bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of secondary malignancies (SM) in patients with large granular lymphocytic leukemia (LGLL): A single institutional experience.
Authors: Isenalumhe Leidy Lismeri , Van den Bergh Magali , Wang Emilie , Schaible Braydon , Ma Zhenjun , Zhang Ling , Sokol Lubomir
Published: September 2018

7542

Background: Large granular lymphocyte (LGL) disorders represent a spectrum of aberrant T-cell or natural killer cell lymphocytic proliferations. LGLL is classically associated with autoimmune conditions and bone marrow (BM) failure disorders. SM has been reported in association with LGLL in about 10%. The aim of this study is to evaluate the impact of SM on the clinical course of LGLL. Methods: This is a retrospective study of LGLL patients (pts) evaluated at Moffitt Cancer Center between January 1995 and May 2016. The diagnostic clinico-pathological criteria consisted of LGL count > 0.5 k/μL with T-cell receptor gene rearrangement. Lower absolute number of clonal circulating LGLs with characteristic immunophenotype associated with BM involvement, cytopenias, splenomegaly and/or associated symptoms were also diagnostic. Pts with myelodysplastic syndrome were excluded. Survival analysis was performed using the Kaplan-Meier method with log-rank test. Chi-square and T-test were used to analyze association among various variables. Significant P-value was considered < 0.05. Results: Out of 668 screened pts with LGL expansions in peripheral blood, 261 met criteria for LGLL. SM were present in 44% (116/261) of LGLL pts, of which 38% were hematological and 80% arose prior to onset of LGLL. Most common solid SM included skin cancer (14%), prostate cancer (12%), and breast cancer (12%), while most common hematological SM consisted of non-Hodgkin lymphoma (17%) and chronic leukemia (14%). 5-year overall survival (OS) for all LGLL pts was 75% and 10-year OS 63%. There was a statistically significant difference in 5-year OS between LGLL pts with SM compared to without (p = 0.049), but no difference between both groups in median OS or 10-year OS. Pts diagnosed with SM prior to LGLL had worse 5-year OS (p = 0.031) and 10-year OS (p = 0.05) compared to all other LGLL pts. Conclusions: This study showed that the frequency of SM is higher than previously described, especially with onset prior to diagnosis of LGLL. Even though median age of LGLL is around 60 years, it appears that age itself cannot explain this phenomenon. Our results suggest that having a SM is a poor prognostic factor in LGLL patients.
Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).
Authors: Batlevi Connie Lee , Hamlin Paul A. , Matasar Matthew J. , Horwitz Steven M. , Gerecitano John F. , Moskowitz Craig H. , Straus David J. , Zelenetz Andrew David , Drullinsky Pamela , Copeland Amanda , Ahsanuddin Salma , Callan Devin , Freidin Benjamin , Porzio Robert , Dang Thu Oanh , Ni Ai , Rademaker Jurgen , Schöder Heiko , Dogan Ahmet , Younes Anas
Published: September 2018

7544

Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]
Rapid, real-time central pathology review for E1412: A novel and successful paradigm for future National Clinical Trials Network diffuse large B cell lymphoma studies.
Authors: King Rebecca L. , Nowakowski Grzegorz S. , Witzig Thomas E. , Scott David W. , Little Richard F. , Hong Fangxin , Gascoyne Randy D. , Kahl Brad S. , Macon William R
Published: September 2018

7547

Background: E1412 statistical design is based on results of lenalidomide/RCHOP (R2CHOP) vs RCHOP in ABC-DLBCL as determined by NanoString gene expression profiling (GEP). Central pathology review (CPR) was conducted to confirm diagnosis and to ensure adequate tissue for GEP. Initially, CPR occurred after randomization and treatment initiation. Due to high ineligibility rate (IR), the protocol was amended to include real-time CPR to determine patient eligibility prior to study enrollment. We describe the revision and how it affected the IR. Methods: Pre-amendment, CPR was done retrospectively. Post-amendment, CPR was done prior to enrollment, in real time, on a submitted tissue block, H&E, and CD20 slides. Based on CPR, if a diagnosis of DLBCL was confirmed, and sufficient tissue remained for GEP, a patient was deemed eligible and the submitter was notified by fax. Protocol goal was notification within 2 working days (WD) of receipt of materials at the CPR site. Results: Pre-amendment, 219 patients were enrolled. Material was typically received at the CPR site 6-9 months after patient registration. The IR with CPR was 36% for all those enrolled, and 26% for patients with adequate tissue for GEP. Post-amendment, 218 patients were submitted for CPR: 145 (67%) were eligible; 73 (33%) were ineligible. Reasons for ineligibility included insufficient tissue (n=27) or a diagnosis other than de novo DLBCL (n=46). Notification of eligibility occurred in a median of 2 WD (Mean 2 WD; Range 1-5 WD). 90% were notified within the protocol goal of 2 WD. GEP for all enrolled was completed within 6 weeks of CPR. Conclusions: The success of this novel, real-time CPR serves as a model for the future of NCTN DLBCL trials. When CPR is performed rapidly prior to enrollment, study slots may more accurately reflect the target population and eliminate excess costs. In the precision medicine era, rapid collection of relevant pathology and biomarker data is essential to trial success. Study Coordinated by ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs), supported by NCI grant # CA180820, CA180794, CA180790, CA180799, CA180833.
Survival outcomes for various treatment modalities in early-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

