bluuebunny/crossref_metadata_2025 huggingface dataset:
CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL.
Authors: Gill Saar , Frey Noelle V. , Hexner Elizabeth O. , Lacey Simon F. , Melenhorst Jan Joseph , Byrd John C. , Metzger Susan , Marcus Taylor , Gladney Whitney , Marcucci Katherine , Hwang Wei-Ting , June Carl H. , Porter David L.
Published: September 2018

7509

Background: Immunotherapy with anti-CD19 CART cells induces complete remission (CR) in the minority of patients with CLL, but where CRs occur they tend to be durable. Based on preclinical evidence of synergy, we combined anti-CD19 CAR T cells with ibrutinib to test the hypothesis that pre- and concurrent treatment would enhance the CR rate. Methods: This is a pilot trial of anti-CD19 CAR T cells in adults with CLL/SLL who were not in CR despite at least 6 months of ibrutinib. Pts must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation. T cells were lentivirally transduced to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Pts were lymphodepleted 1 week before infusion. Ibrutinib was continued throughout the trial. Results: Manufacturing was successful in all pts. Ten pts (9M, 1F; ages 47-77; 0-12 regimens prior to ibrutinib) have been infused. All had abnormalities of TP53 or ATM and two pts had increasing BTK C481S clones. Median marrow CLL burden was 10% (range 10-50%). The median follow-up is 6 months (range 0.5-9). Cytokine release syndrome (CRS) developed in 9 pts; gr1 in 2, gr2 in 6 and gr3 in 1 pt. One pt developed gr4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required. At 3 months, 8 evaluable pts had achieved an MRD-ve marrow CR (89%) by 9-color flow, and all remain in marrow CR at last F/U. There was modest residual splenomegaly in 3/5 patients, and adenopathy resolved in 4/6 subjects with progression in 1/6. MRD assessment by deep sequencing will be presented. Conclusions: We observed 89% MRD-ve marrow CR in pts with high-risk CLL using a well-tolerated combination of CART cells and ibrutinib. Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy. Clinical trial information: NCT02640209.
L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.
Authors: Maddocks Kami J. , González Barca Eva , Jurczak Wojciech , Liberati Anna Marina , Duell Johannes , Nagy Zsolt , Papajík Tomáš , Andre Marc , Kalakonda Nagesh , Dreyling Martin H. , Zinzani Pier Luigi , Ambarkhane Sumeet Vijay , Weirather Johannes , Salles Gilles A.
Published: September 2018

7514

Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.
Updated results of single-agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).
Authors: Grommes Christian , Gavrilovic Igor T. , Kaley Thomas Joseph , Nolan Craig , Omuro Antonio Marcilio Padula , Wolfe Julia , Pentsova Elena , Hatzoglou Vaios , Mellinghoff Ingo K. , DeAngelis Lisa Marie
Published: September 2018

7515

Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326.
Preliminary results of a phase Ib study of GS-4059 in combination with entospletinib in patients with B-cell malignancies.
Authors: Fegan Christopher , Danilov Alexey Valeryevich , Hodson Daniel , Salles Gilles A. , Starodub Alexander , Mitra Siddhartha , Yang Yingsi , Walter Harriet , Morschhauser Franck
Published: September 2018

7518

Background: GS-4059 (ONO-4059) selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK) and entospletinib selectively inhibits spleen tyrosine kinase (SYK). Methods: This ongoing phase 1b study is evaluating the safety and tolerability of GS-4059 combined with entospletinib in patients with previously treated CLL, FL, SLL, MCL, MZL, WM, or non-GCB DLBCL. The study design uses 3+3 dose escalation (Table) withexpansion cohorts at potential phase 2 doses. Results: With a median duration of treatment of 22 weeks (range 3-56), 26/32 enrolled patients continue on treatment. The median age was 70 (43–85) years and 59% were men. Patients had the following diseases: CLL (n = 9), non-GCB DLBCL (7), FL (6), WM (5), MCL (2), SLL (2), and MZL (1). The median number of prior therapies was 2 (1–5). Five patients discontinued all study treatment, 4 due to disease progression (DLBCL x 2, MCL, MZL) and one due to withdrawal of consent. There has been 1 death on study due to progressive disease. The maximum tolerated dose was not reached. 90% of patients treated reported a treatment-emergent AE (TEAE) of which 48% were grade ≥3. Grade ≥3 TEAEs that were present in more than 1 patient were neutropenia (4), anemia, thrombocytopenia, pneumonia and AST/ALT elevation (2 each). The TEAEs present in >10% of patients were fatigue (7), petechiae (5), asthenia, constipation, contusion, dyspepsia, neutropenia and rash (4 each). No patients discontinued treatment due to AEs and all 5 patients with interruption of treatment for an AE successfully re-initiated therapy. 17 patients were evaluable for best overall response with the results as follows: 11 with partial responses (2 each with CLL, DLBCL, FL, SLL, WM, 1 with MCL); 4 with stable disease; 2 with progressive disease. Conclusions: GS-4059 at up to 160 mg in combination with entospletinib up to 400 mg daily was safe and well tolerated, supporting the continued clinical evaluation of the combination for the treatment of B-cell malignancies. Clinical trial information: NCT02457598 Clinical trial information: NCT02457598. [Table: see text]
Cytogenetic and fluorescence in situ hybridization testing in veterans with chronic lymphocytic leukemia.
Authors: Halwani Ahmad Sami , Burningham Zachary , Rasmussen Kelli Marie , Patil Vikas , Low Clarke Alan , Meissner Brian , Kapustyan Tatyana , Lawrence Nicole , Walker Jodi , Keim Holger , Sauer Brian C
Published: September 2018

