bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between thymidylate synthetase (TS) expression and progression-free survival (PFS) in patients receiving pemetrexed (pem) for advanced NSCLC: A prospective study.
Authors: Nicolson Marianne , Kerr Keith M , Shah Riyaz N.H. , Potter Vanessa , Upadhyay Sunil , Taylor Paul , Myrand Scott , Nuguyen Tuan Stevon , Das Mayukh , Fennell Dean Anthony
Published: March 2020

7583

Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p<0.0001, HR= 1.01 (95% CI 1.01, 1.02)], suggesting higher TS values are associated with shorter PFS. When the population was dichotomized at the identified optimal H-score cutpoint of 70, the mPFS in the low expression group (n=40) was 7.1 months (5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group (n=20) [adjusted p=0.0015, HR=0.28 (95% CI 0.16-0.52)]. Similar trends with cytoplasmic TS IHC (p=0.09) and TS qPCR (p=0.05) levels were observed. Statistical correlations were seen among the TS levels. Data is preliminary. Conclusions: Study suggests statistically significant association between low TS IHC nuclear expression and improved PFS in this Phase 2 single-arm trial.
Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic and VEGF pathways: Association with survival of platinum-treated stage IV non-small cell lung cancer (NSCLC) patients.
Authors: Cuffe Sinead , Qiu Xiaoping , Azad Abul Kalam , Qiu Xin , Boyd Kevin , Kuang Qin , Marsh Sharon , Savas Sevtap , Emami Marjan , Perera Nicole , Palepu Prakruthi R. , Chen Zhuo , Patel Devalben , Cheng Dangxiao , Feld Ronald , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Xu Wei , Liu Geoffrey
Published: March 2020

7586

Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received > one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r2=0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G>A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G>A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r2=1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers.
EML4-ALK-gene rearrangement comparative analysis in circulating tumor cells and in tumor tissue of patients with lung adenocarcinoma.
Authors: Ilie Marius , Long Elodie , Butori Catherine , Hofman Veronique , Coelle Celine , Mauro Virginie , Zahaf Katia , Marquette Charles Hugo , Mouroux Jerome , Paterlini-Brechot Patrizia , Hofman Paul
Published: March 2020

7591

Background: The implementation of new theranostic biomarkers in Oncology is leading to impressive therapeutic improvements. In patients with lung cancer, the possibility to use Circulating Tumor Cells (CTCs) as a non-invasive theranostic approach is a clinically appealing challenge. Adenocarcinomas with EML4-ALK rearrangement are a new molecular subgroup of lung tumors with very good response to Crizotinib, an ALK inhibitor. We have thus aimed at developing an informative assay characterizing the ALK-gene status in CTCs isolated from patients with lung cancer. Methods: CTCs were isolated preoperatively using Isolation by Size of Epithelial Tumor cells method (ISET) from 65 patients with lung adenocarcinoma and blindly screened for ALK-gene status. ALK break-apart fluorescence in situ hybridization (FISH) (LSI ALK dual colour probes set) and immunochemistry using an anti-ALK antibody (5A4 clone) were blindly performed on CTCs and corresponding tumor tissues and results were compared. Results: Two patients consistently showed ALK-gene rearrangement and strong ALK protein expression in CTCs and corresponding tumor samples. Negative results (both ALK FISH and ALK immunochemistry) were found in CTCs and corresponding tumor samples from the other 63 patients. Conclusion: We have developed an approach allowing to characterize ALK-gene status in CTCs from patients with lung cancer and shown consistent results in CTC and tumor tissues. These preliminary results encourage larger studies and open new avenues for non-invasive, real-time, theranostic monitoring of cancer patients.
MIMEB: A phase II trial to evaluate FDG-PET/FLT-PET and DCE-MRI for early prediction of efficacy in patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab.
Authors: Scheffler Matthias , Bos Marc Christiaan Allardt , Sos Martin , Nogova Lucia , Mattonet Christian , Papachristou Irini , Kahraman Deniz , Kobe Carsten , Boellaard Ronald , Lammertsma Adriaan A. , Heukamp Lukas Carl , Büttner Reinhard , Elter Thomas , Toepelt Karin , Engel-Riedel Walburga , Stoelben Erich , Neumaier Bernd , Dietlein Markus , Zander Thomas , Wolf Juergen
Published: March 2020

