bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical activity, safety and tolerability of ASN002, a dual SYK/JAK inhibitor, in patients non-Hodgkin lymphoma (NHL) and solid tumors.
Authors: Rasco Drew W. , O'Rourke Timothy J. , Chen Andy I. , Wang Michael , Tolcher Anthony W. , Rao Niranjan Sathyanarayana , Denis Louis J. , Reddy Sanjeeva , Barta Stefan K.
Published: September 2018

7545

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

7550

Background: DRL-Rituximab (T) is a proposed biosimilar of the innovator reference rituximab (USA: Rituxan; EU: MabThera). Physicochemical analyses and nonclinical studies have shown T to be comparable with innovator Rituximab. This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity of T with EU sourced MabThera (R) in DLBCL patients. Methods: Multicentre randomized double-blind 2-arm parallel study conducted in patients aged 18-60 yrs, with a centrally confirmed newly diagnosed CD20+ DLBCL, as first line of treatment. Patients received 6 cycles (C), every 21 days, of either T or R at 375 mg/m2 + CHOP. Primary objective was to compare C1 PK (AUC0-21d & Cmax). Overall Response Rate (ORR) was the key secondary objective, with C6 PK parameters, PD parameters (B-cells measured as CD19+ positive cells in peripheral blood- depletion & repletion), treatment-emergent adverse events (TEAEs), and anti-drug antibodies (ADA) as other secondary objectives. PK similarity criterion was 90% CI of geometric mean ratios (GMRs) of AUC0-21d and Cmax in C1, within 80-125%. Results: 151 patients were randomized (T, 76; R, 75). PK similarity criterion was met. The GMR T/R ratios with 90% CIs for AUC0-21d & Cmax were 100.0% (87.7, 114.0) & 96.2% (88.7, 104.4), respectively. Per protocol, ORR with 95% CI was 82.1% (69.6, 91.1) with T and 87.1% (76.1, 94.3) with R. Trough concentration (C5/C6) GMR (90% CI) of 91.3% (86.3, 96.7) for T & 94.0% (88.9, 99.5) for R indicated steady state. C6 AUC0-21d & Cmax GMR (T/R [90% CI]) were 88.9% (80.3, 98.5) and 94.6% (88.1, 101.7), respectively. T and R led to comparable B-cell depletion and repletion. Incidence of all grades of TEAEs were comparable. TEAEs ≥Grade 3 were 80.3% in T (n = 61) and 88.0% R (n = 66). Neutropenia was the most common TEAE (overall: T, 75.0%; R, 73.3% & ≥ grade 3: T, 64.5%; R, 64.0%). No neutralizing antibodies were observed in either of the arms. Conclusions: These data demonstrate that DRL-Rituximab has comparable PK, PD, efficacy, safety and immunogenicity to MabThera. MabThera already has an established efficacy in longer term follow-up. Clinical trial information: CTRI/2012/11/003129.
Clinicopathologic characteristics and outcomes of transformed diffuse large B-cell lymphoma in hepatitis C virus-infected patients: A case-control study of 84 patients.
Authors: Hosry Jeff , Miranda Roberto N. , Turturro Francesco , Economides Minas P. , Samaniego Felipe , Torres Harrys A.
Published: September 2018

7553

Background: Chronic hepatitis C virus (HCV) infection is associated with development of marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). Preliminary data showed particular characteristics of HCV-associated DLBCL; such as frequent transformation from indolent lymphomas and aggressive oncologic courses. We studied herein the clinicopathologic characteristics and outcomes of HCV-infected patients (pts) with transformed DLBCL. Methods: In this case control study, the medical records and pathology reports of HCV-infected (cases) and HCV-uninfected (controls) pts with transformed DLBCL seen at our institution (6/2004 - 5/2015) were reviewed. Included pts had a concomitant or a history of a low grade lymphoma. To determine their clinicopathologic characteristics, cases were compared to controls at a ratio of 1:3. To determine predictors of oncologic relapse, we compared pts with DLBCL relapse after first line chemotherapy to those who did not relapse in univariate and logistic regression analyses. Results: Twenty-one cases were compared to 63 controls. Compared to controls, cases were younger (median year age [interquartile range], 54 [49-62] v 62 [53-66], P = .01), had advanced Ann Arbor stages, 3-4 (95% v 76%, P = .05), and upper gastro-intestinal involvement (48% v 25%, P = .05). Immunophenotypically, cases had more CD10-negative B-cells (76% v 43%, P = .008) and CD5-positive B-cells (39% v 7%, P = .004) compared to controls, consistent with an activated B-cell phenotype. A comparison between pts who relapsed after first line chemotherapy (n = 42) and those who did not (n = 40) revealed that having CD5-positive B-cells was the only factor associated with DLBCL relapse in univariate (24% v 6%, P = .03) and multivariate analyses (OR = 10.7, P= .02). Conclusions: HCV-infected pts with transformed DLBCL are younger, present with advanced stages, are more commonly CD5-positive, and have an activated B-cell phenotype, suggesting more frequent transformation from MZL compared to HCV-uninfected pts. The higher frequency of CD5-positive B-cells might explain the higher DLBCL relapses previously described in HCV-infected pts.
A single institutional experience of 261 patients with large granular lymphocytic leukemia (LGLL).
Authors: Van den Bergh Magali , Isenalumhe Leidy Lismeri , Wang Emilie , Schaible Braydon , Ma Zhenjun , Zhang Ling , Sokol Lubomir
Published: September 2018