7526

Background: The presence of deletion 17p (del17), determined by chromosome analysis and/or fluorescence in situ hybridization (FISH), is a strong negative prognostic marker in chronic lymphocytic leukemia (CLL). Prior to the introduction of novel agents (ibrutinib, venetoclax), the clinical utility of cytogenetics/FISH was limited by the absence of chemoimmunotherapy regimens that were proven effective in patients with del17. Testing practices for chromosomal aberrations since the introduction of novel agents have not been reported. We report cytogenetic/FISH trends in a nationwide cohort of veterans diagnosed with CLL. Methods: CLL patients diagnosed 2008-2015 and receiving care at VA were identified through the VA Clinical Cancer Registry. Electronic medical records were used to determine cytogenetic/FISH testing (lab records), treatment histories (pharmacy dispensation records), and evidence of system use (heme-onc notes). Cytogenetic/FISH testing was identified by presence of specific keywords in the test name or Logical Observation Identifiers Names and Codes (LOINC) descriptions, then validated by human annotation. The testing rates are reported for the entire cohort, at time of diagnosis, time of regimen initiation (including the 12 months preceding initiation), during the novel era (2014 – 2015) and prior (2008–2013). Results: From 2008 to 2015, 3,638 CLL patients were diagnosed and received care at VA. Documented records of treatment regimens were available for 1,562 patients who received a total of 2,929 treatment regimens. Only 24% (998) of patients were tested at any point in time during their care at the VA, 17% (622) were tested at time of diagnosis, and 19% (542) of treatment courses were preceded by cytogenetic/FISH testing. No testing differences existed following the introduction of the novel agents at diagnosis (both ~ 17%), or prior to regimen initiation (20% vs 16%). Conclusions: Our study suggests CLL patients diagnosed and receiving care at the VA are not routinely undergoing cytogenetics/FISH testing at diagnosis or prior to treatment. Changing this practice pattern will personalize treatments so that del17 CLL patients receive less toxic and more effective therapies.
Phase 2 trial of brentuximab vedotin and gemcitabine for pediatric and young adult patients with relapsed or refractory Hodgkin lymphoma (HL): A Children’s Oncology Group (COG) report.
Authors: Cole Peter D. , McCarten Kathleen , Metzger Monika , Drachtman Richard A. , Horton Terzah M. , Pei Qinglin , Bush Rizvan , Blaney Susan , Weigel Brenda , Kelly Kara M.
Published: September 2018

7527

Background: AHOD1221 (NCT01780662) tested Brentuximab vedotin (Bv) with gemcitabine (GEM) in children or young adults with HL. The primary objective was to describe the complete response (CR) rate within 4 cycles of therapy. Methods: Eligibility criteria included age ≤30 years; no prior Bv exposure; and primary refractory HL or advanced stage disease with early relapse. Each 21-day cycle consisted of Bv on day 1 at the recommended phase 2 dose (RP2D), 1.8 mg/kg and GEM 1000mg/m2 on days 1 and 8. Patients were evaluable for response if they completed 4 cycles of Bv+GEM, had a CR after 2 cycles, or progressive disease at any time. Response was assessed after even cycles, and confirmed by central review. CR was defined by FDG-PET negativity (Deauville 1-2) regardless of residual lesion size. Results: 42 patients were treated with Bv+GEM. Median age was 17.4 years (range 5.4-28.7), and 23 (55%) were female. The majority (n=35; 83%) had primary refractory disease or early relapse <6 months after completion of primary treatment. Common (>10%) adverse events included maculopapular rash (36% in cycle 1), neutropenia (33%) and elevated serum transaminases (21%). GCSF-stimulated peripheral blood stem cell (PBSC) collection was successful in all patients (n=23) for whom it was attempted, with median total collection of 9.4x106CD34+ cells/kg (range 3.5-36.8). 23 of 40 evaluable patients experienced a CR (58%; 95% CI 42-73%) within four cycles, and 6 had a partial response (PR), for an ORR of 73% (95% CI, 59-86%). For 4 patients with PR or stable disease, all target lesions were Deauville 3 or less after cycle 4, considered a CR by modern response criteria (Cheson et al. Blood 2016;128(21): 2489). Conclusions: Bv+GEM is a highly active combination for primary refractory or high-risk relapse of HL, with a CR rate exceeding that seen after either Bv (34%) or GEM (9%) alone. PBSCs can be collected successfully following Bv+GEM, making this an effective reinduction regimen when autologous stem cell transplantation is indicated. Compared to alternate retrieval regimens, Bv+GEM offers the advantage of avoiding agents associated with late treatment sequelae. Clinical trial information: NCT01780662.
Survival outcomes for various treatment modalities in advanced-stage grade 3 follicular lymphoma (FL3): A National Cancer Database (NCDB) study.
Authors: Giri Upama , Vick Eric , Lee Sophia SeoHyeon , Altahan Alaa , VanderWalde Noam Avraham , Dickson Paxton Vandiver , Deneve Jeremiah Lee , Martin Michael Gary
Published: September 2018