7603

Background: Since the introduction of targeted therapy into the treatment of NSCLC, molecular imaging tools gain in importance for assessment of pharmacodynamics, pharmacokinetics and prediction of therapeutic outcome. Tumor metabolism (by FDG-PET), proliferation (by FLT-PET), and vascularization (by DCE-MRI) can be noninvasively assessed to quantify the effects of targeted therapy on tumor biology. We set up a trial to evaluate the effects of combined erlotinib (E) and bevacizumab (B) treatment in patients with advanced non-squamous cell NSCLC and to identify prospectively patients who benefit from this combination. Methods: Patients with non-squamous NSCLC stage IV without prior systemic therapy received at least six weeks of combined E and B. FLT and FDG-PET scans as well as DCE-MRI-scans were performed at baseline, after 1 week of therapy and after 6 weeks of therapy. Standard uptake values of the PET scans and vascularization parameters of the DCE-MRI scans were analyzed and coregistrated. Tumor specimens were analysed within a network screening panel. The primary objective of this trial was to evaluate the accuracy of the imaging tools for early prediction of nonprogression and PFS and its association with molecular markers. Results: Of the 40 patients, all received FDG-PET analyses, whereas FLT-PET was performed in 38 patients and DCE-MRI in 36 patients. Median OS was 13.4 months, median PFS was 5.9 months. Until January 2012, tissue specimens from 25 patients have been genetically analysed. First results show that even patients with KRAS, PI3K and BRAF mutations profiting from the combination either by response or prolonged PFS could be identified by early imaging assessment. Conclusions: The efficacy of E +B in unselected patients with NSCLC was comparable with platinum-based chemotherapy. In order to identify imaging-based predictive biomarkers to identify the subpopulation of patients with pronounced benefit of this combination FDG-, FLT- PET and DCE–MRI were successfully implemented in the treatment plan. Results of the imaging analysis and the correlation with tissue-based biomarkers will be presented.
A phase III randomized intergroup trial (S0016) comparing CHOP plus rituximab with CHOP plus iodine-131-tositumomab for front-line treatment of follicular lymphoma: Results of subset analyses and a comparison of prognostic models.
Authors: Press Oliver W. , Unger Joseph M , LeBlanc Michael Leo , Rimsza Lisa M. , Friedberg Jonathan W. , Czuczman Myron Stefan , Kaminski Mark Stefan , Braziel Rita M , Spier Catherine M , Maloney David G. , Cheson Bruce D. , Miller Thomas P. , Fisher Richard I. ,   Southwest Oncology Group
Published: March 2020

8001

Background: Advanced follicular lymphomas (FL) are considered incurable with chemotherapy and there is no consensus on the best treatment. Outcomes are variable, but can be partially predicted by defined prognostic factors. SWOG and CALGB compared the safety and efficacy of 2 immunochemotherapy regimens in a Phase III trial enrolling 554 patients between 3/1/2001 and 9/15/2008. Methods: Patients were eligible if they had bulky stage II, III or IV FL and had not received prior therapy. Patients randomized to CHOP-R received 6 cycles of CHOP every 21 days + 6 doses of rituximab. Patients randomized to CHOP-RIT received 6 cycles of CHOP, followed by consolidative radioimmunotherapy with tositumomab/iodine I-131 tositumomab. A Cox proportional hazards multi-variable regression analysis assessed the prognostic impact of age, stage, LDH, LN size and number, performance status, hemoglobin, β2 microglobulin, BM involvement, and B symptoms.  The prognostic value of 3 multi-variable models were compared. Results: Outcomes were outstanding with either CHOP-R or CHOP-RIT (2 yr PFS: 76% vs 80% [ p =0.11]; 2 yr OS: 97% vs 93% [p =0.08], respectively).  Subset analyses so far have not identified any subgroups clearly benefitting to a greater degree from CHOP-R or CHOP-RIT in terms of both PFS and OS. Cox multivariable regression analysis identified serum-β2M, LDH level, and FLIPI index as the strongest prognostic factors associated with worse PFS and OS. Conclusions: Both regimens produced outstanding PFS and OS, and no statistically significant differences between them were observed.  FLIPI, FLIPI2, and LDH + β2M models were all strong predictors of patient outcomes.  A combination of LDH + β2M was as good as the FLIPI index, and was simpler to apply.  (Supported in part by NCI grants CA32102 and CA38926 from the NCI and GlaxoSmithKline.) [Table: see text]
Daratumumab, a CD38 mab, for the treatment of relapsed/refractory multiple myeloma patients: Preliminary efficacy data from a multicenter phase I/II study.
Authors: Plesner Torben , Lokhorst Henk M , Gimsing Peter , Nahi Hareth , Lisby Steen , Richardson Paul Gerard Guy
Published: March 2020

