bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on the large-scale screening of ALK fusion oncogene transcripts in archival NSCLC tumor specimens using multiplexed RT-PCR assays.
Authors: Li Tianhong , Huang Eric , Desai Sonal , Beckett Laurel , Stephens Craig , Zeger Gary , Maus Martin Karl Herbert , Danenberg Kathleen , Gandara David R.
Published: March 2020

7594

Background: The ALK inhibitor crizotinib offers a new standard of care for advanced NSCLC patients with EML4-ALK fusion oncogenes. We previously reported a 4.0% frequency of EML4-ALK fusion oncogene transcripts detected in 1889 NSCLC specimens in the RGI database (Li et al., ASCO 2011). Methods: Patented single and multiplexed RT-PCR assays suitable for rapid and accurate detection of all variants of ALK fusion oncogene transcripts were used as previously described, including all 9 known EML4-ALK fusion gene transcripts and ALK RNA levels (Danenberg, ASCO 2010). The sensitivity and specificity on archival formalin-fixed, paraffin-embedded tumor specimens are 99% and 100%, respectively. We here update the detection of EML4-ALK fusion transcripts in the RGI database. Results: Between 12/2009 and 09/2011, 4750 NSCLC specimens in the RGI database were tested for the presence of ALK fusion transcripts. We found 152 (3.2%) NSCLC cases with EML4-ALK fusion positivity, including 87 (57.2%) V1, 15 (9.9%) V2, 47 (30.9%) V3, and 3 (2.0%) V5a variants. Median age (range): 61.1 (33-96). Female: 74 (49%). All EML4-ALK-positive tumors were adenocarcinomas. No EGFR or K-Ras mutation was detected in ALK fusion-positive samples. Expression of chemotherapy-related biomarkers was available from 63 (female: 31, 49%) EML4-ALK-positive cases in the database: 43 (68%) had low TS level of <2.33; 40 (63.5%) had low ERCC1 level of <1.7, and 25 (40%) had low RRM1 level of <0.97. Conclusions: This RT-PCR assay provides a tool for rapid, large-scale screening of NSCLC FFPE tissues for EML4-ALK fusion gene transcripts. The relative value of this RT-PCR assay as a companion diagnostic test for drugs targeting ALK merits evaluation in comparison with the FDA approved ALK FISH test.
Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients treated with crizotinib.
Authors: Salgia Ravi , Solomon Benjamin J. , Shaw Alice Tsang , Camidge D. Ross , Evans Tracey L. , Kim Dong-Wan , Shi Yuankai , Han Ji-Youn , De Pas Tommaso Martino , Ou Sai-Hong Ignatius , Bartlett Cynthia Huang , Wilner Keith D. , Reisman Arlene , Iyer Shrividya
Published: March 2020

7596

Background: Crizotinib is an ALK inhibitor indicated in the US for advanced ALK-positive NSCLC. Visual effects reported by patients treated with crizotinib were characterized using the Visual Symptom Assessment Questionnaire (VSAQ). Methods: Patients with previously treated, advanced ALK-positive NSCLC were administered 250 mg BID crizotinib in an ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients completed the VSAQ at day 1 of each 21 day cycle and at end of treatment. The VSAQ has a recall period of 3 weeks and consists of 7 questions assessing presence, frequency, timing, duration and degree of bother of visual effects and their impact on Activities of Daily Living (ADL). The visual effects assessed included appearance of overlapping shadows/after images, flashing lights and streamers/strings/floaters, difficulty adapting to lights and seeing at night. Patients rated degree of bother on a 5-point scale ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency analyses were performed. Results: As of June 1 2011, visual effects as identified by VSAQ were reported by 63% (114/182) of patients at cycle 2 (C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112). The most commonly experienced visual events were appearance of flashing lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters (C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported each event to last ≤1 minute (C2:61%; C3:71%; C4:77%; C5: 70%). Majority of patients reported event frequency at each cycle of < 7 days/wk (50–78%). Patients reported that the visual effects occurred mostly in the morning (52–62%) and/or evening (62–73%). Majority of patients reported that visual effects were not at all or a little bothersome (C2:62%; C3:61%; C4:66%; C5:65%). Majority of patients indicated no or minimal impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual effects identified by VSAQ in patients treated with crizotinib were frequent, but were reported to be transient with no or minimal impact on ADL.
Does change in health-related quality of life (HRQoL) score predict survival? Analysis of a lung cancer RCT.
Authors: Ediebah Divine Ewane , Coens Corneel , Zikos Efstathios , Quinten Chantal , Ringash Jolie , Gotay Carolyn , Greimel Elfriede , Maringwa John T , King Madeleine , Flechtner Henning , Taphoorn Martin J. B. , Schmucker-Von Koch Jospeh , Weis Joachim , Reeve Bryce B. , Smit Egbert F , Bottomley Andrew
Published: March 2020