7555

Background: LGLL is a rare clonal lymphoproliferative disorder of post-thymic T-cell or natural killer (NK)-cell lineage associated with cytopenias, splenomegaly, autoimmune disorders, and recurrent mucocutaneous infections. Treatment is dictated by the presence of these manifestations and consists of immunosuppressive therapy. Methods: This is a retrospective analysis of clinical and laboratory features, treatment modalities, and outcomes of LGLL patients evaluated at Moffitt Cancer Center between 1995 and 2016. Continuous and categorical variables were tested via Kruskal-Wallis ANOVA and Fisher’s Exact Test. Kaplan-Meier curves were used for overall survival (OS). P-values were two-sided with significance set at < 0.05. Results: We identified 261 patients with LGLL (91.6% T, 8.4% NK). Median age was 66 years [21-90] and M:F ratio 1.2:1. Median follow up was 3.07 years [0-21.88]. 42.9% presented with anemia, 37.1% neutropenia, 30.7% thrombocytopenia, 29.1% bicytopenia and 6.9% pancytopenia. Transfusion dependence was noted in 20.3%, splenomegaly in 27.2% and bone marrow (BM) involvement in 69.3%. 24.9% had autoimmune diseases and 9.2% autoimmune cytopenias. 45.6% were observed while the remainder required at least 1 line of therapy. 5-yr and 10-yr OS were 75.0% and 63.1% respectively. There was no statistically significant difference in OS, complete response or duration of response based on first line agent (methotrexate, cyclophosphamide, cyclosporine A). However, there was a statistically significant improved partial response with methotrexate versus other therapies (p=0.01). A marginally significant association between severe anemia/transfusion dependence and poor overall response rate (p=0.075) to any therapy was noted. There was no statistically significant difference in OS based on absolute LGL count. Mean number of therapies was 1.08 (range 0-6) and was higher in those with LGL count <0.5 k/μL (p=0.0078), BM involvement (p<0.0001), and splenomegaly (p<0.0001). Conclusions: In this large retrospective study, we described the frequency of LGLL-associated manifestations and their impact on the course of LGLL. We confirmed that there is no difference in OS among first line therapies.
Results of GROC-rev salvage regimen: Gemcitabine, rituximab, and oxaliplatin chemotherapy with revlimid for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL).
Authors: Cabanillas Fernando , Liboy Idalia , Cruz Alexis , Solivan Pedro Gil , Rivera Noridza , Pardo Wandaly Ibis , Acosta Mirelis
Published: September 2018