8019

Background: Daratumumab (HuMax-CD38) is a human CD38 monoclonal antibody with broad-spectrum killing activity; it effectively kills CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. From an ongoing first-in-human (FIH) dose-escalation study (ClinicalTrials.gov CT00574288), it has been shown that daratumumab has an acceptable safety profile (Gimsing: ASH 2011 abstract 1873). The objectives of this FIH study are to establish the safety profile and MTD. In addition efficacy is evaluated. Methods: Pts ≥18 years and previously diagnosed with MM requiring systemic therapy and considered relapsed or refractory (RR) to at least two different prior lines of therapy and not eligible for salvage ASCT were enrolled. The design of this study encompasses an accelerated dose-escalation based on a classical 3+3 design. Daratumumab is administrated over a 9 wk period encompassing 2 pre-doses and 7 full-doses. The doses range from 0.005 mg/kg to 24 mg/kg. The decision to dose escalate is based on recommendation by an external Independent Data Monitoring Committee. Evaluation of efficacy data was according to Rajkumar (Blood 2011;117:4691-5). The results presented in this abstract are based on preliminary data analyzed before database lock. Results: Data from 23 pts including the 4 mg/kg group are collected. Preliminary efficacy evaluation is based on best paraprotein response as reflected by change in serum and/or urine M-component. For groups ≤ 1 mg/kg, 3/17 pts achieved a reduction in serum M-component (12%, 14%, 19%), in the 2 mg/kg group, 1/3 pts had a reduction in urine M-component (55%), and in the 4 mg/kg group, 3/3 pts had a reduction in the serum M-component of 49%, 55, and 64%, respectively. In the 4 mg/kg group a marked reduction in the percentage of plasma cells in the bone marrow was seen in all pts (80%, 89%, and 97%). The toxicity was manageable. Conclusions: Daratumumab treatment resulted in reductions in M-component and bone marrow plasma cells in pts with RR MM. Toxicity has been manageable. Additional data will be presented at the meeting.
Role of radiotherapy for elderly DLBCL patients in the rituximab (R) era: Final results of the RICOVER-60-no-rx study of the DSHNHL.
Authors: Held Gerhard , Murawski Niels , Ziepert Marita , Poeschel Viola , Zwick Carsten , Reiser Marcel , Wilhelm Sibylla , Gaska Tobias , Heike Michael , Schubert Joerg , Schmitz Norbert , Loeffler Markus , Ruebe Christian , Pfreundschuh Michael ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8022

Background: 117/306 (38%) of the total of 1,222 elderly (61-80 y) DLBCL pts. treated in RICOVER-60 with 6xR-CHOP-14+2R were assigned to receive additional radiotherapy (Rx) to bulky disease (Pfreundschuh et al., Lancet Oncol. 2008). To study the relevance of Rx to bulky disease (Bx), 166 pts. were prospectively treated without Rx in the R-CHOP-14-noRx amendment of RICOVER-60. Methods: The outcome of 166 R-CHOP-14-noRx patients was compared with the 306 patients who had received 6xR-CHOP-14+2R plus radiotherapy to Bx (≥7.5 cm) in RICOVER-60. Methods: The outcome of 166 R-CHOP-14-noRx patients was compared with the 306 patients who had received 6xR-CHOP-14+2R plus radiotherapy to Bx (≥7.5 cm) in RICOVER-60. Results: 164/166 R-CHOP-noRx patients are evaluable (median observation: 39 mos). Patients in R-CHOP-noRx were older (71 vs. 69 y.; median; p=0.018), more frequently in advanced stages (60% vs. 50%; p=0.037), and with extranodal involvement (63% vs. 53%; p=0.024), while Bx was more frequent in R-CHOP-14-Rx (38% vs. 29%; p=0.038). Overall response to therapy, EFS and OS were similar in the two studies adjusting for the prognostic imbalances between the cohorts. Patients with Bx who received received additional radiotherapy to Bx in R-CHOP-14-Rx had a better 3-year EFS (80% vs. 54%; p=0.001), a better PFS (88% vs. 62%; p<0.001), and a better OS (90% vs. 65%; p=0.001) compared to R-CHOP-14-noRx. This was due the worse outcome of pts. with Bx in R-CHOP-14-noRx not achieving CR or CRu after 6xR-CHOP, since there was no difference in 3-year EFS in patients with Bx in CR or CRu after 6xR-CHOP-14 with and without additional radiotherapy (3-year EFS and PFS: 84% vs. 75%; p=0.430); OS 87% vs. 79%; p=0.839). Conclusions: In the R era, radiotherapy to bulky disease does not improve the outcome of elderly pts. in CR/CRu after completion of R-CHOP-14 immunochemotherapy, but appears to be beneficial for pts. with Bx not achieving CR/Cru. By restricting Bx radiotherapy to patients not achieving a CR/CRu, 43% of the patients with Bx could be spared radiotherapy. Supported by Deutsche Krebshilfe.
Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): A phase I/II study.
Authors: Richardson Paul Gerard Guy , Berdeja Jesus G. , Niesvizky Ruben , Lonial Sagar , Roy Vivek , Hari Parameswaran , Berg Deborah , Liu Guohui , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Kumar Shaji
Published: March 2020