7554

Background: The prognosis, response to therapy and curability of FL3 is controversial. 5-year Overall Survival (OS) in the literature ranges from 35-72% (Ganti 2006). The aim of this study was to compare the OS for patients with advanced-stage FL3 managed with various treatment modalities. Methods: We identified patients (pts) diagnosed with stage III & IV FL3 between 2004 – 2012 from the NCDB and categorized them into 3 groups based on therapy – pts given single agent chemotherapy with or without radiotherapy were combined due to small sample sizes (SA±RT), multi agent chemotherapy without radiotherapy (MA-RT), and multi agent chemotherapy with radiotherapy (MA+RT). We calculated OS using Kaplan-Meier method and compared the results using Log Rank test. Cox regression model was used to identify other factors which had significant impact on OS. Results: 2,808 pts were identified – 1,508 (54%) with stage III and 1,300 (46%) with stage IV disease. Median age was 60 yrs (range 21-90yrs); 1,331 (47%) males, 1,477 (53%) females; 2,559 (91%) whites, 142 (5%) blacks. 170 cases (6%) were treated with SA±RT, 2,508 (89%) with MA-RT and 130 (5%) with MA+RT. There was no significant difference in 5-year OS between MA-RT (83%) and MA+RT (82%; HR 1.07, P=0.76). There was no difference between SA±RT (73%) and MA+RT (82%; HR 0.62, P=0.069) likely due to small sample sizes, but survival for MA-RT (83%) was significantly higher than SA±RT (73%; HR 1.78, p<0.001). Cox regression indicated that age (HR 1.04, P<0.001), sex (HR 0.77 for females, P=0.008), comorbidities (HR 1.48 for Charlson Deyo Score 1, P=0.001; HR 2.59 for Score 2, P<0.001), stage (HR 1.29, P=0.007), insurance status (HR 0.65 for insured, P=0.048) and increasing year of diagnosis (HR 0.91, P<0.001) also had significant impact on OS. Use of MA chemotherapy declined (2004 96% v 2012 91%, P=0.008) but there was no significant trend in use of radiotherapy (2004 5% v 2012 3%) during the periods studied. Conclusions: MA chemotherapy in pts with advanced-stage FL3 was associated with improved survival compared to SA therapy, and radiation does not appear to influence outcomes. Outcomes were superior to what has been previously reported.
Carfilzomib weekly-melphalan-prednisone in untreated elderly multiple myeloma: IFM2012-03.
Authors: Leleu Xavier , Fouquet Guillemette , Karlin Lionel , Kolb Brigitte , Tiab Mourad , Araujo Carla , Roussel Murielle , Bourquard Pascal , Lenain Pascal , Humbrecht-Kraut Catherine , Belhadj Karim , Petillon Marie-Odile , Chretien Marie-Lorraine , Rodon Philippe , Decaux Olivier , Jaccard Arnaud , Hulin Cyrille , Attal Michel , Moreau Philippe , Facon Thierry
Published: September 2018

8004

Background: Melphalan-prednisone-bortezomib (MPV) is a standard of care upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements on MPV’s safety profile, toxicity issues remain. Carfilzomib (K) is a novel generation proteasome inhibitor with a different safety profile from Bortezomib. Carmysap phase I/II study (twice a week Carfilzomib+MP) demonstrated K at 36mg/m² safe and active in eNDMM. We thought to study the K weekly-MP combination in eNDMM. Methods: IFM2012-03 is a multicenter phase I/II study in eNDMM (65 and older) aimed to determine the maximum tolerated dose (MTD) of K weekly. 4 cohorts of 6 patients each were recruited at K 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV of 35-days cycles, with oral Melphalan and Prednisone from days 1 to 4 at usual doses. Patients received a 9-cycles induction followed by a K monotherapy maintenance at 36 mg/m2 IV every 2 weeks for 1 year. 3 dose-limiting toxicities (DLTs) defined MTD at the lower N-1 dose. Results: 24 patients were included at K 36, 45, 56 and 70 mg/m². One DLT occurred at 36 mg/m² (grade 4 lymphopenia), one at 45 mg/m² (tumor lysis syndrome with grade 4 renal insufficiency), two at 56 mg/m² (grade 3 cardiac insufficiency and grade 3 febrile neutropenia) and two at 70 mg/m² (grade 3 nausea/vomiting and grade 3 hepatic cytolysis). One patient died from cardiac dysfunction considered related to K at 56 mg/m². 3 patients stopped therapy and 3 others required dose reduction of K. Following DSMB’s request a second 6-patients cohort was recruited at 70 mg/m², with increased attention around hyperhydration and monitoring HTA. We observed no DLT and no grade 3/4 adverse event in this cohort. Median age was 75 years, 56% patients were R-ISS 2 or 3. For the whole cohort (N=30), the overall response rate was 87% including 67% very good partial responses and 44% complete responses. Conclusions: The MTD of weekly K in the KMP combination is 70 mg/m² upfront for eNDMM, but it seems reasonable to recommend 56mg/m² after 75 years-old for safety reasons. KMP offers high response rates and possibly greater CR rate. However, since the CLARION study (VMP vs KMP) will not allow KMP’s approval in eNDMM in Europe, IFM decided to stop IFM2012-03 after phase I without performing phase II. Clinical trial information: NCT02302495.
Minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) in newly diagnosed transplant eligible multiple myeloma (MM) patients: Results from the EMN02/HO95 phase 3 trial.
Authors: Oliva Stefania , Hofste op Bruinink Davine , ŘÍhová Lucie , Spada Stefano , van der Holt Bronno , Troia Rossella , Gambella Manuela , Pantani Lucia , Grammatico Sara , Gilestro Milena , Offidani Massimo , Ribolla Rossella , Galli Monica , Hajek Roman , Palumbo Antonio , Cavo Michele , Omedè Paola , van der Velden Vincent , Boccadoro Mario , Sonneveld Pieter
Published: September 2018