7607

Background: Over 60 cancer clinical trials have shown that baseline health-related quality of life (HRQoL) scores are prognostic for patient survival. Few studies have investigated the added value of change in HRQoL scores. Our aim was to investigate if change in HRQoL scores from baseline over time is also associated with survival. Methods: We analyzed data from an EORTC 3-arm randomized clinical trial (RCT) in advanced non-small-cell lung cancer (NSCLC) patients, comparing gemcitabine+cisplatin, versus paclitaxel+gemcitabine, versus standard arm paclitaxel+cisplatin. HRQoL was measured in 394 patients using the EORTC QLQ-C30 at baseline and after each chemotherapy cycle. The prognostic significance of sex, age and WHO performance status (0-1 vs. 2) and the 15 QLQ-C30 subscales were assessed with Cox proportional hazard models stratified for treatment (level of significance 0.05). Changes in HRQoL scores from baseline to each chemotherapy cycle assessment were categorized as “improved”, “stable” and “worsened” using a threshold of 10 points difference. Due to expected attrition, the analysis was limited to changes from baseline up to cycle 3. Results: There were 248 patients in cycle 1, 212 in cycle 2 and 196 in cycle 3. We performed analyses separately using data at cycle 1, cycle 2, and cycle 3. In all analyses, HRQoL in various subscales and socio-demographic and clinical variables (physical functioning (hazard ratio [HR] 0.91, 95% CI 0.85-0.98; p=0.0103), pain (1.11, 1.05-1.17; p= 0.0004), age (0.98, 0.97-1.00, p=0.0413) and WHO performance status (1.77, 1.09-2.89; p=0.0218) at cycle 1; pain (1.11, 1.03-1.20; p=0.0016), age (0.98, 0.96-1.00; p=0.0217) and sex (0.63, 0.42-0.95; p=0.0081) at cycle 2; and role functioning (0.93, 0.88-1.00; p=0.0128) and age (0.98, 0.96-1.00; p=0.0081) at cycle 3) predicted survival; however, change in HRQoL was only an independent predictor for improvement at cycle 1. Conclusions: Our findings suggest that change from baseline over time in HRQoL, as measured on subscales of the EORTC QLQ-C30, contains added prognostic value for survival independent of baseline HRQoL scores. Further work is needed to assess the robustness and sensitivity of these findings.
High-dose chemotherapy followed by allogeneic stem cell transplantation in high-risk relapsed and refractory aggressive non-Hodgkin lymphoma: Results of a prospective study of the German high-grade non-Hodgkin lymphoma study group.
Authors: Glass Bertram , Hasenkamp Justin , Wulf Gerald , Dreger Peter , Pfreundschuh Michael , Gramatzki Martin , Silling Gerda , Wilhelm Christian , Zeis Matthias , Pfeiffer Sebastian , Trümper Lorenz , Schmitz Norbert ,   DSHNHL
Published: March 2020

8004

Background: The role of allogeneic stem cell transplantation (alloSCT) in high-risk aggressive NHL is poorly defined; the role of graft-versus-lymphoma effect is unclear. Reduced intensity conditioning has shown limited efficacy in patients with refractory disease. Methods: Patients with primary refractory disease, early relapse (<12 months) or relapse after autologous SCT of aggressive B-cell (n=61) or T-cell (n=23) NHL were enrolled from June 2004 to March 2009. Myeloablative conditioning (fludarabine 125mg/m2, busulfan 12mg/kg, cyclophosphamide 120 mg/kg) was followed by alloSCT from related (n=24) or unrelated (n=60) donors. 57/84 patients received a 10 HLA-loci compatible graft. Results: Overall survival at 3 years was 42% (95% CI, 31% to 52%), progression-free survival (PFS) was 40% (95% CI 29% to 50%). Non-relapse mortality (NRM) was 12% at 100 days and 35% at one year. Graft-versus-host disease (GVHD) and infection were the predominant causes of NRM. Relapse rate was 30% with latest relapse at day +327. Patients with an HLA fully compatible donor (plus ATG with unrelated donors) (n=40) had the best outcome (NRM at 1y 10.4 vs 57.2%, PFS at 3y 64.7% vs 31.8%, p < 0.0001). GVHD > grade I correlated with improved PFS (HR 0.45, p=0.0088). Patients with refractory disease or early relapse (n=60) experienced PFS at 3y of 33%. Conclusions: Lymphoma-debulking (high-dose) chemotherapy followed by alloSCT shows excellent results in heavily pretreated patients with early relapse or primary refractory aggressive lymphoma. There was evidence of graft-versus-lymphoma activity in this setting. For patients with a fully matched (10/10) related or unrelated donor the results compare favorably to autoSCT or alloSCT following reduced-intensity conditioning.
Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma.
Authors: Kolb Brigitte , Hulin Cyrille , Caillot Denis , Benboubker Lotfi , Tiab Mourad , Blin Nicolas , Leleu Xavier , Roussel Murielle , Attal Michel , Facon Thierry , Moreau Philippe
Published: March 2020

8009

Background: Melphalan-prednisone + thalidomide (MPT) or bortezomib (MPV) are approved in frontline MM patients (pts) >65 years. Both regimens demonstrated significant benefit over MP alone in terms of PFS and OS but this benefit could be hampered by the risk of peripheral neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has demonstrated promising activity and favorable toxicity profile, with low rates of PN. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this combination in newly diagnosed MM >65. Methods: In Phase I, Cfz was the only escalating agent starting at 20 mg/m2 (level 1) with maximal planned dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² were given on days 1 to 4, for all dose levels. Based on toxicity assessment, the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD determination was based on occurrence of Dose limiting toxicities (DLTs) during the first cycle only. DLTs were defined as any grade 4 hematologic toxicity or preventing administration of 2 or more of the 8 Cfz doses of the first treatment cycle except grade 4 thrombocytopenia without bleeding or grade 4 neutropenia lasting ≤ 7 days; or grade ≥ 3 febrile neutropenia; or any other grade ≥ 3 nonhematologic toxicity. Results: As of January 20th 2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the MTD was considered to be 36 mg/m². Then, 16 additional pts were included in the phase II at level 3. Overall, 40 pts have been enrolled into the phase I/II study and 26 pts are evaluable for response. The ORR was 92% including 42% at least VGPR. These results compare favorably to those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 and 85%, respectively) in the same population. Conclusions: Frontline carfilzomib (36 mg/m2) + MP is a tolerable and very effective combination in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy data to be presented at the meeting.
Evidence for rituximab (R) underdosing in subpopulations of elderly patients with DLBC: Results of the RICOVER-60 study of the DSHNHL.
Authors: Pfreundschuh Michael , Mueller Carsten , Zeynalova Samira , Held Gerhard , Poeschel Viola , Zwick Carsten , Reiser Marcel , Lengfelder Eva , Steinhauer Hjalmar B. , Limmroth Christina , Schmitz Norbert , Murawski Niels ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8024