8033

Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m2 and the RP2D as 2.23 mg/m2; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.
Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study.
Authors: Kumar Shaji , Bensinger William , Reeder Craig B. , Zimmerman Todd M. , Berenson James R. , Liu Guohui , Berg Deborah , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Niesvizky Ruben
Published: March 2020

8034

Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.
Early determination of treatment sensitivity in HIV-related Hodgkin lymphoma by FDG-PET/CT after two cycles of ABVD chemotherapy: A European Cooperative Study Group on AIDS and Tumors (GECAT) study.
Authors: Mounier Nicolas , Bower Mark , Spina Michele , Besson Caroline , Schiantarelli Clara , Re Alessandro , Bonnet Fabrice , Hentrich Marcus , Wyen Christoph , Van Den Neste Eric , Vandoni Irene , Tirelli Umberto , Borsatti Eugenio
Published: March 2020

8046

Background: The high prognostic value of FDG-PET/CT performed after 2 cycles of chemotherapy for HIV negative Hodgkin lymphoma (HL) is well known. However, experience with PET in HIV-related HL needs to be further studied as nodal FDG uptake can be observed in various opportunistic infections and AIDS-related conditions. Methods: A total of 45 consecutive HL patients (pts) were enrolled in 10 centers from the GECAT. There were 42 males and 3 females. Median age was 46 yo, range [26;64]. Median CD4 count was 391/mm3, range [33;1191]. Viral load was negative in 38 pts (84%) and uncontrolled in 5 pts (11%). Forthy three pts (96%) received concomitant HAART. HL was staged III-IV in 25 pts. International Prognostic Index scored 3-5 in 24 pts. All PET studies were performed after 2 ABVD cycles. They were scored, blinded to treatment outcome, according to the 5-point Deauville visual scale. It was considered as negative when scored 1-3 (i.e tumor FDG uptake less or equal than liver uptake) and positive when scored 4-5 (i.e. more than liver uptake or new lesions). Chemotherapy was not modified : 4-8 cycles of ABVD, as initially planned. Results: Overall, 35 pts (78%) achieved a CR after the end of treatment. Three pts received Involved Field Radiation Therapy. At a median follow-up of 18 months, 3 pts relapsed and 2 of them died from HL. The 2 yr OS and PFS were estimated at 94 and 90%, respectively. PET after 2 cycles of ABVD was negative in 40 pts (89%) and positive in 5 pts (11%). Patients with negative PET had a significantly better outcome than those with positive PET in term of 2 yr PFS (94% vs 60%, P=0.005), and 2 yr OS (100% vs 60%, P=0.0002). The negative predictive value was estimated at 97% and specificity at 93%. All patients who were PET-negative after the 2nd cycle stayed PET-negative after the 4th cycle and entered a durable CR. Conclusions: This largest study in HIV-positive HL showed that interim PET could play a central role in driving risk-tailored treatment. In further studies, de-escalation strategies should be tested for patients responding after 2 cycles of ABVD and those not reponding should be managed with intensive salvage strategies.
Final results of phase I/II trial of vorinostat in combination with cyclophosphamide, etoposide, prednisone, and rituximab (R-CVEP) for elderly patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Straus David J. , Hamlin Paul A. , Matasar Matthew J. , Palomba Maria Lia , Drullinsky Pamela , Zelenetz Andrew David , Gerecitano John F. , Noy Ariela , Hamilton Audrey M. , Wegner Brett , Zhang Zhigang , Elstrom Rebecca L. , Cella David
Published: March 2020