8011

Background: MRD detection is a sensitive tool to measure response in MM. We assessed MRD by MFC in newly diagnosed MM patients (pts) enrolled in the EMN02/HO95 phase 3 trial. Methods: Pts were ≤65 years old and received Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction, intensification with Bortezomib-Melphalan-Prednisone (VMP) vs High-Dose-Melphalan (HDM) followed by stem cell transplant, consolidation with Bortezomib-Lenalidomide-Dexamethasone (VRD) vs no consolidation, and Lenalidomide maintenance. MRD analysis was performed in pts achieving at least a very good partial response (VGPR) before starting maintenance (after HDM, VMP or VRD) and during maintenance every 6-12 months; samples were centralized to 3 European labs. MFC was performed on bone marrow according to Euroflow-based methods (8 colors, 2 tubes) with a sensitivity of 10-5. Quality checks were performed to compare sensitivity and to show correlation between protocols (Hofste op Bruinink D ASH 2016 abstract 2072). Results: 316 pts were evaluable before maintenance: median age was 57 years, 18% (57/316) pts had ISS III and 22% (70/316) had high risk cytogenetic (HR-C) defined as having at least one among del17, t(4;14) or t(14;16); 63% (199/316) had received HDM and 37% (117/316) VMP; thereafter 51% (160/316) had received VRD. 76% (239/316) were MRD negative (MRD-) of whom 64% (153/239) received HDM vs 36% (86/239) VMP, with a median follow-up time of 30 months from MRD enrolment. 3-year PFS was 50% in MRD positive (MRD+) vs 77% in MRD- pts (HR: 2.87, p < 0.001). Subgroup analyses were performed to evaluate the risk factors for MRD+ according to baseline characteristics and therapies: HR-C was the most important risk factor (HR 9.87, interaction-p = 0.001). Finally, 48% of MRD+ pts at pre-maintenance who had a second MRD evaluation after at least 1 year of lenalidomide became MRD-. Conclusions: MRD by MFC is a strong prognostic factor in MM pts receiving intensification with novel agents or transplant; lenalidomide maintenance further improved depth of response; HR-C is the most important prognostic factor in MRD+ pts. Clinical trial information: NCT01208766.
Evaluation of an oral direct anti-Xa anticoagulant, apixaban, for the prevention of venous thromboembolism in patients with myeloma treated with IMiD* compounds: A pilot study (MYELAXAT).
Authors: Pegourie Brigitte , Pernod Gilles , Karlin Lionel , Benboubker Lofti , Orsini Frederique , Tiab Mourad , Auger-Quittet Sophie , Rodon Philippe , Royer Bruno , Leleu Xavier , Bareau Benoit , Cliquennois Manuel , Fuzibet Jean-Gabriel , Voog Eric , Belhadj Karim , Decaux Olivier , Rey Philippe , Slama Borhane ,   IFM Group
Published: September 2018

8019

Background: The risk of venous thromboembolism (VTE) is higher in myeloma patients recieving IMiD* compounds (IMiD*: registered). A VTE prophylaxis using low-molecular-weight heparin or aspirin is proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficiency and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with IMiD* compounds, using apixaban in a preventive scheme. Methods: Myeloma patients requiring Melphalan-Prednisone-Thalidomide in first line, or Lenalidomide-Dexamethasone in relapse, asymptomatic regarding VTE at inclusion, were enrolled between 2014 - 2016. All patients recieved apixaban, 2.5 mg x 2/day for 6 months, and were monthly monitored. Venous (pulmonary embolism – PE, or symptomatic proximal or distal deep vein thrombosis - DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. Based on meta-analysis of Carrier regarding VTE recurrence, and results from the ADOPT study in medical conditions regarding hemorrhages, < 13 symptomatic VTE events, < 3 severe and < 14 clinically relevant non major (CRNM) bleeding were expected on the treatment period. Results: 104 patients were enrolled (mean age 69.8 +/- 7.8yrs), 11 in first line, 93 in relapse. No PE or arterial cardiovascular events were reported. Two venous thrombotic events were registered, i.e an asymptomatic proximal DVT (patient in relapse) and a symptomatic distal DVT, although apixaban was stopped 14 days before, due to Lenalidomide-induced thrombopenia. Only one major and 11 CRNM hemorrhages were reported. Conclusions: Referring to the incidence of thromboembolic events in Carrier’s meta-analysis, and to hemorrhagic events in medical patients recieving apixaban in primary VTE prophylaxis, apixaban used in a preventive scheme seems to be efficient and safe in preventing VTE in myeloma patients treated with IMiD* compounds. Clinical trial information: NCT02066454.
Acupuncture for symptom reduction in myeloma patients undergoing hematopoietic stem cell transplantation: A randomized, sham-controlled trial.
Authors: Deng Gary E. , Giralt Sergio , Chung David J. , Landau Heather Jolie , Siman Jonathan , Search Benjamin , Coleton Marci , Vertosick Emily , Shapiro Nathan , Chien Christine , Wang Xin Shelley , Cassileth Barrie R. , Mao Jun J.
Published: September 2018