7556

Background: Currently there is no optimal salvage regimen for relapsed/refractory NHL (R/R NHL). Prognosis of pts who fail to achieve CR to salvage therapy is dismal. We sought to improve the CR rate by adding Lenalidomide (L) to GROC (ASCO #8530, 2008). Methods: Primary endpoint was rate of conversion to CR after switch to L for pts whose best response to GROC was <CR. Secondary endpoint was progression free survival (PFS) of all pts as well as those who achieve <CR on chemotherapy and were crossed over to L.Pts who failed to achieve at least PR after GROC x2 and those who didn’t achieve CR after GROC x6, were crossed over to L 25 mg x 3 weeks q 28 days. CRs were maintained on L x 2 yrs. Results: 34 pts were enrolled of which 32 are evaluable. Median age: 61 and 56% males. Histologies included DLBCL (81%), PTCL (9%), follicular grade 3-B (9%). Stage was III-IV in 75% and median IPI=2. Best overall response rate (ORR) at any point during treatment= 19/32 (59%) and CR 13/32 (41%). ORR before crossover to L=13/32 (41%) and CR= 8/32 (25%). There were 24 who failed to achieve CR on GROC (19 who didn’t respond at all and 5 whose maximum response was PR). Of these, 21 crossed over to L and 7 (33%) responded (CR in 5, PR in 2). The fact that 5 pts attained a CR to L thus improving the CR rate from 25% to 41% after exhibiting refractoriness to GROC is noteworthy. Of the 7 responders to L, all are alive and only 1 relapsed. At 2 yrs., overall survival (OS) was 48% and PFS 35%. This compares favorably with our previous GROC study without L in which 2 yr. OS= 33% and PFS 29%. In total, 11 pts were eligible for ASCT after chemo plus L and 8 were transplanted (3 refused). Of these eight, 6 remain in CR at 11, 18, 21, 22, 52, 74 mos. At 2 yrs, PFS for transplanted pts is 73% and for those whose response to GROC before crossover to L was <CR, it is 27 mos. Toxic events included 2 neutropenic fevers, 1 MDS (34 mos. after ASCT) and 1 AML (11 mos. after ASCT). Both of these remain continuously in CR after allo SCT. Conclusions: 2 yrOS=48% and PFS=35% with GROC-Rev are the best observed with any salvage regimen we have tested. L is active as a single agent in 29% of cases whose best response to GROC was <CR. A larger study is desirable to confirm these data. Clinical trial information: NCT01307592.
Development of a clinical trial immunohistochemistry (IHC) assay using a novel antibody to CD38.
Authors: Wakamiya Karen , Hudson Marsha , Finkelstein Hayley , Nguyen Mai , Alvarez Sara , Neill Brad , William Josette , Hanks Debra Ann , Jansson Malinka , Northrup Adam , Alvarez John David , Oroudjev Emin
Published: September 2018

7561

Background: CD38 is a type II transmembrane glycoprotein expressed on normal lymphoid and myeloid cells and can be highly expressed in hematologic malignancies. An IHC prototype assay was developed to detect CD38 expression in formalin-fixed, paraffin-embedded (FFPE) tissue specimens from three relapsed or refractory non-Hodgkin’s lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL) for selection of patients for treatment with daratumumab in a Phase 2 clinical trial (NCT02413489). Methods: This assay is based on EnVision FLEX IHC technology using CD38, clone DAK-CD38, primary antibody that has been developed and manufactured by Agilent Technologies. The assay staining protocol was developed for Dako PT Link and Autostainer Link 48. Specificity of DAK-CD38 staining was demonstrated by Western blot analysis of cancer cell lysates, as well as IHC on both normal and cancer tissue. Assay precision and robustness were evaluated using commercially procured FFPE DLBCL, FL and MCL specimens. Results: CD38 IHC DAK-CD38 detected a broad range of CD38 expression in DLBCL, FL, and MCL specimens. FFPE specimens derived from cancer cell lines exhibited a range of IHC staining intensity and confirmed the reported expression of CD38 in the scientific literature. All precision and robustness results met acceptance criteria for both IHC intensity and percent positive cells staining. Conclusions: Our studies demonstrate that the Dako CD38 IHC DAK-CD38 assay is sensitive, specific, precise, and robust for the detection of CD38 expression in DLBCL, FL and MCL. This assay may also have the potential to be used for the detection of CD38 in additional tumor types.
Phase 1 trial evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell lymphoma (CTCL).
Authors: Foss Francine M. , Querfeld Christiane , Porcu Pierluigi , Kim Youn H. , Pacheco Theresa , Halwani Ahmad Sami , DeSimone Jennifer , William Basem M. , Seto Anita G , Ruckman Judy , Landry Michele L , Jackson Aimee L , Pestano Linda A , Dickinson Brent A , Sanseverino Mark , Rodman David M , Rubin Paul , Gordon Gilad Shalag , Marshall William S.
Published: September 2018