7551

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 early-stage FL3 managed with single- and multi-agent chemotherapy (CT) with and without radiotherapy (RT). Methods: We identified patients (pts) diagnosed with stage I & II FL3 between 2004 – 2012 from the NCDB and categorized into 3 groups based on therapy – pts given single agent CT with or without RT were combined due to small sample sizes (SA±RT), multi-agent CT without RT (MA-RT), and multi-agent CT with RT (MA+RT). We calculated OS for each group using Kaplan-Meier method and compared the results using Log Rank test. Cox regression model was used to identify factors which had significant impact on OS. Results: 1,563 pts were identified – 827 (53%) with stage I and 736 (47%) with stage II FL3. Median age was 61 yrs (range 18-90yrs); 750 (48%) males, 813 (52%) females; 1423 (91%) whites, 76 (5%) blacks. 112 (7%) received SA±RT, 886 (57%) MA-RT and 565 (37%) MA+RT. 5-year OS for MA+RT (95%) was significantly more than MA-RT (87%; HR 0.33, P<0.001) or SA±RT (88%; HR 0.38, P=0.007). Cox regression indicated that age (HR 1.05, P<0.001), sex (HR 0.66 for females, P=0.02), comorbidities (HR 1.60 for Charlson Deyo Score 1, P=0.04; HR 3.07 for Score 2, P=0.001), stage (HR 1.79, P=0.001), insurance status (HR 0.22 for insured, P<0.001) and increasing year of diagnosis (HR 0.92, P=0.03) also had significant impact on OS. Median radiation dose for the MA+RT was 36Gy (interquartile range 30.6 – 36Gy), and the proportion of patients who received greater than 36Gy decreased from 55% in 2004 to 38% in 2012 and at the same time, the proportion of patients who received intensity modulated RT increased from 5% in 2004 to 15% in 2012. Use of MA CT declined (2004 95% v 2012 89%, P=0.02) but there was no significant trend in use of RT (2004 39% v 2012 34%) during the periods studied. Conclusions: For pts with early-stage FL3, there was an association of improved survival with the use of MA+RT over other treatment strategies and appear to have outcomes superior to what has been previously reported.
Response status as predictor of survival after autologous hematopoietic cell transplant (AHCT), without or with consolidation (with bortezomib, lenalidomide (Len) and dexamethasone) and len maintenance (AM vs. ACM) versus tandem AHCT and len maintenance (TAM) for up-front treatment of patients (pts) with multiple myeloma (MM): BMT CTN0702-stamina (NCT01109004).
Authors: Somlo George , Pasquini Marcelo C. , Blackwell Beth , Devine Steven Michael , Ganguly Siddhartha , Efebera Yvonne , Giralt Sergio , Hari Parameswaran , Koreth John , Landau Heather Jolie , McClune Brian L. , Quazilbash Mussafar , McCarthy Philip L. , Shah Nina , Vesole David H. , Vij Ravi , Vogl Dan T. , Krishnan Amrita Y. , Stadtmauer Edward A. , Geller Nancy
Published: September 2018

8010

Background: The Stamina trial primarily aimed to identify the best strategy among AM, ACM, and TAM, leading to longer PFS (LBA-1, ASH, 2016). Here we report on interim, exploratory results of the association between PFS and overall survival (OS) and baseline MM response, risk category, and treatments (Rx). Methods: Pts with MM, < 71 years, < 12 mos from diagnosis were randomized to melphalan 200mg/m2(mel) and AHCT (AM), tandem mel AHCT (TAM), or mel AHCT and 4 cycles of RVD ((ACM). Pts received Len till progression. Pts were stratified by high risk vs. standard ( del13q, del17q, t(4;14), t(14;16), t(14;20) and hypodyploid; high β2 microglobulin). Kaplan Meier estimates of PFS and OS were performed as a function of Rx and ≥ very good partial response (VPGR including CRs) vs. < VGPR. Cox proportional hazard models explored associations between PFS or OS and risk category, Rx, and ≥ VPGR vs. < VGPR. Results: Between 6/2010-11/2013, 758 pts (AM, N = 257; ACM, N = 254; TAM, N = 247) aged 20-70 years (median 57y) were enrolled (24% high-risk). Baseline ≥VGPR responses were 45.5- 49.8%. PFS at 38 months was similar. For < VGPR, 38-mos PFS with TAM:55.8% (95%CI: 45.8%, 64.7%); ACM: 54.0% (44.7%, 62.5%); AM: 50.1% (40.6%, 58.9%); For ≥VGPR, 38-mos PFS with TAM: 57.1% (46.8%, 66.1%); ACM: 60.1% (50.1%, 68.7%); AM: 55.1% (45.1%, 64.0%). Analyzing response, risk category, and Rx revealed no association between baseline response and PFS (Baseline response < VGPR, hazard ratio (HR): 1.21,95% CI: 0.97-1.52) or OS (baseline response < VGPR, HR 1.02, 95%CI:0.70-1.48). High risk category had an adverse association for PFS (HR 1.62, 95% CI: 1.27-2.07) and OS (HR 1.51 (95% CI:1.01-2.26). Conclusions: In this analysis < VGPR at baseline was not associated with PFS or OS. High-risk had an adverse association. Whether accomplishment of CR/minimal residual disease after AM, ACM,or TAM predicts for longer PFS and OS is the subject of ongoing analysis. Clinical trial information: NCT01109004.
Bendamustine with ixazomib and dexamethasone (BID) for double refractory relapsed multiple myeloma (RRMM): Phase I safety and dosing results.
Authors: Dhakal Binod , D'souza Anita , Hamadani Mehdi , Arce-Lara Carlos Eduardo , Schroeder Katrina , Gauger Katelyn , Crone Karen , Pasquini Marcelo C. , Chhabra Saurabh , Hari Parameswaran
Published: September 2018