8021

Background: Hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for a number of hematologic malignancies, but is associated with a high symptom burden for patients. We conducted a randomized sham-controlled trial to evaluate the preliminary efficacy and safety of acupuncture as an integrative treatment for managing common symptoms during HCT. Methods: Adult patients with multiple myeloma undergoing high dose melphalan followed by autologous peripheral blood HCT were randomized to receive either true or sham acupuncture once daily for five days starting on the day after chemotherapy. Symptom burden was assessed with the MD Anderson Symptom Inventory (MDASI) at baseline, during transplantation, and at 15 and 30 days after transplantation. Results: Among 60 participants, symptoms that are significantly reduced by true acupuncture more than sham acupuncture at 15 days include the following: nausea, lack of appetite, and drowsiness (p = 0.042, 0.025, and 0.010, respectively). Patients receiving sham acupuncture were more likely to increase use of pain medication post-transplantation (odds ratio 5.31, p = 0.017). Acupuncture was well tolerated with few attributable adverse events. Conclusions: True acupuncture may prevent escalation of symptoms including nausea, lack of appetite, and drowsiness experienced by patients undergoing autologous HCT, and to reduce the use of pain medications. These findings need to be confirmed in a future definitive study. Clinical trial information: NCT01811862.
Pomalidomide (POM) + low-dose dexamethasone (LoDEX) after lenalidomide (LEN)-based second-line (2L) treatment (Tx) in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): Analysis of progression-free survival (PFS) by level of disease control.
Authors: Siegel David , Schiller Gary J. , Song Kevin W. , Agajanian Richy , Stockerl-Goldstein Keith , Kaya Hakan , Sebag Michael , Reu Frederic J. , Malek Ehsan , Talamo Giampaolo , Mouro Jorge L , Chung Weiyuan , Srinivasan Shankar , Qian Max , Rizvi Syed , Thakurta Anjan , Bahlis Nizar J.
Published: September 2018

8027

Background: Recent trials of triple therapy in 2L and third-line (3L) Tx excluded pts refractory to LEN. This is not reflective of standard of care in first line and 2L where LEN is given until progressive disease (PD). MM-014 enrolled pts with RRMM and 2L LEN-based Tx failure. Here we report results only from cohort A of pts receiving POM + LoDEX. Cohort B will investigate POM + LoDEX + daratumumab. Methods: Adult pts with MM, 2 prior Tx lines, and PD after ≥ 2 cycles of 2L LEN-based Tx received POM + LoDEX. The primary endpoint was overall response rate (ORR). Other endpoints included time to response (TTR), PFS, second primary malignancies (SPMs), and biomarkers. Results: Of 51 pts in cohort A, 39 (76.5%) discontinued Tx. Most pts (88.2%) were refractory to their last LEN Tx, (median Tx duration 24.6 mos) and 72.5% had prior bortezomib. At a median follow-up of 13.6 mos, ORR was 29.4% (2.0% complete response, 9.8% very good partial response, and 17.6% partial response [PR]) and median TTR was 1.9 mos; 66% of pts had ongoing response at 1 yr. Minimal response [MR] was reached in 15.7%. Median PFS was 13.8 mos. Pts with ≥ MR had similar Tx durations as those achieving ≥ PR. Additional results in Table. Post-Tx T-cell populations were significantly higher vs baseline (CD3+, 72.6% vs 67.8%; CD3+/CD8+, 36.9% vs 32.1%). Relative changes from baseline were significantly greater in pts with response vs pts with no response (CD3+, 10.4 vs −0.8; CD3+/CD4+, 4.2 vs −3.5). Conclusions: This update confirms the safety and efficacy of POM + LoDEX following 2L LEN-based Tx failure in pts with RRMM. Hematologic adverse event (AE) rates improved and median PFS was longer with 3L use than previously reported with POM + LoDEX use in later Tx lines. In addition, achieving disease control of ≥ MR led to similar PFS rates as reaching ≥ PR. Clinical trial information: NCT01946477. [Table: see text]
Safety and efficacy of daratumumab-based regimens in elderly (≥75 y) patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Subgroup analysis of POLLUX and CASTOR.
Authors: Mateos Maria-Victoria , Spencer Andrew , Nooka Ajay K. , Pour Ludek , Weisel Katja C. , Cavo Michele , Laubach Jacob , Cook Gordon , Iida Shinsuke , Benboubker Lotfi , Usmani Saad Zafar , Yoon Sung-Soo , Bahlis Nizar J. , Chiu Christopher , Schecter Jordan Mark , Wu Kaida , Qin Xiang , Soong David , Dimopoulos Meletios A.
Published: September 2018