7564

Background: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL, selected based on its activity in mycosis fungoides (MF) cell lines. The objective of this first-in-human study is to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of MRG-106 in MF patients. Methods: This Phase 1 trial employs a dose-escalation design to evaluate either intratumoral (IT, 75 mg/dose) or subcutaneous (SC, ≤ 900 mg/dose) administration of MRG-106. Patients were required to have biopsy-proven stage I-III MF and plaque- or tumor-stage lesions. Results: Fifteen patients (12M/3F, median age 59 years) have been dosed over 1-4 weeks. All patients tolerated the IT or SC administrations well with only minor local injection reactions in 8 patients. Thirteen of 15 patients completed dosing as scheduled. There were no clinically significant MRG-106 related adverse events with the exception of one grade 3 pruritus. The MTD has not yet been reached. In the IT cohort, a reduction of ≥50% in the baseline Composite Assessment of Index Lesion Severity (CAILS) score was observed in the MRG-106 treated lesions in all 4 evaluable patients who completed dosing; such responses were maintained to the End of Study visit (Day 28 or 35). Histological examination of pre- and post-treatment biopsies of the MRG-106-injected lesion from most patients revealed a trend in reduction in neoplastic cell density and depth; 1 patient had a complete loss of the neoplastic infiltrate. Gene expression analysis of the pre- and post-treatment biopsies showed reduction of the PI3K/AKT, JAK/STAT, and NFkB survival pathways and increased cell death consistent with the expected MRG-106 mechanism of action. In the SC cohorts, 3/8 patients had a maximal decrease in their modified Severity-Weighted Assessment Tool (mSWAT) of > 39% indicative of a significant response. One patient at the 900 mg SC dose level had a possible flare of their disease after 3 doses that resolved after 3 weeks. Conclusions: Based on favorable clinical safety, efficacy and PK data, additional patients are being accrued. Updated results will be presented as available. Clinical trial information: NCT02580552.
Results of a phase II trial of efficacy and safety of entospletinib (ENTO) in patients with lymphoplasmacytoid lymphoma/Waldenstrom's macroglubulinemia (LPL/WM).
Authors: Assouline Sarit E. , Kolibaba Kathryn S. , Klein Leonard M. , Coleman Morton , Smith Mitchell Reed , Abella-Dominicis Esteban , Ye Wei , Shi Wen , Andorsky David Jacob , Sharman Jeff Porter
Published: September 2018

7565

Background: ENTO is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk, a mediator of B-cell receptor [BCR] signaling). Targeting the BCR-signaling pathway has been a focus in B-cell related hematological malignancies including LPL/WM. Methods: This reports the LPL cohort in a phase 2 trial that more broadly evaluated efficacy and safety of ENTO (800 mg BID) in patients with relapsed and refractory (R/R) B-cell malignancies. Tumor response was assessed at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 24. Results: 17 LPL patients (median age 72 years [range: 47–89], 65% male, and median of 3 prior regimens [range: 1–8]) were enrolled. Prior therapies included anti-CD20 antibodies (100%), alkylating agents (71%; bendamustine 24%), purine analogues (24%), and vinca alkaloid (41%). No patient had prior ibrutinib. Median treatment duration was 16 weeks (range: 1-84), with 3 patients continuing on treatment. The most common treatment-emergent AEs (any grade/≥grade 3, independent of causality) were fatigue (53%, 6%), constipation (47%, 0%), nausea (47%, 6%), diarrhea (29%, 6%), insomnia (29%, 0%) and lab abnormalities including neutropenia (53%, 12%), increased creatinine (53%, 0%), increased ALT (41%, 6%) and decreased WBC (41%, 6%). One death due to progressive disease (PD) was reported within 30 days from last dose. 12 (71%) patients were evaluable for tumor response. 5 patients (29%) discontinued prior to initial tumor assessment: PD (n = 2), withdrawal consent (n = 2) and AE (n = 1). ORR was 24% (90% CI: 9%, 46%), with 1 (6%) patient achieving PR, 3 with minor response (18%) and 7 (41%) maintaining stable disease. Reductions of IgM from baseline were greatest in the patient with PR. PFS rate at week 24 was 82% (95% CI: 44%, 95%). Median time to treatment failure and median time to response were 3.7m and 1.9 m respectively. Median duration of response has not been reached. Conclusions: ENTO was well tolerated and demonstrated limited activity in patients with R/R LPL. Further development of ENTO in LPL will focus on its role in combination therapies. Clinical trial information: NCT01799889.
Phase I/II dose expansion of a trial investigating bendamustine and pomalidomide with dexamethasone (BPd) in patients with relapsed/refractory multiple myeloma.
Authors: Sivaraj Dharshan , Green Michael M. , Kang Yubin , Rizzieri David , Diehl Louis F. , Beaven Anne W. , Li Zhiguo , Garrett Anderson , McIntyre Jackie , Long Gwynn Douglas , Chao Nelson Jen An , Gasparetto Cristina
Published: September 2018