Background: Gender and weight independently influence R clearance and R serum elimination half life (Mueller et al., Blood 2012). To investigate whether the differences in R pharmacokinetics translate into different outcomes, we analyzed elderly patients (pts) with different R pharmacokinetics treated in the RICOVER-60 study. Methods: 1222 elderly pts. (61-80 y) were randomized to receive 6 or 8 cycles of CHOP-14 with or without R given on days 1, 15, 29, 43, 57, 71, 85, and 99. For this study, subgroup analyses were performed for pts with faster R clearance: elderly male (vs. female) pts and elderly weighty (upper quartile: >77kg) vs. slim (lower quartile: ≤60 kg) female pts. Results: Elderly females had a slower R clearance (8.21 ml/h vs. 12.68 ml/h; p=0.003) and a prolonged R half life compared to men (t1/2ß=30.7 vs. t1/2ß=24.7 d; p=0.003). Female pts had a higher 3-year PFS (68% vs. 61%; p=0.062) and OS (74% vs. 68% p=0.086). The differences in outcome were due to a greater outcome improvement by the addition of R in females: the difference in 3-year PFS between female and male pts was 5.1% (p=0.448) in pts. receiving CHOP-14 only and 7.7% (p=0.053) when R was added. In a multivariate analysis the relative risk for progression in male compared to female patients was not significantly elevated after CHOP-14 (1.1; p=0.348), but was significantly higher after R-CHOP-14 (1.6; p=0.004). With respect to weight, addition of R resulted in a significantly improved 3-year PFS (74% vs. 49%; p=0.006) in female pts with a body weight within the lower quartile (≤60 kg) who have an R serum half life of >38.1 days, while there was no improvement by the addition of R (72% vs. 71%; p=0.816) in female pts. with a body weight within the upper quartile (>77kg), who have a serum half life of <29.3 days. Conclusions: The reduced benefit of adding R to CHOP in elderly DLBCL pts. with a shorter rituximab serum half life (and hence lower serum levels) suggests that the respective subpopulations (males and weighty females) are underdosed when R is dosed based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts with a shorter R serum half life can improve the outcome of the respective pts.
Outcome of elderly DLBCL patients with 6xCHOP-14 and 8 rituximab (R) applications given over an extended period (SMARTE-R-CHOP-14 trial of the DSHNHL).
Authors: Murawski Niels , Held Gerhard , Zeynalova Samira , Mueller Carsten , Poeschel Viola , Viardot Andreas , Haenel Mathias , Keller Ulrich , Reiser Marcel , Ziepert Marita , Schmitz Norbert , Pfreundschuh Michael ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8025

Background: 6xCHOP-14 with 8xR given over an extended period improved 3-year EFS (67% vs. 54%; p=0.030) and OS (80% vs. 67%, p=0.034) of poor-prognosis patients (IPI=3-5) in the SMARTE-R trial compared to the RICOVER-60 trial where patients received 8xR every 2 weeks. Because we had recently shown (Mueller et al., Blood 2012) that elderly male patients have a faster R clearance (12.68 ml/h vs. 8.21 ml/h; p=0.003) and shorter serum elimination half life (t1/2ß=24.7 vs. t1/2ß=30.7 days; p=0.003) than females, we analyzed whether these differences translated into different outcomes by comparing the results achieved by elderly female and male patients in the RICOVER-60 and SMARTE-R trials. Methods: In SMARTE-R, 189 evaluable elderly (61-80 y) pts. with DLBCL received 6 cycles of 2-weekly CHOP-14 combined with 8xR on days -4, -1, 10, 29, 57, 99, 155, and 239. The primary endpoint was event-free survival (EFS). 306 pts treated within the RICOVER-60 trial with 6xCHOP-14 + 8 R given on days 1, 15, 29, 43, 57, 71, 85 and 99 served as controls. Results: The 3-year EFS of 51 poor-prognosis male patients in SMARTE-R was 67% compared to 47% of 66 poor-prognosis male patients treated in RICOVER-60 (p=0.037); the respective figures were 71% vs. 53% (p=0.051) for PFS and 80% vs. 60% (p=0.027) for OS. In contrast, female poor-risk patients had only a small benefit from the extended rituximab exposure in SMARTE-R (n=48) compared to RICOVER-60 (n=57): 67% vs. 61% (p=0.354) for EFS; 71% vs. 67% (p=0.489) for PFS; and 80% vs. 76% (p=0.528) for OS. Conclusions: Elderly male patients with poor-prognosis DLBCL who have a faster R clearance and shorter R serum elimination half life than female patients, benefit significantly from the longer R exposure in SMARTE-R with a gain of 20% in 3-year OS, while the outcome of female patients was only slightly improved. Even though R maintenance has failed to demonstrate any benefit in the primary treatment of DLBCL to date, these results underline the importance of a minimum exposure time of R in order to exploit its full therapeutic potential in DLBCL. Supported by Deutsche Krebshilfe.
Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).
Authors: Trappe Ralf Ulrich , Dierickx Daan , Reinke Petra , Neuhaus Ruth , Morschhauser Franck , Zaucha Jan M. , Mollee Peter , Zimmermann Heiner , Dreyling Martin H. , Duehrsen Ulrich , Verhoef Gregor E.G. , Lehmkuhl Hans , Subklewe Marion , Huettmann Andreas , Tousseyn Thomas , Tarella Corrado , Leblond Veronique , Anagnostopoulos Ioannis , Riess Hanno , Choquet Sylvain ,   German PTLD Study Group and European PTLD Network
Published: March 2020