8012

Background: Bendamustine has promising activity in RRMM. This phase I (NCT02477215) study assessed the overall safety and activity of the combination of bendamustine with ixazomib & dexamethasone in pts. with MM pts. refractory to proteasome inhibitors and IMIDs. Methods: Design: Open label dose escalation (3+ 3 design) Doses: Bendamustine at escalating doses of 70, 80 and 90 mg/m2 on days 1,2 of each cycle with weekly ixazomib (4mg) and dexamethasone (40 mg) on days 1,8, 15 in 28-day cycles for up to 8 cycles in responders and 4 cycles if no anti-MM response. Primary end point was safety, maximum tolerated dose (MTD) and the recommended phase II (RP2D) dose. Results: As of Jan 2017, the phase I portion is complete (N= 15). The median age was 67 years with 5 (range: 2-10) median number of prior therapies. Prior therapies included bortezomib (100%), lenalidomide (100%), carfilzomib (47%), oprozomib (7%), thalidomide (7%), pomalidomide (7%) and 87% autotransplant. Five (33%) pts. completed their planned courses of therapy (4 or 8 cycles) and 3 (20%) continued on active therapy. Seven (47%) pts. discontinued study treatment (6 related to disease progression). Grade 3/ 4 adverse events were: lymphopenia (67%), neutropenia (27%), thrombocytopenia (33%), decreased WBC counts (13%), hematuria (7%), diarrhea (7%), anemia (7%), lung infection (7%), and skin ulceration (7%). Three (20%) pts. died of myeloma progression. In dose cohort 3 (bendamustine 90 mg/m2), 2 /6 pts. developed hematologic DLTs (neutropenia and thrombocytopenia) meeting MTD; RP2D was determined to be 80 mg/m2. The table below shows responses among pts receiving at least 2 cycles. The median duration of response was not reached at median follow up of 8 months (range, 4-13+) in responders. Conclusions: BID has an acceptable safety profile and a promising ORR of 45% and CBR of 73% in pts. with advanced double refractory MM. Clinical trial information: NCT02477215. [Table: see text]
Cost effectiveness of carfilzomib (CAR), ixazomib (IXA), elotuzumab (ELO), or daratumumab (DAR) with lenalidomide and dexamethasone (LEN+DEX) vs LEN+DEX in relapsed/refractory multiple myeloma (R/R MM).
Authors: Alsaid Nimer , McBride Ali , Agarwal Amit Balkrishna , Mutairi Abdulaali , Anwer Faiz , Abraham Ivo
Published: September 2018

8030

Background: CAR, IXA, ELO, and DAR in triplet combination with LEN+DEX have shown superior efficacy over LEN+DEX in R/R MM, but their comparative efficacy and cost effectiveness has not been estimated. Methods: Network meta-analysis [NMA] and Bücher method were used to indirectly estimate comparative progression-free survival (PFS) efficacy. A 2-state Markov model (progression-free, progressed or death) was specified. Inputs included: cost of chemotherapy, administration, adverse events (AE) management, disease monitoring; utilities for health states; and disutilities for AEs. Incremental cost effectiveness (ICER) and cost utility ratios (ICUR) were calculated for resp. PFS life years (PFS LY) and quality adjusted life years (PFS QALY) gained in base case and probabilistic sensitivity analyses (PSA). Results: NMA and Bücher indirect comparison methods yielded similar PFS hazard ratios (HR), revealing superiority of DAR+LEN+DEX over other triplets in terms of PFS (Table). Using the exponential distribution to fit PFS data, our cost effectiveness analysis indicated that all 4 triplet regimens were associated with additional PFS LY and QALY gained over LEN+DEX at additional cost. DAR+LEN+DEX was associated with the greatest PFS LY and QALY gained at the lowest relative cost, yielding superior ICER and ICUR estimates compared to other triplet regimens. Conclusions: The superior PFS efficacy of DAR+LEN+DEX is associated with positive cost effectiveness and cost utility in the setting of R/R MM. [Table: see text]
Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).
Authors: Lentzsch Suzanne , Weisel Katja C. , Mateos Maria-Victoria , Hungria Vania , Munder Markus , Nooka Ajay K. , Mark Tomer , Quach Hang , Scott Emma Catherine , Lee Je-Jung , Sonneveld Pieter , Casneuf Tineke , Chiu Christopher , Qin Xiang , Amin Himal , Thiyagarajah Piruntha , Schecter Jordan Mark , Qi Ming , Spencer Andrew
Published: September 2018