8008

Background: The combination of bendamustine, pomalidomide, and dexamethasone (BPd) displays promising activity in heavily pretreated RRMM. In the Phase I portion, MTD was 120 mg/m2bendamustine/3mg pomalidomide/40mg dexamethasone. We report our combined findings from the additional phase II expansion cohort for the first phase I/II trial of BPd in patients with RRMM (NCT01754402). Methods: All patients had to be refractory to prior lenalidomide as well as be pomalidomide naïve, and must have relapsed or have been refractory to their most recent therapy. Treatment consisted of oral pomalidomide PO QD on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1, and dexamethasone 40mg on days 1, 8, 15, and 22 of a 28-day cycle. Bendamustine was administered at 120 mg/m2 for cycle 1, day 1. Results: A total study population of 38 patients was enrolled, with 34 evaluable for toxicity and 32 for efficacy, with 7 patients still receiving treatment. Data cut-off was January 18, 2017. The median age was 67 years, median number of prior regimens was 5, median time from diagnosis was 3.6 years, and median follow-up was 11.7 months. 82% of patients had a prior stem cell transplant, 100% had prior bortezomib, 32% had prior carfilzomib, and all were lenalidomide refractory. Cytogenetic abnormalities included 6 patients with del(17p), 4 with t(4;14), 7 with del(13), and 7 with t(11;14). Patients received a median of 4 cycles of therapy. Best response assessments in 32 evaluable patients showed 3 sCR, 3 VGPR, 17 PR, 7 SD, and 2 PD for an ORR of 72%. The median PFS and OS were 9.6 months and 21.3 months respectively for the entire cohort, with 16 of 32 still alive at follow-up. Grade ≥3 drug-related AEs included fatigue (8%), neutropenia (45%), anemia (26%), thrombocytopenia (24%), and diarrhea (8%). 71% of patients experienced grade ≥3 AEs including neutropenia, anemia, and diarrhea. Conclusions: The BPd regimen is relatively tolerable and achieves a promising overall response rate (ORR of 72%) and durable responses in a heavily pre-treated lenalidomide–refractory population with prior bortezomib exposure, and a median of 5 lines of prior therapy. Clinical trial information: NCT01754402.
Lenalidomide induction and maintenance therapy for transplant eligible myeloma patients: Results of the Myeloma XI study.
Authors: Jackson Graham H. , Davies Faith , Pawlyn Charlotte , Cairns David A. , Striha Alina , Waterhouse Anna , Jones John , Kishore Bhuvan , Garg Mamta , Williams Cathy , Karunanithi Kamaraj , Lindsay Jindriska , Jenner Matthew , Cook Gordon , Kaiser Martin , Drayson Mark , Owen Roger G. , Russell Nigel , Gregory Walter , Morgan Gareth John ,   On Behalf of the NCRI Haemato-Oncology Clinical Studies Group
Published: September 2018

8009

Background: Immunomodulatory (IMiD) agents are effective therapies for multiple myeloma (MM), with Lenalidomide (Len) having fewer side effects than Thalidomide (Thal), enabling long-term treatment. The optimum IMiD induction and maintenance regimen are unknown. We therefore compared triplet induction regimens of Len vs Thal and examined the role of maintenance Len vs observation, enabling us to explore the interaction of Len induction with Len maintenance. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. For TE patients the induction question compared Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation. 2042 TE patients underwent the induction randomization (CRD 1021, CTD 1021). After a median follow up of 36.3 months, 965 PFS and 415 OS primary endpoint events had occurred. Secondary endpoints included response and toxicity. Results: In TE patients, CRD induction was associated with deeper responses than CTD: ≥VGPR CRD 60% vs CTD 53%. This was associated with a significantly improved median PFS (HR 0.85, 95%CI 0.75, 0.96, CRD 35.9 months vs CTD 32.9, p=0.0116) and 3 year OS: 82.9% vs 77.0% (HR 0.77, 95%CI 0.63, 0.93, p=0.0072). Maintenance therapy with Len was associated with a significantly longer median PFS compared to observation (HR 0.47, 95%CI 0.38, 0.60) across all subgroups including patients with high-risk disease. Exploratory analysis across the TE pathway suggested that CRD induction with Len maintenance was optimum: 60 month PFS CRD-R 50.2%, CTD-R 39.1%, CRD-obs 18.5%, CTD-obs 23.4%. Conclusions: CRD was associated with deeper responses than CTD, and with a PFS and OS benefit. The best outcomes were associated with Len induction plus Len maintenance. Our findings support continuing Len therapy through induction until disease progression. Clinical trial information: NCT01554852.
Risk stratification of smoldering multiple myeloma (SMM): Predictive value of free light chains and group-based trajectory modeling (GBTM).
Authors: Chari Ajai , Wu Vernon , Moshier Erin
Published: September 2018