8030

Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG > 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of >3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.
Impact of t (11;14) on the outcome of autologous hematopoietic cell transplantation (Auto-HCT) in multiple myeloma.
Authors: Sasaki Koji , Lu Gary , Hosing Chitra , Popat Uday R. , Ahmed Sairah , Shah Nina , Bashir Qaiser , Dinh Yvonne , Orlowski Robert Z. , Champlin Richard E. , Qazilbash Muzaffar
Published: March 2020

8040

Background: Approximately 15-20% of patients with multiple myeloma (MM) present with t(11;14)(q13;q32) involving IgH and CCND1-XT genes. In this study, we report the impact of the t(11;14) on the outcome of patients with MM. Methods: We performed a retrospective chart review on patients with MM who underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between 2/2000 and 8/2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available before transplant. The primary objective was to compare the progression free survival (PFS) and overall survival (OS) of patients with t(11;14) to patients without chromosomal abnormalities. Results: CC or FISH studies were available for 1239 patients: 863 normal, 28 with t(11;14), 348 with other abnormalities. Concurrent high-risk abnormalities on CC or FISH were seen in 15/28 patients with t(11;14): del(13q) in 11 , del(17p) in 3, and t(14;16)(q32;q23) in 1. Induction treatment in patients with t(11;14) was: bortezomib + dexamethasone +/- thalidomide/lenalidomide : 15 (53%), thalidomide or lenalidomide + dexamethasone: 11 (39%), others 2 (8%); they received auto-HCT after a median of one line (1-7) of therapy. Median follow up in surviving patients was 39 months. There was no significant difference in median time from diagnosis to auto-HCT from diagnosis (6.9 vs. 7.7 months, p=1.0), disease status at auto HCT (>PR1: 82 vs. 76%, <PR1: 7 vs. 11%, relapsed 10 vs. 13%), complete remission (CR: 21% vs. 32%; p=0.30), very good partial remission (VGPR: 29% vs. 21%; p=0.23) or overall response (75% vs. 85%; p=0.18) between patients with t(11;14) and normal karyotype. Median PFS in patients with t(11;14) and normal karyotype was 15.7 months and 35.9 months, respectively (p=0.017). Median OS in patients with t(11;14) and normal karyotype was 51.4 months and 88.4 months, respectively (p=0.03). There was no difference in PFS (p=0.25) or OS (p=0.71) in patients with t(11;14), with or without other high-risk chromosomal abnormalities. Conclusions: In this large single center study with a long follow up, we demonstrated that t(11;14) in MM is associated with a shorter PFS and OS in the context of auto-HCT.
Biweekly regimen of nonpegylated liposomal doxorubicin with cyclophosphamide, vincristine, and prednisone plus rituximab (R-COMP-14) as primary treatment for diffuse large B-cell lymphoma (DLBCL): Long-term follow-up of a phase II study.
Authors: Herrero Joaquin , Gómez-Codina Jose , Provencio Mariano , Rueda Antonio , Sabin Pilar , Llanos Marta , Lobo Francisco , Vicente David , Garcia Arroyo Francisco Ramon ,   Grupo Oncologico para el estudio y Tratamiento de los Linfomas (GOTEL)
Published: March 2020

8062

Background: To evaluate the efficacy and toxicity of dose-dense biweekly schedule of (R-COMP-14) in patients newly diagnosed of agrressive diffuse B cell lymphomas (DLBCL). Methods: In this single-arm, open-label, multicenter trial, 60 pts were included between 2004 to 2008. Received rituximab (375 mg/m2) D1 + cyclophosphamide (750 mg/m2)D1 + vincristine (1.4 mg/m2; max. 2 mg)D1 + prednisone (100 mg/d D1 and D5) and non-pegylated liposomal doxorubicin (50 mg/m2) every two weeks. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses. Granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim was administered on day 2. The primary efficacy endpoint was (CR) and objective response rate (ORR). Survival follow-up data were updated. Results: 59 evaluable patients with a median age of 50 years (21-65) were analyzed. Clinical Characteristics: 22 Pts stage I-II (aaIPI≥1 (37%), 17 (29%) stage III, and 19 (32%) in stage IV. aaIPI=1 41(67%), aaIPI2/3= 18(33%).LVEF basal: 65,5[50-93]. Extra-nodal disease: 42%. B symptoms: 44.1%. The mean calculated dose intensities of cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and rituximab were 98,7%, 98,7%, 76,1% and 98,3% respectively. Among 60 eligible patients (96,7% completed six cycles and 74,4% completed all eight cycles. ORR was 81%, and CR rate of 54,2%. IC 95% [40,7-67,8]. The main toxicity was neutropenia Gr=III-IV/ and febrile neutropenia in 20% of patients. Neurotoxicity Gr=III-IV in 3,4%. No cardiac toxicity Gr: III-IV was reported. No toxic deaths. After a median follow-up of 25-64m(44m) the 5-year overall survival (OS), event-free survival, (EFS) and disease free survival (DFS) were 80%, 67%, and 77% respectively. Forty two patients (71%) had (<60 y) and med. OS(p=0,017) and med EFS(p=0,014) was 72,3% and 68,1 in aaIPI=1 and 50,4% and 33,8 in aaIPI>1. Conclusions: Dose dense R-COMP-14 is an effective regimen in patients with (DLBCL) comparable o R- CHOP-14. Good tolerability profile with no Gr: III-IV cardiac toxicity or reduction of LVEF.
Efficacy of ocaratuzumab (AME-133v) in relapsed follicular lymphoma patients refractory to prior rituximab.
Authors: Wayne Jennifer L. , Ganjoo Kristen N. , Pohlman Brad L. , De Vos Sven , Flinn Ian W. , Dang Nam H. , Mapara Markus Y. , Smith Mitchell R. , O'Reilly Adrienne M. , Marulappa Shashidhara Y. , Jain Vinay Kumar
Published: March 2020