8036

Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10–4, 10–5, and 10–6using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P< 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P< 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P< 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10–5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.
Daratumumab-based combination therapies (DCT) in heavily-pretreated patients (pts) with relapsed and/or refractory multiple myeloma (RRMM).
Authors: Lakshman Arjun , Abeykoon Jithma P. , Kumar Shaji , Rajkumar S.Vincent , Kourelis Taxiarchis , Buadi Francis , Dingli David , Lacy Martha , Gonsalves Wilson I. , Dispenzieri Angela , Kyle Robert A. , Lin Yi , Go Ronald S. , Warsame Rahma M. , Hayman Suzanne R. , Russell Stephen , Leung Nelson , Gertz Morie A. , Kapoor Prashant
Published: September 2018

8038

Background: Daratumumab-based Combination Therapies (DCT) with bortezomib (V)/ lenalidomide (R)/ pomalidomide (P) and dexamethasone (d) showed exceptional activity in RRMM in trials. Experience outside of trials since the approval of Daratumumab (D) in 2015 is limited. Methods: RRMM pts seen at Mayo Clinic, MN from 12/2015 -12/2016 were reviewed. Pts who received ≥ 1cycle of DCT were included. Time-to-event analyses were done from date of starting DCT. Common terminology criteria for adverse events v4.0 were used to grade toxicities. Results: Of 130 pts, 59% were males and median age at DCT initiation was 67 (43-93) years, ECOG performance score was ≥2 in 29%. Pts were classified as mSMART high (22%), intermediate (22%) or standard (56%) risk. Median time from diagnosis to initiation of DCT was 51.3 (5-156) months (m), and median number of prior therapies was 4 (1-14). 14% of pts were refractory to prior D monotherapy. Fifty-three (41%), 34 (26%) and 25 (19%) received DPd, DRd and DVd respectively. Eighteen (14%) pts received ‘other’ DCT. Median time to first response (≥ PR) was 3.1 m (95% CI 2.1-4.6). Overall response rate was 46%, [CR-2%, VGPR-18%, PR-26%]. Minimal response was seen in 17%, with clinical benefit rate of 62%. Median estimated follow up from initiation of DCT was 5.5 m (CI 4.2-6.1). The median duration of response was 6.1 m [CI 5.1- not reached (NR)]. Median progression free survival (PFS) was 5.5 m (CI 4.1-7.8) and median time to next therapy (TTNT) was 5.9 m (CI 4.6-9.4). Median PFS for DPd, DRd, DVd and other DCTs were 4.6 (CI 2.7-NR), 7.8 (CI 5-NR), 3.9 (CI 2.1-NR) and 3.9 (CI 2.8-8.2) m, respectively (p = 0.3). Median PFS for quadruple refractory (n = 28) MM was 2.8 m (CI 2.2-5.3) vs 5.9 m (CI 4.9-NR) for the rest (p < 0.01). Median overall survival (OS) from DCT was NR (CI 11.4-NR). Grade 3 or higher hematological toxicities were seen in 42% of pts. Other toxicities included infections (37%), fatigue (31%), infusion reactions (16%) and diarrhea (10%). Conclusions: DCT are effective in RRMM, but the PFS remains short particularly in quadruple refractory pts, reflecting the challenges encountered in managing heavily-pretreated, and often less fit patients, in routine practice.
Comparative efficacy of multiple myeloma therapies for treatment of first relapse: A systematic literature review and network meta-analysis.
Authors: Maiese Eric M , Le Moine Jean-Gabriel , Ainsworth Claire , Ahdesmäki Outi , Howe Emma
Published: September 2018

8042

Background: Treatment for multiple myeloma (MM) in the US has undergone significant advances, with several new therapies recently FDA approved for relapse/refractory MM (RRMM), including carfilzomib+lenalidomide+dex (KRd), carfilzomib+dex (Kd), daratumumab+lenalidomide+dex (DRd), daratumumab+bortezomib+dex (DVd), ixaxomib+lenalidomide+dex (IRd), and elotuzumab+lenalidomide+dex (ERd). These new therapies have shown improvements in clinical outcomes in randomized controlled trials (RCTs). However, with few head-to-head RCTs, there is little comparative evidence to determine the most effective treatment for specific patients. A systematic literature review (SLR) and network meta-analysis (NMA) was conducted to determine the comparative efficacy (progression free survival (PFS)) of MM therapies for treating first relapse. Methods: The SLR searched MEDLINE, Embase, and the Cochrane Library for RCTs investigating the efficacy of treatments for RRMM (to August 2016). NMA was conducted on the PFS hazard ratios (HR), where available in RCTs for patients with one prior line of treatment, using Bayesian fixed effects mixed treatment comparisons. Results: Data formed two evidence networks. Network 1: RCTs with Rd; Network 2: RCTs with Vd. Analyses found DRd and DVd had the highest probability of being the best treatment (0.96 and 0.89, respectively). Compared to other MM therapies, DRd and DVd had the lowest risk of progression or death (PFS HR <1.0) (Table 1). For example, compared to KRd, DRd had a 41% (PFS HR 0.59) reduced risk of progression or death. Conclusions: This analysis provides comparative evidence among treatments where head-to-head RCTs have not been conducted. For treating first relapse, compared to other MM treatments, this analysis found that DRd and DVd had the highest probability of providing the longest progression free survival. [Table: see text]
Randomized trial of cisplatin and etoposide in combination with veliparib or placebo for extensive stage small cell lung cancer: ECOG-ACRIN 2511 study.
Authors: Owonikoko Taofeek Kunle , Dahlberg Suzanne Eleanor , Sica Gabriel , Wagner Lynne I. , Wade James Lloyd , Srkalovic Gordan , Lash Bradley Walter , Leach Joseph W. , Leal Ticiana A.B. , Aggarwal Charu , Ramalingam Suresh S.
Published: September 2018