8031

Background: A serum free light chain ratio (FLCR) ≥ 100 and bone marrow plasma cell (BMPC) ≥ 60% have recently been classified as myeloma defining events to identify a group of SMM patients at high risk (ie. > 50% risk at 2 years) of organ damage. However rates of progression for FLCr range from 30% to 98%. Reasons for the discrepancy include selection/referral bias, patient heterogeneity, and lack of consideration of disease evolution. The objective of this study was to determine the predictive value of baseline FLCR > 100 and BMPC > 60% in our patient population and also to determine the significance of m spike and FLC evolution using GBTM. Methods: We retrospectively investigated the predictive value of these events, including involved–uninvolved FLC (dFLC), in 273 consecutive SMM patients seen at our institution between 2010 and 2015. GBTM uses the outcomes of groups of individuals with similar trajectories over time (vs apriori assumptions of % change) to model population trajectories. Results: In patients with FLCR ≥ 100 at diagnosis, the median time to progression was 23 mos with 2-year progression of 52%. In patients with BMPC ≥ 60% at diagnosis, median time to progression was 25 months with 2-year progression of 47%. For 111 patients available for analysis, GBTM two distinct trajectories in dFLC during the 1st year. 18% of patients fell into a high risk group experiencing a 171% increase in dFLC at 1 year vs the remaining patients only had a 16% increase. The high risk group had a median TTP of 13.7 mos versus not reached for the remaining (log-rank p = 0.0063). Similarly the 25% of patients who had a 62% increase in mean m spike within 1 year had TTP of 27 mos versus the remaining 75% who had no increase had a median TTP of 84 mos (log rank p = 0.0943). Conclusions: Our results not only confirm a more modest 52% 2 year risk of PD with an FLCR > 100 and dFLC > 100, but also suggest that a high risk dFLC trajectory evolution may help identify a SMM high risk group, with a median TTP of only 13.7 mos. Results of multivariate analysis and sensitivity/specificity comparisons of baseline as well as evolving biomarkers will be presented at the meeting.
Semaphorin 4D to suppress bone formation in multiple myeloma.
Authors: Lontos Konstantinos , Adamik Juraj , Zhang Peng , Sun Quanhong , Roodman David , Suvannasankha Attaya , Galson Deborah Lynn
Published: September 2018

8039

Background: Myeloma bone disease is characterized by osteoclast activation and long-term osteoblast suppression. We investigated if Semaphorin 4D (Sema4D; CD100) plays a role in these processes. Sema4D has been shown to be a potent osteoblast inhibitor (Negishi-Koga T et al, Nat Med. 2011). A study recently identified that the breast cancer cell line MDA-MB-231 utilizes Sema4D to create osteolysis (Yang Y et al, PLOS One 2016). There have been previous data that Sema4D is increased in the serum of myeloma patients (Terpos et al, Blood 2012) and that co-culturing myeloma cell lines with osteocytes increases the expression of Sema4D mRNA in both (Suvannasankha et al, Blood 2016). We sought to investigate if myeloma cells are using Sema4D to suppress bone formation and if they affect the levels of Sema4D produced by osteoclasts. Methods: We used lentivirus carrying shRNA for Sema4D or control (Scr) to knock down the level of the protein in the 5TGM1 murine myeloma cell line. Knockdown was verified by qPCR and Western Blot. We subsequently co-cultured the 5TGM1 cells with the MC3T3-subclone M4 (MC4) murine stromal cell line for 2 days, removed the myeloma cells and then differentiated the MC4 cells using ascorbic acid and β-glycerolphosphate. At day 5, we analyzed the cells for Runx2 (a critical gene for the differentiation of stromal cells into osteoblasts) expression utilizing qPCR. Also, we performed qPCR in primary osteoclast (OCL) mouse cells differentiating into OCL with RANKL with or without pre-treatment with myeloma-conditioned media for 3 days before the addition of RANKL. Results: When 5TGM1-Scr were co-cultured with MC4 cells the expression of Runx2 on day 5 was decreased (p=0.02). Strikingly, the 5TGM1-shSema4D cells when co-cultured with MC4s did not have the same effect and allowed the upregulation of Runx2 expression on day 5 (p=0.01). Myeloma-conditioned media increased Sema4D expression by OCL throughout the 5 days of differentiation 2 to 3-fold (p=0.01 for day 5). Conclusions: The myeloma cells seem to be utilizing Sema4D both directly and indirectly to inhibit bone formation. Targeted therapy against Sema4D may improve outcomes and fracture-free survival for multiple myeloma patients.
Rates of peripheral neuropathy (PN) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM) treated with carfilzomib vs comparators in pivotal phase III trials.
Authors: Niesvizky Ruben , Hungria Vania , Ho Joy , Suvorov Aleksandr , White Darrell , Ben-Yehuda Dina , Zhou Lifen , Iskander Karim S. , Rosinol Laura
Published: September 2018