8081

Background: Ocaratzumab, previously known as AME-133v, is a humanized next-generation anti-CD20 monoclonal antibody. It has been optimized with a 13 to 20-fold increase in binding affinity to CD20 and improved binding to the low-affinity (F/F and F/V) polymorphisms of FcγRIIIa (CD16), which are thought to predict lower response rates and shorter duration of responses to rituximab. Methods: In a phase I dose escalation study in relapsed follicular lymphoma (FL) patients, ocaratuzumab was well-tolerated at doses up to 375 mg/m2 (Forero-Torres et al. CCR 2012). In a follow-on phase II trial, 44 patients with relapsed FL following prior rituximab and the low-affinity FcγRIIIa polymorphism (F-carriers) received 375 mg/m2 of ocaratuzumab weekly for 4 doses. In this study, overall response rate (ORR) was 36% and median progression free survival (PFS) was 91 weeks (Ganjoo et al. Haematologica 2011). Results: Amongst the 56 patients receiving 100 and 375 mg/m2 of ocaratuzumab, 8 patients had a previous time to progression of ≤ 180 days following their last rituximab treatment. These patients had a median of 2 prior rituximab treatments, (range 1-6 treatments), and median PFS following last treatment of 159 days. Five of the 8 patients showed a longer PFS after ocaratuzumab administration, compared with last rituximab treatment. All 5 patients expressed the homozygous low-affinity genotype of FcγRIIIa (F/F). At the time of study closure, 3 of the patients were still in remission (indicated by * in the table). Conclusions: This retrospective analysis suggests that ocaratuzumab may be non-cross-resistant to rituximab in patients with the low-affinity FcγRIIIa polymorphism. Prolonged PFS in selected patients following ocaratuzumab suggests that the increased binding affinity to CD16 and improved antibody-dependent cell-mediated cytotoxicity (ADCC) of this antibody is clinically relevant. As a single agent, ocaratuzumab may provide prolonged clinical benefit in relapsed FL patients and a clinical trial comparing ocaratuzumab to rituximab is in preparation. [Table: see text]
Effect of matrix metallopeptidase 13 (MMP13) on multiple myeloma (MM) cells, osteoclast (OCL) activity, and bone resorption.
Authors: Fu Jing , Li Shirong , Feng Rentian , Jin Mei Hua , Sabeh Farideh , Weiss Stephen , Lentzsch Suzanne
Published: March 2020

8099

Background: MM cells produce OCL-activating factors that induce excessive bone resorption resulting in lytic lesions. The role of MMPs in invasion/progression of solid tumors is well-known, but its function in MM has not been well elucidated. Our group has shown that MMP13 is highly expressed in primary MM cells and in sera of MM patients. Levels of MMP13 significantly correlate with the extent of bone disease. MMP13 is induced by IL-6 via AP-1 activation in MM cells and enhances fusion of OCL precursors resulting in excessive bone resorption. OCL formation using MNCs of mmp-13-/- mice resulted in a fusion defect, significantly decreased OCL size and activity, which could be reversed by exogenous MMP13 (ASH 2009, IMW 2011). Methods: Methods will be presented in the Results section. Results: RT-PCR and western blotting revealed that IL-6 treatment of MM cells induced MMP13 transcription (30-fold) and secretion (>1000-fold). Protein expression of the AP-1 members c-Jun and c-Fos was induced by IL-6, which correlated with MMP13 upregulation. Our data further indicate that the catalytic activity of MMP13 is not required to enhance OCL formation and bone resorption. To prove this, we generated the MMP13 activity-dead mutation MMP13-E223A construct by site-directed mutagenesis PCR-based cloning. The mutated protein was overexpressed in HEK293 cells and purified from the supernatant to confirm whether loss of catalytic activity blocks MMP13 function. To further investigate the in vivo role of MMP13 in MM bone disease, MMP13 expression was knocked down (KD) in murine 5TGM1-MM cells by pKLO. 1 puro lentiviral infection containing sh-RNA targeting mouse MMP13 sequence. MMP13-KD 5TGM1-MM cells or WT-5TGM1-MM cells were intratibially injected into RAG2-/- mice. Development of lytic bone lesions are monitored by micro-QCT and data will be available at the time of presentation. Conclusions: Our data suggest that MMP13, secreted by MM cells, plays a critical role in the development of lytic lesions. Targeting MMP13 represents a promising approach to treat or to prevent bone disease in MM.
Patterns of nonhematologic malignancies in a population of African American veterans with monoclonal gammopathy of unknown significance (MGUS).
Authors: Ghanem Hady , Namburi Swathi , Rivera Gabriel , Amdur Richard , Schechter Geraldine P.
Published: March 2020