8505

Background: Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib (V) with cisplatin/etoposide (CE) doublet for first-line therapy of extensive stage SCLC (ES-SCLC). Methods: Patients with ES-SCLC stratified by gender and serum LDH levels, were randomized to receive four 3-wk cycles of CE (75mg/m2 and 100 mg/m2) along with V (100mg bid on d1-7) or placebo (P). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS). Using an overall one-sided 0.10 level logrank test, this study had 88% power to detect a 37.5% reduction in the PFS hazard rate. Results: 128 eligible pts were enrolled across 33 US sites. Median age, 66 yrs; men, 52%; PS 0/1 (29%/71%). The estimated median PFS was 6.1 m vs. 5.5 m [unstratified HR: 0.75; 1-sided p = 0.06) favoring CE+V. The median OS was 10.3 m vs. 8.9 m respectively for CE+V and CE+P [stratified HR: 0.83 (80% CI 0.64-1.07); 1-sided p = 0.17]. There was a significant treatment by strata interaction in PFS: male pts with high LDH derived benefit [PFS HR of 0.34 (80% CI: 0.22-0.51)]; among pts not in this strata: PFS HR = 0.81 (80% CI: 0.60-1.09). The best objective response rate was 71.9% vs. 65.6% (2-sided p = 0.57). Salient grade ≥3 adverse events occurring in 5% of patients are summarized in the table below. Analysis of tumor samples for predictive biomarkers is planned. Conclusions: The addition of veliparib to doublet chemotherapy was associated with improved PFS in patients with extensive stage SCLC. Clinical trial information: NCT01642251. [Table: see text]
Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).
Authors: Stinchcombe Tom , Stahel Rolf A. , Bubendorf Lukas , Bonomi Philip , Villegas Augusto E. , Kowalski Dariusz , Baik Christina S. , Isla Dolores , De Castro Javier , Garrido Lopez Pilar , Rittmeyer Achim , Tiseo Marcello , Stanzel Sven Franz , de Haas Sanne , Lam Lisa , Lu Michael , Peters Solange
Published: September 2018

8509

Background: T-DM1 is an antibody-drug conjugate approved for HER2-positive metastatic breast cancer. We report primary results from a fully enrolled, ongoing phase 2 study (NCT02289833) of pts with previously treated HER2-overexpressing mNSCLC who received single-agent T-DM1. Methods: Eligible pts had HER2-overexpressing mNSCLC and were previously treated with platinum-based therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks and were analyzed in 2 cohorts based on centrally determined HER2 status (immunohistochemistry [IHC]2+ vs IHC3+ [≥10% cells stained with 2+ or 3+ intensity, respectively]). HER2 amplification was assessed via ISH (HER2 gene ratio ≥2.0). The primary endpoint is objective response rate (ORR; proportion of pts with confirmed [≥4 weeks] complete or partial response per RECIST v1.1). Results: The clinical cutoff date for this analysis was Oct 26, 2016.Of 393 screened pts, 102 (27%) were IHC2+ and 29 (7%) were IHC3+. In total, 49 pts (IHC2+, n = 29; IHC3+, n = 20) received T-DM1. At cutoff, median follow-up was 16.3 (range 0.9*–22.4; * = censored observation) months. No IHC2+ pt had a response (0%, 95% CI 0–11.9); 4 IHC3+ pts had partial responses (20%, 95% CI 5.7–43.7) with a median duration of response of 7.3 (range 2.9–8.3) months. Median progression-free survival (PFS) in IHC2+ and IHC3+ pts was 2.6 (95% CI 1.4–2.8) and 2.7 (95% CI 1.4–8.3) months, respectively. At 6 months after start of study treatment, 9 pts (IHC2+, n = 4; IHC3+, n = 5) were still at risk for a PFS event. Median overall survival was 12.2 (95% CI 3.8–not estimable [NE]) months in IHC2+ pts and 12.1 (95% CI 9.3–NE) months in IHC3+ pts. Of 16 pts with HER2 amplification (IHC2+, n = 5; IHC3+, n = 11), 3 responded, all in the IHC3+ cohort (27.3%, 95% CI 6.0–61.0). Eleven pts (22%) experienced a grade 3–4 adverse event, with fatigue and dyspnea being the only events reported in > 1 pt (n = 2 each). Conclusions: This is the first study to report on the clinical activity of T-DM1 in HER2-overexpressing mNSCLC. Objective responses were observed in IHC3+ pts. Additional molecular analyses are underway to refine markers for optimal pt selection. Clinical trial information: NCT02289833.
Molecular analysis of thymic epithelial tumors (TETs): A report by The Cancer Genome Atlas (TCGA) research network.
Authors: Loehrer Patrick J. , Tsao Anne S. , Radovich Milan , Felau Ina
Published: September 2018