8054

Background: Standard treatment of relapsed/refractory DLBCL in elderly patients who are not candidates for autologous stem cell transplantation (auSCT) has not been established. Cyclophosphamide (C), etoposide (E), prednisone (P) and procarbazine (CEPP) has been used by many clinicians based on limited data (Blood 76: 1293-98, 1990). Vorinostat (V) is a histone deacetylase inhibitor that is approved for relapsed cutaneous T-cell lymphoma and has activity in B-cell lymphomas. This trial defined the maximum tolerated dose (MTD) of V added to standard therapy and determined the response rate of this combination. Methods: Patients ≥age 60 with relapsed/refractory DLBCL not candidates for auSCT were enrolled on R-CVEP (R 375mg/m2 IV, d1; C 600mg/m2 d1 and 8, E 70mg/m2 IV d1, 140mg/m2 d2 and 3; V PO and Pred 60mg/m2 PO d1-10) every 28 days for 6 cycles. In the phase I component V was administered at doses of 300mg/d or 400mg/d for 10 days. The phase I was a 3 + 3 design and the phase II a two stage design requiring 8/20 complete responses (CR) for expansion. Assessment of response utilized end-of-treatment positron emission tomography (PET) (JCO 25: 579-86, 2007). Quality of life (QOL) was measured with the FACT-Lym v.4. Results: 27 pts. were enrolled. 1 died before treatment. For 26 pts: median age 76 yrs. (69-88), 14 females and 12 males, baseline PS (ECOG) 1 (0-2). Median follow-up for survivors: 9.2 mo. Phase I: 6 pts. at 300mg/d (no dose-limiting toxicity-DLT), 6 pts. at 400mg/d (2 grade 3 neutropenia = DLT). MTD 300mg/d x 10d. For 20 pts. at V 300mg/m2 (6 phase I + 14 phase II): 2 off study for toxicity, 1 withdrew consent, 6 CR (30%), 5 partial response (PR) (25%), 6 progressed (30%). Phenotypic overall responses (OR): germinal center (GC) 4/8 (2 CR), non-GC 6/10 (3 CR), transformed CLL 1/2 (1 CR). Median progression-free survival: 10 mo. QOL results will be presented. Conclusions: OR rate for V added to conventional chemotherapy and R was 55% (CR 30%, PR 25%) in relapsed/refractory DLBCL in elderly pts. not candidates for auSCT. This could provide a baseline for comparison with future clinical trials in this understudied population.
Association of prior rituximab exposure among patients undergoing autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma with inferior outcomes in males compared with females.
Authors: Lazaryan Aleksandr , Copelan Edward Alan , Bejanyan Nelli , Dean Robert M. , Sobecks Ronald M. , Hill Brian Thomas , Pohlman Brad L. , Kalaycio Matt E. , Bolwell Brian James , Sweetenham John W.
Published: March 2020

8055

Background: The combination of rituximab with CHOP remains the standard upfront therapy of patients (pts) with advanced diffuse large B-cell lymphoma (DLBCL). Gender disparity in survival of pts with DLBCL appears to be significantly modified by the use of rituximab in both upfront (Ngo, 2008; Pfreundschuh, 2009; Riihijarvi, 2010) and post-transplant maintenance (CORAL trial) settings. The presence of interaction between gender and prior rituximab exposure remains unknown in pts with relapsed/refractory DLBCL undergoing autologous stem cell transplantation (ASCT). Methods: We conducted a retrospective cohort study of 320 consecutive pts who underwent ASCT for relapsed/refractory DLBCL at our center from 01/1998 to 12/2010. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier method and by Cox proportional hazards regression analysis in SAS 9.1 (Cary, NC). Results: Among all pts (median age=54 yrs (IQR, 45-61); 92% Caucasians) 210 (66%) were males and 110 (34%) were females. 85 pts (27%) received more than two prior chemotherapy regimens. 174 pts (55%) had pre-ASCT exposure to rituximab as a part of induction or salvage regimens. Preparative regimen for ASCT uniformly consisted of Bu/Cy/VP-16. In the stratified univariate analysis of pts treated with rituximab prior to the ASCT, male pts had inferior RFS (p=0.02; hazard ratio [HR]=1.86, 95% CI, 1.09-3.18) and OS (p=0.03; HR=1.94, 95% CI, 1.05-3.58). In pts who did not receive rituximab prior to the ASCT, no difference in RFS or OS according to gender was observed (all p>0.4). Gender disparity among rituximab recipients was even more evident for both RFS (p=0.004; HR=2.22, 95% CI, 1.28-3.83) and OS (p=0.005; HR=2.42, 95% CI, 1.3-4.5) in the multivariable analyses controlling for age at transplant, number of prior chemotherapies, and pre-ASCT disease response. Conclusions: Our data support an emerging concern that male patients with DLBCL have inferior outcomes when treated with rituximab. The present study has extended this observation to pts with relapsed/refractory DLBCL treated with ASCT.
Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A North American (NA) multi-institutional experience.
Authors: Maeda Lauren Shizue , Geiger Jessica L. , Savage Kerry J. , Rose Jim , Pinter-Brown Lauren C. , Lunning Matthew Alexander , Abramson Jeremy S. , Bartlett Nancy , Vose Julie , Drape Jacqueline , Muffly Lori S. , McMillan Alex , Evens Andrew M. , Smith Sonali M. , Horwitz Steven M. , Ansell Stephen Maxted , Advani Ranjana
Published: March 2020

8060

Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p<0.0001), respectively). For all stages, treatment with CMT compared with CT or RT alone was also associated with better PFS and OS, 18.0 vs 3.9 months (p<0.0001), and 41.5 vs 10.2 months (p=0.002) respectively. Non-anthracycline-based regimens were associated with better PFS (p=0.001) and OS (p=0.045). No survival differences were seen between Asian and non-Asian pts. Conclusions: This series represents one of the largest experiences of ENKL in NA. Our data are consistent with Asian studies in: 1) majority of pts present with early stage disease; 2) overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. Advances in understanding biology and international collaborative efforts are required to improve outcome in this rare entity.
Progression-free survival for subsequent relapses in patients with peripheral T-cell lymphoma (PTCL).
Authors: Horwitz Steven M. , Delarue Richard , Lunning Matthew Alexander , Vose Julie , Coiffier Bertrand
Published: March 2020