8033

Background: Daratumumab (D) plus lenalidomide and dexamethasone (Rd; POLLUX) or with bortezomib and dexamethasone (Vd; CASTOR) demonstrated prolonged PFS and tolerability compared with Rd and Vd alone, respectively, in RRMM pts. We examined the safety and efficacy profiles of DRd and DVd in elderly (≥75 y) pts from these phase 3 studies. Methods: Pts with ≥1 prior line of therapy were enrolled. All pts in POLLUX were treated until progression; CASTOR pts received 8 cycles of Vd ± daratumumab. Different D (16 mg/kg) dosing schedules were used in POLLUX (qw for cycles 1-2, q2w for cycles 3-6, and q4w thereafter) and CASTOR (qw in Cycles 1-3, q3w for Cycles 4-8, and q4w thereafter). Elderly pts received a reduced dexamethasone dose (20 mg once weekly). Results: In POLLUX, 29/286 (DRd) and 35/283 (Rd) were ≥75 y, with 86% and 91% having ECOG status ≤1, respectively. With 17.3 months of median follow up, 10% in DRd and 11% in Rd discontinued due to treatment-emergent adverse events (TEAEs). Common (>10%) grade 3/4 TEAEs for DRd included neutropenia and hypokalemia (Table). Twelve (41%) DRd pts experienced infusion-related reactions (IRR) and 4 (14%) experienced grade 3/4 IRR; none discontinued due to IRR. Median PFS was not reached (NR) in DRd vs 11.4 months in Rd (HR 0.19; 95% CI, 0.06-0.55; P=0.0007), and ≥CR % was significantly higher with DRd vs Rd (52% vs 9%; P=0.0002). In CASTOR, 23/251 (DVd) and 35/247 (Vd) were ≥75 y, with 100% and 94% having ECOG status ≤1, respectively. With 13.0 months of median follow up, rates of discontinuation due to TEAEs were similar (15% vs 20%). Thrombocytopenia, fatigue, and pneumonia were common grade 3/4 TEAEs for DVd (Table). Thirteen (65%) pts reported IRR (10% grade 3/4) and no pts discontinued due to IRR. Median PFS was NR in DVd vs 8.1 months in Vd (HR 0.27; 95% CI, 0.12-0.61; P=0.0007), and significantly higher ≥CR % was observed in DVd vs Vd (25% vs 3%; P=0.0154). Conclusions: The safety and efficacy profiles in elderly pts were generally comparable with the overall population in each study. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]
Safety and feasibility of consolidation pembrolizumab following concurrent chemoradiation for unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN14-179.
Authors: Durm Greg Andrew , Johnson Cynthia , Jalal Shadia Ibrahim , Sadiq Ahad Ali , Jabbour Salma , Zon Robin , Kloecker Goetz H. , Reckamp Karen L. , Fisher William B. , Hanna Nasser H.
Published: September 2018

8523

Background: The standard of care for unresectable stage III NSCLC is concurrent chemorad. Following treatment, the risk of radiation pneumonitis is greatest at 1-3 mo. Pneumonitis risk increases with consolidation chemotherapy. A previous trial by our group (Hanna et al, JCO 2008) of consolidation docetaxel showed 80.8% completed 3 planned cycles of chemo with a grade 3-5 pneumonitis rate of 9.6% and 1 death. PD-1 inhibitors are also associated with an increased risk of pneumonitis in the metastatic setting. We conducted a phase II trial of consolidation pembro initiated 1-2 mo after concurrent chemorad, a period during which pts are at high risk of developing pneumonitis. Methods: Pts with stage III NSCLC who completed chemorad with either carbo/paclitaxel, cis/etop, or cis/pemetrexed plus 59-66.6 Gy of radiation and had no PD received pembro 200mg IV q3wk for up to 1 yr. Primary endpoint is time to metastatic disease. The objective of the study is to evaluate both safety and efficacy, and here we report preliminary safety and feasibility results. Evaluable pts for this analysis had ≥3 mo of f/u or went off study due to PD, toxicity, or death < 3 mos after initiation of pembro. Results: 93 pts enrolled. Median age 67 (range 46-84), 59 (63.4%) were male. 87 (93.5%) were former or current smokers. 68 (73.1%) received carbo/pac, 24 (25.8%) received cis/etop, and 1 received cis/pemetrexed. SqCC (n = 41), non-SqCC (n = 43), NSCLC NOS (n = 8), mixed (n = 1). IIIA (n = 56), IIIB (n = 37). At the time of analysis, 83 of 93 pts were evaluable. 66 of 83 (79.5%) received ≥ 3 mo of pembro. 17 (20.5%) pts developed any grade pneumonitis with 14 of 17 occurring in the first 12 wks (median 9 wks). Only 3 (3.6%) pts developed grade 3-5 pneumonitis related to pembro. There was 1 pneumonitis-related death and a second death from respiratory failure possibly related to pembro. Conclusions: This early report indicates that most patients can safely receive consolidation pembro within 1-2 mo of completing chemorad. The incidence of serious pneumonitis during the first 3 mo of treatment appears low. Updated safety data on all 93 pts will be presented at the ASCO meeting. Clinical trial information: NCT02343952.
A multicenter, randomized, open-label, phase II trial of erlotinib versus etoposide plus cisplatin with concurrent radiotherapy in unresectable stage III non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutation.
Authors: Xing Ligang , Wu Gang , Wang Lvhua , Li Jian-Cheng , Wang Jianhua , Yuan Zhiyong , Chen Ming , Xu Yaping , Zhu Zhengfei , Lu You , Han Chun , Xia Tingyi , Xie Conghua , Li Guang , Yu Jinming
Published: September 2018

