrs, with a centrally confirmed newly diagnosed CD20+ DLBCL, as first line of treatment. Patients received 6 cycles (C), every 21 days, of either T or R at 375 mg/m2 + CHOP. Primary objective was to compare C1 PK (AUC0-21d & Cmax). Overall Response Rate (ORR) was the key secondary objective, with C6 PK parameters, PD parameters (B-cells measured as CD19+ positive cells in peripheral blood- depletion & repletion), treatment-emergent adverse events (TEAEs), and anti-drug antibodies (ADA) as other secondary objectives. PK similarity criterion was 90% CI of geometric mean ratios (GMRs) of AUC0-21d and Cmax in C1, within 80-125%. Results: 151 patients were randomized (T, 76; R, 75). PK similarity criterion was met. The GMR T/R ratios with 90% CIs for AUC0-21d & Cmax were 100.0% (87.7, 114.0) & 96.2% (88.7, 104.4), respectively. Per protocol, ORR with 95% CI was 82.1% (69.6, 91.1) with T and 87.1% (76.1, 94.3) with R. Trough concentration (C5/C6) GMR (90% CI) of 91.3% (86.3, 96.7) for T & 94.0% (88.9, 99.5) for R indicated steady state. C6 AUC0-21d & Cmax GMR (T/R [90% CI]) were 88.9% (80.3, 98.5) and 94.6% (88.1, 101.7), respectively. T and R led to comparable B-cell depletion and repletion. Incidence of all grades of TEAEs were comparable. TEAEs ≥Grade 3 were 80.3% in T (n = 61) and 88.0% R (n = 66). Neutropenia was the most common TEAE (overall: T, 75.0%; R, 73.3% & ≥ grade 3: T, 64.5%; R, 64.0%). No neutralizing antibodies were observed in either of the arms. Conclusions: These data demonstrate that DRL-Rituximab has comparable PK, PD, efficacy, safety and immunogenicity to MabThera. MabThera already has an established efficacy in longer term follow-up. Clinical trial information: CTRI/2012/11/003129.