8103

Background: Monoclonal Gammopathy of Unknown Significance (MGUS) is characterized by the presence of a monoclonal immunoglobulin in the serum or the urine with no evidence of hematologic malignancy. A possible relationship between MGUS and increased incidence of NHM has been suggested in Caucasian populations. However, data in African Americans with MGUS are lacking. Methods: Non-MGUS controls were selected randomly from patients who did not have a paraprotein detected on electrophoresis (NMGUS) and were matched 2-to-1 to MGUS cases. Descriptive statistics and comparisons are presented to compare MGUS and NMGUS groups. Results: 492 male patients with MGUS patients were matched with 984 male NMGUS patients. 451 patients had abnormal serum protein studies (91.6%) and 40 had light chain disease (8.4%). Median age at diagnosis of MGUS was 68 years (28-81). 144 MGUS patients (29.2%) and 296 NMGUS patients (30%) had 1 or more NHM. The median age of diagnosis of 1st NHM was 70 (25-94) in the MGUS group and 68.4 in the NMGUS group (34.5-94.4). 19 MGUS patients (3.8%) and 27 NMGUS patients had 2 different types of NHM (2.7%). 1 MGUS patient (0.2%) and 3 NMGUS patients (0.3%) had 3 NHM. 57 patients had MGUS before NHM (11.5%) and 69 patients were diagnosed with MGUS after the diagnosis of NHM (14%), and median differences between diagnosis of MGUS and 1st NHM were 4 years (1-12 years) and 5 years (1-38 years) respectively. Types of NHM were comparable, and prostate cancer was the most prevalent NHM in both groups (15% of MGUS patients and 17% of NMGUS patients). Median time of follow up was 49.3 months for MGUS patients and 35.2 months for NMGUS patients 140 of the MGUS patients (28.4%) and 214 non-MGUS patients (21.75%) had died at data cut-off. Conclusions: Based on these observational data, prevalence and types of NHM appear to be comparable in MGUS and NMGUS African American patients. All cause mortality appears to be higher for NHM patients if they had MGUS. This pattern will need to be verified prospectively in a larger group of patients.
Does stage migration exist in active multiple myeloma (MM)?
Authors: Kapoor Prashant , Kumar Shaji , Gertz Morie A. , Lacy Martha , Dingli David , Russell Stephen J. , Buadi Francis , Zeldenrust Steven R. , Lust John Anthony , Hayman Suzanne R. , Kyle Robert A. , Rajkumar Vincent , Dispenzieri Angela
Published: March 2020

8105

Background: Tumor stage migration can artifactually inflate cancer survival rates and overestimate benefits of newer therapies. We have previously shown a favorable impact of widely used novel agents in MM patients. However, it is not known whether use of well tolerated and easily administrable novel agents results in their introduction at lower levels of MM burden (and therefore add to improved outcome). Our goal was to assess for stage migration in newly diagnosed active MM patients. Methods: We reviewed records of 1,467 patients with active MM at Mayo Clinic, at initiation of therapy from 3 consecutive 5-year intervals: 01/1996-12/2000 (Group 1), 01/2001-12/2005 (Group 2), 01/2006- 12/2010 (Group 3). These intervals reflect the practice changing approaches at our center transitioning from the use of alkylator-based to novel agent-based initial therapy. Traditional parameters and staging systems were used to estimate tumor burden. We performed one way analysis of variance (ANOVA) to assess for differences in these parameters among the groups. A p-value of <0.05 was considered significant. Results: Group 3 shows an upward trend for hemoglobin (Hgb), and lower creatinine and bone marrow plasma cell (BMPC) percent. Compared to other groups, a greater proportion of Group 3 patients are assigned to lower Durie Salmon (DS) stages (Table) suggesting reduced tumor burden at therapy initiation. In contrast, the International Staging System (ISS) which is not used for decisions regarding therapy initiation divides cohorts in similar proportions. Conclusions: Stage migration is evident in our cohort of active MM patients presenting in the time periods of evolving initial therapeutic strategies. Future studies should take into account the bias introduced by this phenomenon in interpreting survival analysis of MM patients. [Table: see text]
Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma.
Authors: Chapman Paul B. , Hauschild Axel , Robert Caroline , Larkin James M. G. , Haanen John B. A. G. , Ribas Antoni , Hogg David , Hamid Omid , Ascierto Paolo Antonio , Testori Alessandro , Lorigan Paul , Dummer Reinhard , Sosman Jeffrey Alan , Garbe Claus , Maio Michele , Nolop Keith B. , Nelson Betty J , Joe Andrew K. , Flaherty Keith T. , McArthur Grant A.
Published: March 2020