8531

Background: Concurrent chemoradiotherapy is the standard treatment for patients(pts) with unresectable stage IIIA/IIIB NSCLC. In EGFR mutant pts, tyrosine kinase inhibitor(TKI) exhibits clinical benefits over chemotherapy regimens in terms of efficacy and safety as well as specific enhancement of radiation effects. This multicenter, randomized, open-label, phase II trial aimed to compare the erlotinib and etoposide/cisplatin with concurrent radiotherapy (RT) in pts with EGFR-mutant. Methods: Histopathology/cytology confirmed stage IIIA/B unresectable NSCLC pts (age 18-75) with ECOG PS 0-1 and EGFR exon 19 or 21 mutation were included and randomized (1:1) into two arms: erlotinib (E) and etoposide/cisplatin (EP). E arm was treated with oral erlotinib (150mg/day for 2 years or till either disease progression or intolerable toxicities) and RT (200cGy/day, 5 days/week for 6 weeks from first day erlotinib). EP arm was treated with sequential etoposide (50 mg/m2 IV days 1-5, 29-33) and cisplatin (50mg/m2IV day 1,8, 29,36) and RT (from first day drug). Primary endpoint is progress free survival (PFS). Secondary endpoints are objective response rate(ORR), local control rate(LCR), overall survival(OS), quality of life(QoL) and safety. Results: 252 pts were screened, and 41 were enrolled into E(n=20) and EP(n=21) arms. Characteristics of age, sex, histologic type, N2, EGFR 19 and 21 mutation were well balanced in each arm. Comparing with EP, median PFS of E arm was significantly improved (27.86 vs 6.41 months; HR 0.053, 95% CI: 0.006-0.463; P<0.001). ORR and DCR were 60.0% vs. 38.1%( P=0.217), and 65% vs. 47.6%( P=0.350), respectively. Two arms had same incidence of adverse effects (CTCAE Grade≥1, 86.7%[13/15]), and most common sAE(Grade≥3) was rash (20%, 3/15) and hematological toxicity(26.7%, 4/15), respectively. Conclusions: In unresectable stage III EGFR mutant NSCLC pts, concurrent erlotinib/RT provides a statistically significant PFS improvement with well tolerability. These results warrant a phase III study to confirm. (RECEL, NCT01714908). Clinical trial information: NCT01714908.
Risk factors associated with brain metastases in ECOG-ACRIN E1505, a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely resected stage IB (>/= 4 cm) - IIIA non-small cell lung cancer (NSCLC).
Authors: Varlotto John M. , Dahlberg Suzanne Eleanor , Wakelee Heather A. , Ramalingam Suresh S. , Schiller Joan H.
Published: September 2018

8539

Background: ECOG-ACRIN E1505 was a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely-resected Stage IB (>4CM) – IIIA non-small cell lung cancer. Prior studies have shown that the risk of brain recurrence in patients after definitive surgical resection is approximately 10%; however, covariates associated with development of brain recurrence have varied across these studies. We sought to estimate the incidence of and risk factors for brain recurrence. Methods: Among the 1501 patients enrolled to ECOG-ACRIN E1505, 121 patients developed brain metastases as their first site of recurrence and are the subject of this investigation. All 1501 patients underwent a pneumonectomy (N = 192) or (bi)lobectomy and had an R0 resection. The cumulative incidence of brain recurrence was estimated after adjusting for recurrence at other sites and death as competing events. A multivariable regression model was fitted using the methodology of Fine and Gray to evaluate the effect of covariates on the subdistribution of brain recurrence. Results: With a median follow-up of 50.3 months, a total of 121 brain metastases had been reported as the first site of recurrence. The incidence of brain recurrence at 12 months post-randomization was 3.7% (95% CI: 2.8% – 4.7%), and it increased to 8.5% (95% CI: 7.0% - 10.0%) at 3 years, and to 9.9% (95% CI: 8.0% - 11.7%) at 6 years. Risk factors for brain metastases included pneumonectomy(HR=1.8; p=0.01), and nonsquamous histology(HR=2.04; p=0.003), but bevacizumab(HR=0.64; p=0.02) was associated with potentially protective effect. Conclusions: The cumulative incidence of brain recurrence increased over time to 9.9% at 6 years in this population of patients with surgically-resected non-small cell lung cancer. Treatment, tumor histology, and type of resection appear to be associated with the risk of brain recurrence. Clinical trial information: NCT00324805.
Tolerability of veliparib (V) in combination with carboplatin (C)/paclitaxel (P): Based chemoradiotherapy (CRT) in subjects with stage III non-small cell lung cancer (NSCLC).
Authors: Kozono David E. , Salama Joseph Kamel , Stinchcombe Tom , Bogart Jeffrey , Petty William J. , Guarino Michael J. , Bazhenova Lyudmila , Larner James Mitchell , Weiss Jared , DiPetrillo Thomas A. , Feigenberg Steven J. , Xu Tu , Hu Beibei , Nuthalapati Silpa , Rosenwinkel Lindsey , Bensman Lindsey , Johnson Eric Feral , McKee Mark D. , Vokes Everett E.
Published: September 2018