8041

Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m2]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m2] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]
Racial differences in abnormalities by FISH in minorities with multiple myeloma: A single-center experience.
Authors: Gonzalez Velez Miguel , Jaramillo Restrepo Valentina , Duma Narjust , Palascak Matthew , McKenna Marshall , Richter Joshua Ryan , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa
Published: September 2018

8044

Background: Racial disparities of FISH abnormalities in multiple myeloma (MM) have been well described in whites (W) but partially described in minorities (M) (Paulus et al, ASH 2016, 4432). We aimed to explore racial-based differences of FISH abnormalities using the largest cohort of m to date. Methods: CD-138 selected FISH was done on 799 consecutive patients (pts). Pts without symptomatic MM, and biopsy >6 months after diagnosis were excluded. The abnormalities evaluated included standard and intermediate risk: IGH rearrangements (IGH r), t(4;14), t(11;14), and high risk: t(14;20), t(14;16), del13q, del 17p, 1q21. Chi-square was used for statistical analysis. Due to smaller numbers, all m (Hispanic (H), Black (B), Asian (A) and Other (O)) were included into the same group for statistical analysis. Results: 482 pts were eligible, 343 (71%) were W, 52 (10%) H, 50 (10%) B, 19 (3%) A, and 18 (3%) O. Median age was 65 years, 54% were male, and 26% ISS stage 3. There were no were no statistically significant differences in FISH abnormalities between the m (Table1). Overall W had more abnormalities in IGH r, t(4;14), t(11;14), t(14:20), 1q21 gain compared to M. Most notably W had more IGH r (39% vs 28%; p=0.019) and t(11;14) (20% vs 12%; p=0.024). There were no statistically significant differences between W and m in the high risk FISH abnormalities. Conclusions: We had significant differences in FISH compared to M. W had more IGH r and t(11;14) than M, and there was no difference in high risk FISH abnormalities between W and M. This study confirms the biological racial disparities that exist in minorities with MM. Further studies with more inclusion of minorities are needed to elucidate these disparities and its effects on risk stratification and outcomes. [Table: see text]
Trends in survival and costs among US multiple myeloma patients.
Authors: Maiese Eric M , Evans Kristin , Chu Bong-Chul , Irwin Debra E.
Published: September 2018

8046

Background: Survival among multiple myeloma (MM) patients has improved over time, but little is known about concurrent changes in healthcare costs. This study examined trends in both survival and healthcare costs over the same time periods in US MM patients. Methods: The MarketScan Commercial and Medicare claims dataset was used to identify 5199 adult patients diagnosed with MM from Jan. 2006 to Dec. 2014. Patients had no prior evidence of cancer, were continuously enrolled for >12 months prior to MM diagnosis, and were followed through the earliest event (death, end of enrollment, or end of the study period (9/30/2015)). Multivariate GLM and Cox proportional hazards models estimated healthcare costs and survival probabilities, respectively, for two time periods during which patients were diagnosed with MM (2006-2010 vs 2011-2014) while controlling for demographic and clinical characteristics. The recycled prediction method was used to calculate the incremental cost estimates between the time periods. Results: Patients diagnosed in 2011-2014 had a 35% lower risk of death compared to those diagnosed in 2006-2010 (HR [95% CI] = 0.65 [0.57-0.74]. Patients diagnosed in 2011-2014 had 18% (95% CI: 6-31%) higher all cause and 26% (95% CI: 6-50%) higher MM-related per patient per month costs compared to those diagnosed in 2006-2010 (Table). Conclusions: Among MM patients, survival has improved at a greater rate than the increase in healthcare costs. In addition to improvements in MM treatment, changes in overall disease management may have contributed to both the increased expenditures and survival improvements observed in this study. [Table: see text]
Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM).
Authors: Nowak Anna K. , Grosso Federica , Steele Nicola , Novello Silvia , Popat Sanjay , Greillier Laurent , John Tom , Leighl Natasha B. , Reck Martin , Pavlakis Nick , Soerensen Jens Benn , Planchard David , Ceresoli Giovanni Luca , Hughes Brett Gordon Maxwell , Mazieres Julien , Socinski Mark A. , Velema Derek , von Wangenheim Ute , Morsli Nassim , Scagliotti Giorgio V.
Published: September 2018