8063

Background: In B-cell lymphoma, overall response (ORR) is lower and progression free survival (PFS) is often shorter with each subsequent progression. However, this has not been described for PTCL. Methods: We undertook a retrospective analysis in two U.S. centers (MSKCC and UNMC) and in GELA studies. All data for PTCL were reviewed to collect data for each line of therapy: treatment, response, PFS, date of next treatment, and survival. When date of progression could not be defined we calculated PFS as the time to next treatment. Pts who did not progress, died during first line, or were untreated at progression 1 were excluded. Data were collected for 4 lines of treatment, front line and 3 progressions. Results: 254 pts were identified. 205 were analyzed (49 excluded for missing data): GELA 116, MSKCC 51, and UNMC 37. Diagnoses were PTCL NOS in 34% and 60%, AITL in 49% and 35%, ALCL Alk- in 3% and 5%, and others in 15% and 18% for GELA and US centers respectively. 67% were male, median age was 51 vs 58 y. Advanced stage was more frequent in GELA (79% vs. 56% for US); baseline IPI was ≥2 in 90% vs 71%. Multidrug regimens were given in 99% and 80% for front line, 67% and 66% for 2nd line, 61% and 50% for 3rd line, 53% and 54% for 4th line, for GELA and US. Significantly fewer pts received each subsequent line of therapy with 205 pts receiving 2nd line, 96 pts 3rd line and 38 pts 4th line. No pt ≥65 y received 4th line treatment. Responses and PFS are listed in the table. Conclusions: For pts with PTCL, similar to B-cell lymphomas, ORR and PFS decrease with each line of therapy. When evaluating the activity of therapies in relapsed PTCL, line of therapy is a consideration and this series provides a benchmark for comparison. Based on this dataset, it is possible that better responses will be seen as new agents are moved into earlier treatment paradigms. [Table: see text]
Dose- and time-intensified ABVD without radiotherapy (RT) for advanced-stage Hodgkin lymphoma (HL) with mediastinal bulky disease (MBD).
Authors: Corazzelli Gaetano , Russo Filippo , Frigeri Ferdinando , Volzone Francesco , Capobianco Gaetana , Arcamone Manuela , Morelli Emanuela , Becchimanzi Cristina , Marcacci Giampaolo , De Filippi Rosaria , Saggese Mariangela , Pinto Antonio
Published: March 2020

8066

Background: The role of consolidation RT on MBD after upfront chemotheraphy for advanced HL is debated, also given the supradditive iatrogenic risk. We present the results achieved in the subset of patients (pts) with MBD (max width > 1/3 of thoracic diameter) accrued in a phase II study of an intensified ABVD program without RT. Methods: The current analysis derives from the final evaluation of our trial for advanced HL (stage IIXB-IV) conducted from 06/2004 to 03/2010 (Russo et al, ASH 2009 abst 715). Pts were scheduled to 6 cycles of a ‘time-densified’ ABVD (3-week intercycle, drugs on days 1 and 11) with the first 4 cycles being also ‘dose-intensified’: doxorubicin (ADM) 35 mg/m2, days 1 and 11 and G-CSF on days 6-8 and 17-19. Results: Of 82 accrued pts, 39 had BMD at presentation. Median age was 29yrs (r 16-58); male 46%; stage IIB 48%, III 8%, IV 43%; B-sympt 87%, E-disease 53%; IP Score ≥3 51%. All pts completed the intensified program. Median actual dose intensities for ADM, bleomycin, vinblastine and dacarbazine were 23.12, 6.69, 3.96 and 245 mg/week, respectively; the increase over conventional ABVD was 85% for ADM and averaged 32% for the other agents. PET2 negativity was achieved in 36/39 (92%; 95% CI 79-98), complete responses (CR) in 37/39 [94%; 95% CI 82-99]. At a median f.u. of 54 mo.s (r 20-91) all pts are alive with an event-free survival of 89% (95% CI, 80-98). Events were: <CR (n=1, CS IVB), progression (n=1, CS IIIA), relapse [n=2; at 10 (CS IVA ) and 15 (CS IIB) months after treatment]; all these pts had isolated mediastinal recurrence. CTCAE v3.0 toxicity: Grade (G) 2 nail changes (31%), G2-G3 hemorrhoids (12%-3%), G3 infection (13%) and constipation (5%), G3-G4 stomatitis (7%-2%). No acute or delayed G3-G4 cardiac events, nor G3-G4 decline in pulmonary function (FEV1, DLCO,FEF25-75) were seen. Conclusions: Intensified ABVD can achieve PET2 negativity in a very high proportion of pts with MBD and ensure a long-term disease-free status even without RT. While results need confirmation on a randomized basis, the low mediastinal failure rate seems in line with recent suggestions that RT could be omitted in MBD when CR is achieved upon intensified chemotheraphy.
Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42).
Authors: Mohrbacher Ann , Kang Min H , Yang Allen S. , Groshen Susan G. , Vergara Lori , Gutierrez Martin , Murgo Anthony J. , Kummar Shivaani , Quick Donald , Reynolds C. Patrick , Newman Edward M. , Maurer Barry
Published: March 2020