8546

Background: CRT is a standard for patients with Stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A Phase 2 study indicated favorable efficacy of V vs placebo when added to C/P in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a Phase 1/2 trial was initiated to study the safety and efficacy of V/C/P-based CRT in the treatment of Stage III NSCLC. Methods: Subjects without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m2 weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with allowed over-enrollment followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m2 for up to two 21-day cycles. Results: Thirty-one subjects (median age 64; 10 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7) and 200 mg (8). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 subject, respectively. Four (13%) subjects discontinued study during CRT. No DLTs have been observed and an MTD has not yet been identified. The most common any grade AEs were fatigue (16), esophagitis (15), nausea (13), neutropenia (12), thrombocytopenia (12), constipation (10) and decreased appetite (10). 21 SAEs were observed including 8 with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1) and G5 sepsis during consolidation (1). Of 21 subjects evaluable for tumor assessment, best response was CR (1), PR (11), SD (6), and PD (3). Conclusions: V/C/P-based CRT followed by V/C/P consolidation therapy is a tractable regimen for the treatment of Stage III NSCLC. A randomized placebo-controlled Phase 2 extension of this study is planned. Clinical trial information: NCT02412371.
Prognostic impact of PD-L1 expression in correlation with HLA class I expression status in stage I adenocarcinoma of the lung.
Authors: Yoneda Kazue , Hirai Ayako , Shimajiri Shohei , Hanagiri Takeshi , Tanaka Fumihiro
Published: September 2018

8548

Background: Programmed death-ligand 1 (PD-L1) and human leukocyte antigen (HLA) class-I, expressed on tumor cells (TCs), are important regulators in cancer immunity. The current study was conducted to assess prognostic impact of PD-L1 status in correlation with HLA class-I status in lung adenocarcinoma. Methods: A total of 94 patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. PD-L1 expression on TCs was evaluated with immunohistochemistry, in correlation with several clinicopathological and molecular features including HLA class-I expression on tumor TCs. Results: Seventeen patients (18.1%) had tumor with positive PD-L1 expression (percentage of TCs expressing PD-L1, ≥ 5%), and the incidence was higher in smokers with higher smoking index and in poorly differentiated tumor. There was no significant correlation between HLA class-I expression and PD-L1 expression. PD-L1-positivity was a significant factor to predict a poor survival (5-year survival rate, 66.7% versus 85.9%; P = 0.048), which was enhanced in tumor with normal HLA class-I expression (p = 0.029) but disappeared in tumor with reduced HLA class-I expression. Conclusions: The prognostic impact of PD-L1 expression on TCs in early-stage resectable lung adenocarcinoma was distinct according to HLA class-I expression on TCs.
Differential expression of immune inhibitory markers in association with HLA class I and the immune microenvironment in resected lung adenocarcinomas.
Authors: Zhang Mingjuan Lisa , Kem Marina , Mooradian Meghan , Eliane Jean-Pierre , Huynh Tiffany , Iafrate A. John , Gainor Justin F. , Mino-Kenudson Mari
Published: September 2018

8551

Background: Similar to programed death ligand 1 (PD-L1), indoleamine 2,3-Dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well-studied in lung adenocarcinoma (ADC). Methods: PD-L1 and IDO1 expression were evaluated in 261 resected ADC using tissue microarrays and H-scores (cutoff 5). We compared IDO1 with PD-L1 expression in association with clinical features, tumor-infiltrating lymphocytes (TILs), HLA class I (β-2 microglobulin; B2M) expression, molecular alterations, and patient outcomes. Results: There was expression of PD-L1 in 89 (34.1%) and IDO1 in 74 (28.5%) cases, with co-expression in 49 (18.8%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) TILs. PD-L1 expression and abundant CD8+ were inversely associated with a loss of B2M membranous expression (p = 0.0019 and p < 0.001, respectively). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ TILs (p < 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p < 0.001) and KRAS mutants (p = 0.021), whereas there was no difference in IDO1 expression between different molecular alterations. As for survival, PD-L1 was significantly associated with decreased progression-free (PFS) and overall survival (OS), while IDO1 was associated only with decreased OS. Interestingly, there was a significant difference in the 5-year PFS and OS (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. Conclusions: While PD-L1 +/- IDO1 expression is observed in association with B2M expression, CTL/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in ADC. Thus, blockade of IDO1 may represent an alternative and/or complementary therapeutic strategy to reactivate anti-tumor immunity.