8520

Background: Thymoma (T) and thymic carcinoma (TC) are the most common malignancies of the anterior mediastinum. Additionally, thymoma has an unique association with autoimmune disorders, notably myasthenia gravis (MG). Histologic classification of TETs has been largely based on the gross description of the epithelial cell appearance and the relative abundance of associated lymphocytes. A comprehensive molecular analysis of TETs has not heretofore been conducted. Methods: The TCGA Research Network conducted multi-platform analyses of 117 TETs (T = 105; TC = 10 and micronodular T = 2), which included whole-exome, transcriptome, methylome and targeted proteome analysis. Patient characteristics: median age = 60 years (range 17-84); M:F (%) = 52:48; Masaoka Stage (I-36, IIA-39, IIB-19; III-15; IVA-1; IVB-5); mg was present in 32 patients. No patient had prior therapy for metastatic disease, but 14 had prior chemotherapy and 39 had prior radiation therapy in adjuvant setting. WHO histologic classification (blinded review) revealed A = 10; A/B = 48, B1 = 12, B2 = 25, B3 = 10, micronodular T = 2 and TC = 10. Results: T has one of the lowest mutational loads of any tumor in the TCGA. A unique transcription factor, GTF2I, was the most commonly observed mutation in WHO Types A and A/B. All GTF2I mutations were exclusively at the amino acid 424 locus. This is the only tumor with this specific mutation within the entire TCGA database. HRAS, NRAS and TP53 mutations were less commonly noted among all TETs. Four distinct molecular-driven subtypes of TETs were identified that strongly correlated with the current WHO histologic classification. Increased aneuploidy and overexpression of muscle auto-antigens were associated with mg phenotype. Conclusions: Based on molecular analysis, four clusters were identified that correlated strongly with the current WHO Histologic Classification. Also identified was a unique mutation in GTF2I, which was associated with WHO Type A and A/B thymoma. This international effort represents the largest and most comprehensive molecular analysis of TETs conducted to date is expected to have important clinical and translational implications for this rare disease.
Typical bronchial NETs as a misleading biology.
Authors: Mandair Dalvinder , Diamantopoulos Leonidas-Nikolaos , Demetriou George , Laskaratos Faidon , Toumpanakis Christos , Caplin Martyn E.
Published: September 2018

8528

Background: Bronchial Neuroendocrine tumours (NETs) are rare with an incidence of between 0.2 – 2 per 100,000 population. There has been an increase in prevalence due to increased awareness, enhanced immunohistochemistry and greater use of Computed tomography (CT). Bronchial NETs are classified according to the WHO guidelines developed in 2004 where they are graded by histological classification into ‘typical’, ‘atypical’ NETs or small and large neuroendocrine carcinoma’s (NECs). Typical NETs are regarded as being low-grade malignant however metastatic disease can still develop. Aims: We sought to determine the incidence of metastatic typical bronchial NETs, their survival and investigate the imaging and treatment used in their management. Methods: We performed a retrospective analysis of all bronchial NETs managed at our centre from 2001 to 2016. From those identified as typical NETs, we analysed clinical records in those with advanced disease (Stage IV). Results: From a total of 251 bronchial NETs, there were 147 ‘Typical’ NETs, 30(20%) of whom had advanced disease compared to 82 'Atypical' bronchial NETs of whom 55 had advanced disease (67%). The median age at diagnosis was 58 (range 24-77). In the 'Typical' NETs, 24/30 had liver metastases, 19/30 skeletal metastases, and 16 had carcinoid syndrome (CS). Functional imaging with FDG PET scan was positive in 7/10 patients and somatostatin receptor scintigraphy (SRS) positive in 16/20 and in 4/11 there was avidity with both. 20 patients were treated with somatostatin analogues predominantly for CS symptoms. 11 patients treated with peptide radiolabelled receptor targeted therapy (PRRT) with a median Time-To-Progression (TTP) of 27 months. 11 patients received chemotherapy with median TTP of 16 months with 4 patients demonstrating partial response. Conclusions: Typical bronchial NETs can lead to advanced disease in up to 20% of patients. Their behavior can be aggressive and is not predictable by histology alone. Functional imaging with both FDG and SRS may help determine the most appropriate treatment. Both PRRT and chemotherapy can be considered in progressive disease.
The role of adjuvant therapy in the management of resected large cell neuroendocrine carcinoma (LCNEC) of the lung: A National Cancer Database (NCDB) analysis.
Authors: Kujtan Lara Ann , Muthukumar Varsha , Toor Muhammad , Kennedy Kevin F , Masood Ashiq , Davis J Russell , Subramanian Janakiraman
Published: September 2018