8502^

Background: We previously reported results of the planned OS interim analysis for BRIM-3 (50% of the planned 196 deaths required for final analysis) at which time the independent Data Safety Monitoring Board recommended release of results due to compelling efficacy (hazard ratio [HR] for death, 0.37 [95% CI 0.26–0.55]); p<0.0001 and PFS HR 0.26 [95% CI 0.20–0.33]; p<0.0001) and that DTIC-treated patients be permitted to cross over to receive vem. Median follow-up for vem patients was 3.75 months, and longer follow-up would estimate median OS more reliably. Updated OS with median 6.2 months follow-up and 199 total deaths showed HR for death 0.44 (95% CI 0.33–0.59) favoring vem and median OS for vem not reached. We report here the results of an updated OS analysis performed in Nov 2011 with ~10 months median follow-up on vem. Methods: 675 patients with previously untreated, unresectable Stage IIIC or IV melanoma that tested positive for BRAFV600E mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) from Jan to Dec 2010 to vem (960 mg po bid) or DTIC (1000 mg/m2 IV q3w). Co-primary endpoints were OS and PFS. OS data for DTIC patients who crossed over to vem were censored at the time of crossover. Results: Median lengths of follow-up on vem and DTIC were 10.5 months (range 0.4–18.1) and 8.4 months (range <0.1–18.3), respectively. There were 334 deaths. Median OS rates with vem and DTIC were 13.2 months (95% CI 12.0–15.0) and 9.6 months (95% CI 7.9–11.8), respectively. 12-month OS rates were 55% for vem and 43% for DTIC. HR for death was 0.62 (95% CI 0.49–0.77) in favor of vem. 81 DTIC patients crossed over to vem. 44 (13%) vem and 65 (19%) DTIC patients received ipilimumab post-progression. Conclusions: With longer follow-up, vem treatment continues to be associated with improved OS in the BRIM-3 study. An updated analysis, with estimated median follow-up of ~13 months and including response data, will be conducted in Apr 2012 and presented at the meeting.
Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL).
Authors: Hodi F. Stephen , Sznol Mario , McDermott David F. , Carvajal Richard D. , Lawrence Donald P. , Topalian Suzanne Louise , Wigginton Jon , McDonald Dan , Kollia Georgia , Gupta Ashok Kumar , Sosman Jeffrey Alan
Published: March 2020

8507

Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. This study describes the activity and safety of BMS-936558 in patients (pts) with previously treated advanced MEL and underscores the importance of the PD-1/PD-L1 pathway in MEL therapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 95 MEL pts were treated with BMS-936558 at 0.1 (n=13), 0.3 (n=17), 1 (n=28), 3 (n=17), or 10 mg/kg (n=20). ECOG performance status was 0/1/2 in 56/36/3 pts. The majority of pts (60/95) had received prior immunotherapy (IT), primarily interferon-alpha or IL-2 (prior anti-CTLA-4 excluded). Prior B-raf inhibitor therapy was noted in 7/95 pts. The number of prior therapies was 1 (n=35), 2 (n=34), or ≥3 (n=26). Sites of metastatic disease included lymph node (n=60), liver (n=32), lung (n=55), and bone (n=10). Median duration of therapy was 15 wk (max 120 wk), with 40 pts still receiving treatment. The incidence of grade 3-4 related AEs was 19% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity was observed at all dose levels (Table). Of 20 pts with OR at the time of data lock, 12 had OR duration ≥1 yr and 6 pts were on study with OR duration between 1.9 and 11.3 mo. OR were seen in pts with visceral or bone metastases. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. Conclusions: BMS-936558 had durable clinical benefit in pts with advanced MEL, including those who had received prior IT. Further development of BMS-936558 in MEL is ongoing. [Table: see text]
Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with stage III/IV melanoma: 10 mg/kg cohort interim results.
Authors: Hamid Omid , Hwu Wen-Jen , Richards Jon M. , Weber Jeffrey S. , Wolchok Jedd D. , Sznol Mario , Minor David R. , Pavlick Anna C. , Urba Walter John , Hodi F. Stephen , Yang Arvin , Michener Tracy , Balogh Agnes , McDermott David F.
Published: March 2020

8508

Background: The EAP (CA184-045), begun in 8/07, currently provides the largest safety database for Ipi outside of controlled clinical trials (CCTs) and included pts with brain metastases (BM) and primary ocular (OM) and mucosal (MM) melanoma. The EAP was amended in 10/08 to administer a 3 mg/kg dose based on the current label (Hodi et al. NEJM 2010). We now report interim data from pts treated in the US at 10 mg/kg from 8/07-10/08. Methods: Pts with unresectable Stage III or IV melanoma who progressed on at least 1 systemic therapy or had no alternate treatment options were eligible. Pts received 10 mg/kg Ipi i.v. q 3 wks up to 4 doses (induction) followed by 10 mg/kg q 12 wks (maintenance) until no longer clinically benefiting or unacceptable/unmanageable toxicity occurred. All serious adverse events (SAEs) and on-study deaths were collected; overall survival (OS) was assessed retrospectively. Results: Of 906 treated pts, 830 were included in the analysis; 39 from prior Ipi trials + 37 from sites whose IRB did not agree to collect OS were excluded. Pts got a median of 4 doses; 31% got ≥5 doses. ECOG 0/1/2 was 53%/39%/8% (1 pt was ECOG 3); 27% had BM, 5% had OM, and 4% MM. Primary reasons for discontinuation were disease progression (67%) and drug toxicity (11%). Incidence of drug-related SAEs was 27% with diarrhea 10%, colitis 8%, endocrinopathies 4%, and dermatitis 0.8%. 2 pts (0.24%) had on-study hepatitis SAEs, both considered drug-related and resulted in discontinuation. There were 3 (0.36%) drug-related intestinal perforations. 2 deaths (0.24%) were the outcome of drug-related SAEs; 1 multi-organ failure and 1 acute respiratory distress syndrome (both ≤70 days from last induction dose). 72 (9%) pts currently remain on treatment (i.e. >3 years). Available OS data showed that 138 pts (17%) were still at risk after 3 years. For 27% of pts the last known alive date was >30 days before data cutoff (with most >2 yrs). Conclusions: Data from the US EAP must be interpreted with caution compared to CCTs. To date, incidence of SAEs for hepatitis and intestinal perforation, and drug-related death at 10 mg/kg Ipi monotherapy is consistent with that seen in BMS clinical trials. Durable OS (>3 yrs) was observed in at least 17% of pts.
Tumor-specific circulating cell-free DNA (cfDNA) BRAF mutations (muts) to predict clinical outcome in patients (pts) treated with the BRAF inhibitor dabrafenib (GSK2118436).
Authors: Long Georgina V. , Ascierto Paolo Antonio , Grob Jean Jacques , Hamid Omid , Kefford Richard , Lebbe Celeste , Minor David R. , Ribas Antoni , Schadendorf Dirk , Fecher Leslie Anne , Trefzer Uwe , Arya Nikita , Gagnon Robert C. , Goodman Vicki L. , Siegfried Anne , Mazumdar Jolly , Martin Anne-Marie
Published: March 2020