8073

Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer activity in preclinical studies. Due to limited bioavailability of a capsule formulation an intravenous intralipid-like emulsion formulation (4-HPR ILE) was developed to increase systemic exposures. Methods: 4-HPR was administered as a continuous intravenous infusion for 120 hrs every 21 days. Systemic toxicities, responses, and pharmacokinetics were assessed. Accelerated Simon design proceeded until moderate or dose-limiting toxicities (DLT) were scored on Course 1. Doses were 80 mg/m2/day to 1810 mg/m2/day. Patients with asymptomatic hypertriglyceridemia were scored separately. All patients were heavily pretreated. Results: Toxicity-evaluable patients = 25. At 1810 mg/m2/day, two patients experienced DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 mg/m2/day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, one experienced DLT pleural effusions; at 905 mg/m2/day (6 pts) 2 experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-to-plasma level relationship with mean steady-state 4-HPR levels of ~mid-20’s μM (640 mg/m2); ~mid-30’s μM (905 mg/m2/day); and ~mid-50’s μM (1280 mg/m2). Responses to date include a 64% CR+PR+SD response rate (36% CR+PR response rate) in 11 relapsed T-cell lymphomas which included histone deacetylase inhibitor-refractory patients, and a PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD = 1280 mg/m2/day x 5 days, every three weeks. 4-HPR ILE was safely administered and obtained 4-HPR plasma levels 6 -7 times higher than previously obtained using oral capsules. Durable complete responses were observed in T-cell lymphomas from 905 – 1810 mg/m2/day. An expanded cohort is accruing to a dosing schedule modified to decrease asymptomatic hypertriglyceridemia of 600 mg/m2 on Day 1 (to allow for induction of serum lipases) followed by 1200 mg/m2 Days 2-5. Supported by NCI U01 CA062505 and CPRIT RP10072.
Costimulatory molecule profiles and NK cell recovery after autologous hematopoietic cell transplantation (HCT) in multiple myeloma (MM) patients.
Authors: Htut Myo , Gallez-Hawkins Ghislaine , Palmer Joycelynne , Liu Xueli , Spielberger Ricardo Tomas , Parker Pablo Miguel , Farol Len , Franck Anne , Li Xiuli , Jeannet Laëtitia , Reburiano Eunicia , Jimenez Valerie , Duarte Lupe , Sahebi Firoozeh , Karanes Chatchada , Forman Stephen J. , Krishnan Amrita Y. , Zaia John
Published: March 2020

8089

Background: Increased immune responses post autologous HCT may be of benefit in long term disease control. Responses may be mediated by NK cell function and possibly other alternate pathways, including costimulatory molecule pathways. This pilot study assesses the expression of inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and CD28) molecules on NK cells after auto-HCT in MM patients and evaluates the effect of lenalidomide treatment on these pathways. Methods: 17 patients with MM undergoing HCT, median age 56.7 years (36 – 67), were included in the study. Peripheral blood samples were taken 3 days prior to HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 patients were receiving lenalidomide with d91 as median start date. NK cells and their costimulatory molecules were evaluated by flowcytometry using 2 six color panels of antibodies. One way ANOVA test and Kruskal-Wallis test (non-parametric) were applied to analyze the data using the Graphpad Software. Results: See table below. NK cell number was highest (median: 26% of total lymphocytes) at d14 (p: < 0.0001) compared to pre and post HCT levels. At d180, TNF-R OX40 expression was significantly increased in ≤PR group (n=5) (median: 9.5% of NK cells) compared to ≥VGPR (n=12) (0.8%; p=0.0084). In addition, NK cell number was higher in the lenalidomide group (n=13) (median: 15.15 % of total lymphocytes) compared to the no lenalidomide group (n=4) (6.74%; p=0.0108) at d180 post HCT. Significantly lower level of CTLA-4 expression was also found in the lenalidomide group (0.33% vs. 2.54%; p=0.0362). Conclusions: We observed NK cell recovery to baseline values at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was higher in ≤PR group than ≥VGPR group. Lenalidomide treatment was associated with higher NK cells number and decreased expression of CTLA-4. This observation could be a possible marker of enhanced host NK cell immune response against MM. Future clinical trials will explore therapies that increase NK cell responses. [Table: see text]
Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma.
Authors: Srivastava Geetika , Rana Vishal , Lacy Martha , Gertz Morie A. , Dispenzieri Angela , Hayman Suzanne R. , Buadi Francis , Dingli David , Lust John Anthony , Zeldenrust Steven R. , Russell Stephen J. , Rajkumar Vincent , Kumar Shaji
Published: March 2020