8529

Background: Large cell neuroendocrine carcinoma (LCNEC) is characterized by aggressive behavior and poor outcomes compared with other non-small cell lung cancers (ONSCLC). Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with early stage NSCLC (pathologic stage I, II, IIIA) from 2004-2012 who underwent surgical resection. Patients were divided into two groups: LCNEC and ONSCLC. One-way ANOVA was used to compare continuous variables, and chi-squared testing was used to compare categorical variables. Multivariate logistic regression analyses were used to obtain hazard ratios. Results: We identified 1672 patients with resected LCNEC and 134139 with resected ONSCLC. A higher proportion of patients with ONSCLC had a Charlson-Deyo co-morbidity score of 0 compared to LCNEC patients (50.6% vs. 43.8%; p < 0.001). No other significant differences in clinical and demographic characteristics were identified. Overall survival was lower for LCNEC patients across all stages when compared to patients with resected ONSCLC (46 months versus 74 months; 5-year survival 45% versus 57%; p <0.001). Multivariate analysis confirmed the survival benefit for adjuvant chemotherapy in resected LCNEC across all stages, including stage IA, although it did not reach statistical significance (hazard ratio 0.72 (0.51-1.02), p= 0.64; Table). Conclusions: Adjuvant chemotherapy significantly improves survival for stage IB, II and IIIA LCNEC compared to surgery alone. Patients with stage IA LCNEC appear to benefit from adjuvant chemotherapy although it did not reach statistical significance. The overall magnitude of benefit from adjuvant chemotherapy appears to be higher for patients with LCNEC compared to ONSCLC. [Table: see text]
Randomized trial of thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer (NSCLC): Long-term follow-up of Japan Clinical Oncology Group (JCOG) Study JCOG0301.
Authors: Atagi Shinji , Mizusawa Junki , Ishikura Satoshi , Takahashi Toshiaki , Okamoto Hiroaki , Tanaka Hiroshi , Goto Koichi , Nakagawa Kazuhiko , Harada Masao , Takeda Yuichiro , Nogami Naoyuki , Fujita Yuka , Kasai Takashi , Kishi Kazuma , Sawa Toshiyuki , Takeda Koji , Tomii Keisuke , Satouchi Miyako , Seto Takashi , Ohe Yuichiro
Published: September 2018

8532

Background: In the phase III JCOG0301 trial, concurrent chemoradiotherapy (CRT) was compared with radiotherapy (RT), demonstrating clinically significant survival benefits in elderly patients with locally advanced NSCLC after a median follow-up of 19.4 months. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT are poorly understood for elderly patients. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT alone (RT arm: irradiation with 60 Gy in 30 fractions) or CRT (CRT arm: the same RT with additional concurrent use of carboplatin 30 mg/m2 per fraction up to the first 20 fractions). The primary endpoint was overall survival (OS). Prognosis and adverse events data were collected beyond those in the initial report of this trial. Kaplan-Meier survival curves and 3- and 5-year survival proportions were calculated. Late toxicities were defined as occurring later than 90 days after RT initiation. Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100; CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better OS than the RT arm (HR = 0.743, 95% CI = 0.552 – 0.998, one-sided p = 0.0239 by stratified log-rank test). In the RT and CRT arms, median OS was 16.5 and 21.7 months, 3-year survival was 16.3% and 34.3%, and 5-year survival was 9.2% and 15.2%, respectively. %Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) were seen since the initial report. There were 7 treatment-related deaths, all of which were recorded in the initial report: 4 (4.0%) in the RT arm and 3 (3.0%) in the CRT arm. Conclusions: Long-term follow-up confirms the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT, as compared with RT alone. Clinical trial information: 00132665.
Feasibility of endobronchial ultrasound fine-needle aspiration for massively parallel next-generation sequencing in cancer patients.
Authors: Turner Simon R. , Buonocore Darren , Rekhtman Natasha , Dogan Snjezana , Desmeules Patrice , Lin Oscar , Arcila Maria E. , Jones David Randolph , Huang James
Published: September 2018

8535

Background: Next generation sequencing (NGS) is an important emerging tool in precision oncology, allowing identification of a growing number of clinically validated and investigational therapeutic molecular targets. A potential limitation is that some NGS assays require more DNA input than more limited molecular assays. Endobronchial ultrasound fine-needle aspiration (EBUS-FNA) is a minimally invasive procedure for sampling mediastinal and pulmonary lesions, but it is unknown if it provides adequate material for NGS. Methods: An IRB approved, retrospective review was performed of patients undergoing EBUS-FNA by thoracic surgeons at our institution 3/1/14 - 9/28/16. NGS was performed using an assay developed at our institution that detects mutations in up to 410 genes (MSK-IMPACT). Samples diagnostic for malignancy and with MSK-IMPACT requested were identified. Pathology and clinical data were drawn from the medical record and MSK-IMPACT results were examined. Results: 784 EBUS-FNA were done in the study period. MSK-IMPACT was requested on 115 positive samples. MSK-IMPACT was successful in 99 samples (86.1%), identifying an average of 12.7 mutations at a mean coverage depth of 806X. In 17 (17.2%) samples, tumor content was suboptimal ( < 20% of nucleated cells), with fewer identified mutations than in cases with higher tumor content (6.8 vs 13.9, p = 0.01). NGS was performed on paraffin-embedded cell blocks in 93 cases (93.9%), and in 6 cases DNA extraction was performed from residual cytological material isolated from supernatant including cell-free DNA. Failures were attributable to low cell content (7), high contamination by benign cells (4) or both (1) and processing issues (4). No difference in surgical or radiologic parameters were identified for failed or suboptimal samples. Conclusions: In our practice, EBUS-FNA has a high rate of success for obtaining adequate tissue for NGS. Ability to utilize cell-free DNA for molecular studies – a new process in our lab – allows increased success of molecular testing in scant samples. Further studies may identify factors contributing to NGS failure and to improving success for samples with minimal cellularity.
Retrospective analysis of clinical outcomes of early stage ALK-positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Dagogo-Jack Ibiayi , Santini Fernando , Eng Juliana , Yeap Beow Y. , Izar Benjamin , Chin Emily , Litvak Anya , Jones David Randolph , Kris Mark G. , Shaw Alice Tsang , Gainor Justin F. , Chaft Jamie E.
Published: September 2018