8518

Background: Tumor specific cfDNA levels in blood increase with tumor burden and decrease following treatment. cfDNA can harbor muts consistent with the tumor. Thus cfDNA could be a useful biomarker of therapeutic response. BREAK-2, an open label, single arm, Phase II study evaluated efficacy, safety and tolerability of dabrafenib in BRAF V600E/K mut+ metastatic melanoma pts. Exploratory objectives of BREAK-2 were to evaluate whether (i) tumor and cfDNA BRAF muts are correlated; (ii) cfDNA levels correlate with baseline tumor burden and (iii) cfDNA muts predict clinical outcome with dabrafenib. Methods: BRAF mut status was established for 92pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 91/92 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using the BEAMing technology. Spearman correlation coefficients (R) were used to determine the association between cfDNA fraction (mut DNA molecules > 0.01%) and estimated baseline tumor burden, calculated by the sum of RECIST measurements of target lesions. Logistic regression and Cox proportional hazards models were used to assess the association between cfDNA mut status and objective response rate (ORR) and progression free survival (PFS), respectively. Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 83%, and 96% respectively. Higher cfDNA V600E mut fraction was associated with higher baseline tumor burden (R=0.73; p-value < 0.0001; n=60); lower ORR (O.R. = 0.83; 95% CI = 0.72, 0.96; p-value=0.0134; n=46) and shorter PFS (H.R.=1.09; p-value=0.0006; n=46). Median PFS was 27.4 weeks in the overall V600E pt population (n=76) and 20.0 weeks in the cfDNA V600E pt population (n=46). Otherwise, the response endpoints were comparable between the two populations. There was no correlation between V600K mut fraction (n=14) and any efficacy endpoints. Conclusions: cfDNA was useful for detecting BRAF muts in pts treated with dabrafenib and increasing V600E mut fraction was associated with reduced ORR and shorter PFS, suggesting higher amounts of mut cfDNA in V600E mut+ pts predicts poorer clinical outcome.
The NIBIT-M1 trial: Activity of ipilimumab plus fotemustine in patients with melanoma and brain metastases.
Authors: Maio Michele , Testori Alessandro , Ascierto Paolo Antonio , Ridolfi Ruggero , Santinami Mario , Pilla Lorenzo , Queirolo Paola , Grosso Marco , Simeone Ester , Nicoletti Stefania Vittoria, Luisa , Rivoltini Licia , Ferrucci Pier Francesco , Parmiani Giorgio , Di Giacomo Anna Maria
Published: March 2020

8529

Background: Patients (pts) with metastatic melanoma (MM) often develop treatment-resistant brain metastases (mets). Treatment includes fotemustine (FTM), which crosses the blood-brain barrier. Ipilimumab (ipi) has shown activity in pts with MM and asymptomatic brain mets (Heller et al. ASCO 2011; abs 8581). In the phase II NIBIT-M1 trial, MM pts with asymptomatic brain mets were eligible for treatment with ipi plus FTM. Here, data from this pt subset are reported. Methods: Eligible pts received induction therapy with ipi 10 mg/kg every 3 wks (Q3W) x4 and FTM 100 mg/m2 weekly for 3 wks, followed by ipi Q12W from Week (W) 24 and FTM Q3W from W9. The primary objective was the immune-related (ir) disease control rate (irDCR: complete/partial response [CR/PR] or stable disease [SD] using the ir response criteria). Secondary objectives included ir objective response rate (ORR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from W12 to W36 and Q12W thereafter. Results: Among 86 enrolled pts, 20 had brain mets. Of these, 7 had prior whole brain radiotherapy (n=4) or radiosurgery (n=3). As of December 2011, the irDCR was 50% (10/20; 95% CI, 27.2–72.8%) with an irORR of 40% (95% CI, 19.1–63.9%: 2 CRs and 6 PRs). Pts with irDC also had stability/reduction (n=5) or disappearance (n=5) of brain mets. Among pts with progressive disease, all but one had progression in the brain. With median follow-up of 8.3 months (range: 0.4–16.9), median irPFS was 4.6 months (95% CI, 0.7–12.3). The 1-year OS rate was 52.9% (95% CI, 26.6–79.2); median OS was not reached. Induction with ipi and FTM was completed by 55% and 85% pts, respectively. Grade 3/4 drug-related adverse events (AEs) occurred in 60% pts; most commonly myelotoxicity (50%), increased ALT/AST (5%) and gastrointestinal (5%). AEs were generally manageable and reversible per protocol guidance. CNS AEs of any grade (i.e., haemorrhage, headache and seizure) occurred in 25% pts (grade 3/4 in 2 pts) and were attributed to disease progression. Conclusions: The combination of ipi plus FTM is active and safe in pts with MM and brain mets, regardless of prior treatment, and will be further explored in the phase III NIBIT-M2 trial.