8096

Background: The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma. While the short-term outcomes with respect to response and toxicity is well-known, long-term outcome with this combination as initial therapy is not well described. Methods: We studied 286 consecutive patients with newly diagnosed MM seen at our institution, who received initial therapy with Len-Dex, and who had complete follow up records. Data regarding the clinical course was obtained from medical records. Results: The median (range) age at diagnosis was 63 (28-92) yrs; 166 (58% were ≤ 65 yrs and175 (61%) were male. The median estimated follow-up was 3.9 yrs (95% CI, 3.4, 4.2) and 203 (71%) pts were alive at the time of last follow up. The median estimated duration on Len-Dex was 5.3 mos (95% CI, 4.6, 6.4). The best overall response (≥PR) was 72%, including 26% with VGPR or better and 14 (5%) not being evaluable for a response. At last follow up, 41 (14%) patients were continuing on therapy. There were 93 pts (32%) who stayed on therapy for 12 months or more. Among these patients, the ORR was 86%, including 45% with VGPR or better. The median overall survival (OS) for the entire cohort from diagnosis was 7.4 yrs (95% CI; 5.8, NR) and the estimated 5-yr survival was 67%. There were 16 (5.5%) pts who died within a year of diagnosis. The median time to first disease progression, irrespective of transplant status, was 30.2 mos (95% CI, 25, 42). Overall, 143 (50%) of the patients have gone to stem cell transplant. Censoring those patients who proceeded to SCT prior to relapse at the time of BMT, the median TTP was 25.5 mos (95% CI, 22, 29). The median OS was 7.4 yrs for those ≤65 yrs, compared with 6.2 yrs for the older patients (P=0.01). The 5-yr OS estimate for patients in ISS stage 1, 2 and 3 were 82, 65, and 44 months respectively. Conclusions: The current study provides long-term estimates of responses and survival in a series of patients treated initially with lenalidomide and dexamethasone. The median survival of nearly 8 years reflects the efficacy of the novel agents both at diagnosis and at relapse and confirms the survival improvements seen in MM in the last decade.
Role of immune-related conditions in smoldering myeloma and MGUS.
Authors: Kwok Mary , Korde Neha , Manasanch Elisabet E. , Bhutani Manisha , Maric Irina , Calvo Katherine R. , Zingone Adriana , Costello Rene , Cherry Benjamin M. , Yancey Mary Ann , Mulquin Marcia , Roschewski Mark J. , Landgren Ola
Published: March 2020

8104

Background: Recent guidelines emphasize tailored follow-up and the need for clinical trials for high-risk smoldering myeloma (SMM). Emerging evidence from epidemiological studies suggests that immune-related conditions play a role in the causation of myeloma precursor disease (SMM and monoclonal gammopathy of undetermined significance; MGUS) and are of clinical importance for the risk of developing multiple myeloma. The aim of our study is to assess whether there is an altered biology in SMM/MGUS patients with preceding immune-related conditions. Methods: From our ongoing prospective SMM/MGUS natural history study, we evaluated 56 SMM and 60 MGUS patients. Information on autoimmunity was identified at baseline. All patients underwent extensive clinical and molecular characterization. At baseline, all patients underwent bone marrow biopsy evaluation using immunohistochemistry and multi-color flow cytometry of plasma cells. We assessed expression patterns of adverse plasma cell markers (CD56 and CD117), and applied risk models based on serum immune markers and bone marrow findings. Results: Among enrolled SMM and MGUS patients, 7 (12%) and 9 (15%) had a preceding autoimmune disorder. We found SMM patients with (vs. without) a preceding autoimmune disorder to have a substantially lower rate of CD56 (28% vs. 61%) and CD117 (28% vs. 61%) expressing plasma cells. When we compared the same markers in MGUS patients, CD56 and CD117 expression patterns were similar among patients with vs. without preceding autoimmunity (10% vs. 17%, and 50% vs. 48%). Using the Mayo Clinic risk model, none of the SMM patients with a preceding autoimmune disorder had high-risk features; in contrast, 3/41 (7%) of those without a preceding autoimmune disorder were high-risk SMM. Using the Mayo Clinic risk model, none of the MGUS patients were high-risk independent of autoimmune status. Conclusions: Our prospective clinical study found SMM patients with preceding immune-related conditions to have less adverse biology, supportive of epidemiological studies suggesting the risk of developing multiple myeloma is substantially lower in these patients.