8536

Background: ALK rearrangements are important oncogenic drivers in NSCLC. However, the prognostic implications of these rearrangements are unclear due to 1) conflicting results from small series of patients (pts) with early-stage ALK+ NSCLC, and 2) use of highly effective ALK tyrosine kinase inhibitors (TKI) in the metastatic setting. To assess the prognostic significance of ALK rearrangements in resected NSCLC, we performed a retrospective analysis of survival outcomes among pts with resected ALK+, EGFR+, or KRAS+ NSCLC treated at two institutions. Methods: We reviewed charts of pts that underwent resection for stage 1-3 NSCLC at Massachusetts General Hospital or Memorial Sloan Kettering Cancer Center between 1/2009 and 12/2012. Recurrence-free survival (RFS) was estimated for each genotype. Results: Among 764 pts (480 KRAS+, 255 EGFR+, 29 ALK+), we identified 555 (73%), 101 (13%), and 108 (14%) pts with stage I, 2, and 3 NSCLC, respectively. ALK+ pts were distributed across all stages: 10 (34%) stage I, 6 (21%) stage 2, and 13 (45%) stage 3 NSCLCs. Chemotherapy was administered to 14 ALK+ ( 0% stage 1, 67% stage 2, 77% stage 3), 45 EGFR+ (3% stage 1, 44% stage 2, 81% stage 3), and 96 KRAS+ pts (4% stage 1, 56% stage 2, 71% stage 3), respectively, for early-stage NSCLC. Thirteen (7%) stage 1 EGFR+ patients received adjuvant EGFR TKI. Although median RFS was not reached for EGFR+ pts, it was 24.3 months (95%CI 11.4 to 65.3) for ALK+ pts and 72.9 months (95%CI 59.7 to undefined) for KRAS+ pts. RFS for ALK+ NSCLC was significantly shorter than the other groups (HR 2.9, 95%CI: 1.75-4.89 vs. EGFR and HR 1.8, 95%CI: 1.12-2.93 vs. KRAS). When adjusted for stage, ALK+ NSCLC remained associated with worse RFS compared to EGFR+ NSCLC (HR 1.8, 95%CI: 1.09-3.12), but not when compared to KRAS+ NSCLC (HR 1.30, 95%CI: 0.79-2.12). Conclusions: Early stage ALK+ NSCLC is associated with shorter RFS than EGFR+ NSCLC. The propensity for relapse and the significant anti-tumor activity of ALK TKIs in pts with metastatic NSCLC suggest that enrollment of patients on trials of adjuvant ALK TKIs should be prioritized.
Interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer: An analysis of institutional and public data.
Authors: Jalali Ali , Wang Jing , Lee Won-Chul , Zhang Jianhua , Wu Chia Chin , Gibbons Don Lynn , Tang XiMing , Kalhor Neda , Izzo Julie , Behrens Carmen , Fossella Frank V. , Tsao Anne S. , Lee J. Jack , Swisher Stephen , Heymach John , Futreal Andrew , Wistuba Ignacio Ivan , Herbst Roy S. , Papadimitrakopoulou Vassiliki , Zhang Jianjun
Published: September 2018

8538

Background: In many types of cancer, infiltration of tumor by immune cells, as a reflection of the immune response against the tumor, is thought to play a critical role in clinical outcome. Tumors, however, tend to evade the immune response as they progress. In this study, we characterize the interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer (NSCLC). Methods: We performed histologic immune profiling and microarray expression analysis on primary tumor specimens from 275 NSCLC patients (PR: PROSPECT trial) as well as RNA-Seq expression analysis on biopsy specimens from 50 patients with advanced NSCLC (B2: BATTLE-2 trial). RNA-Seq data from the TCGA lung cancer project was also analyzed. Immune Infiltration Score (IIS) was computed from the expression data using the Estimate package in R. Immune Suppression Score (ISS) was defined as the difference between the mean of CD3, CD4, CD8, FOXP3, and PD1 counts in the periphery and core of the tumor. Results: Tumor IIS is correlated (all p < 0.0005) with tumor immune infiltration as measured by inflammatory cell count on frozen tumor or several immune marker counts in tumor core. IIS is positively associated with survival (p = 0.04) independently of age (p = 0.008) and stage (p = 8e-10). IIS in the top half is associated with higher median survival vs. bottom half (10.2 vs 2.2 months, p < 0.0001) in B2. In TCGA lung adenocarcinoma samples, IIS is higher in stage I/II disease vs stage III/IV (p = 0.003). For all immune markers in PR samples, periphery of the tumor on average has higher counts vs tumor core (p < 0.0011), and this difference (suppression score) is higher in stage III/IV samples vs stage I/II for CD3, CD4, and CD8 (all p < 0.04) and for FOXP3 and PD1 (p < 0.1). ISS is negatively associated with survival (p = 0.02) independently of age (p = 0.06) and stage (p < 0.0001). Conclusions: As NSCLC tumors progress, immune infiltration in the periphery of the tumor increases while infiltration in the core decreases, reflecting increasing immune suppression. Tumor immune infiltration and suppression, as measured by IIS and ISS, are significant predictors of survival, independently of age and stage.