8506

Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.
Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers.
Authors: Chaft Jamie E. , Forde Patrick M. , Smith Kellie Nicole , Anagnostou Valsamo , Cottrell Tricia , Taube Janis M. , Rekhtman Natasha , Merghoub Taha , Jones David Randolph , Hellmann Matthew David , Yang Stephen C. , Broderick Stephen , Rusch Valerie W. , Velculescu Victor E. , Topalian Suzanne Louise , Pardoll Drew M. , Brahmer Julie R.
Published: September 2018

8508

Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24-63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT02259621.
Treatment of lung cancer patients in multidisciplinary (MDC) and serial care (SC) clinics.
Authors: Ray Meredith , Faris Nicholas Ryan , Rugless Stewart Fedoria Elaine , Smeltzer Matthew , Boateng Nana , Meadows Meghan Brooke , Foust Courtney , Jackson Bianca , Patel Anita , Fehnel Carrie , Houston-Harris Cheryl , Signore Raymond S , Robbins Edward T , Osarogiagbon Raymond U.
Published: September 2018

8522

Background: MDC may improve the quality of care for complex diseases. We compared the use of stage-appropriate treatment for lung cancer patients in a co-located MDC to serially-referred (SC) patients within the same healthcare system. Methods: Prospective cohort study of newly-diagnosed lung cancer patients enrolled before onset of treatment from MDC or the standard clinics (SC). Eligible pts had ECOG PS 0-2. Stage-appropriate treatment selection was determined using National Comprehensive Cancer Network (NCCN) guidelines based on clinical stage just before treatment onset. Differences in stage-based treatment rates were calculated using Chi-squared tests. Results: 162 had MDC and 317 SC. Compared to serial care patients, MDC patients were more likely black (37% v 30%) female (51% vs 48%), older (median 69 vs median 66) and less likely commercially insured (36% v 43%). Surgical resection was more frequently used for early stage patients in MDC: 72% v 58% for stage IA/IB (p = 0.2259); 58% v 31% for stage IIA/B and IIIA (T3N1M0) (p = 0.0375). MDC patients also had trends towards higher rates of recommended concurrent chemoradiation therapy for stage IIIA (T4N0-1M0) (75% vs 53%) (p = 0.5835), IIIB (T1-3N3, T4N2) (78% v 68%), but equal rates of concurrent chemoradiation therapy for stage IIIA (T1-3N2M0) (68% vs 68%). Stage IV patientss were more likely to receive chemotherapy or targeted therapy in MDC v SC (87% vs 80%) (p = 0.3795). Conclusions: Lung cancer patients in the MDC model are more likely to receive recommended stage-appropriate treatment than those in the usual serial care model, despite relatively adverse demographic characteristics. Clinical trial information: NCT02123797.
The role of adjuvant chemotherapy in stage IB non-small cell lung cancer: A decision, effectiveness, and cost-effectiveness analysis.
Authors: Hudson Jessica Lynn , Aung Wint Y , Santos Carlos AQ , Chang Su-Hsin , Olsen Margaret A , Meyers Bryan F , Morgensztern Daniel , Puri Varun
Published: September 2018

8526

Background: Despite complete surgical resection (SR), half of stage I non-small cell lung cancer (NSCLC) patients die from systemic relapse. An independent risk factor for systemic progression is pathologic stage IB subtype (T2aN0M0, AJCC 7). The role of adjuvant chemotherapy (AC) in stage IB NSCLC is controversial. We studied the effectiveness and cost-effectiveness of AC after SR in stage IB NSCLC. Methods: Propensity score matching was performed on the National Cancer Database (2004-2011). The Kaplan-Meier method generated conditional probabilistic incremental 1- to 5-year survival after SR stratified by receipt of AC. Medicare allowable charges for SR, AC, and their respective complications were used. Decision analysis modeling and microsimulation were performed to account for proportions of chemotherapeutic agents administered in real-world settings. The incremental cost-effectiveness ratio (ICER) was calculated over a 5-year horizon. Probabilistic and two-way sensitivity analyses were performed. Results: 3662 of 18709 patient (19.6%) who met inclusion criteria received AC for SR stage IB NSCLC, with usage ranging from 15-27% annually. After propensity score matching, an overall survival benefit of AC was conferred over SR alone (at 5 years: 68.9% vs 60.4%, p < 0.001). The incremental cost of AC over SR alone was $11,541. The incremental effectiveness of AC was 0.28 life-years, with an ICER of $41,218. In two-way sensitivity analysis, AC plus SR dominated for the entire range of cost and survival estimates. In probabilistic sensitivity analysis, AC plus SR dominated the model above a willing-to-pay threshold of $16,000. AC costs could nearly double and the ICER remained under conventional thresholds. However, only 3 of the 4 common AC regimens were cost effective. Conclusions: In stage IB NSCLC, surgery is insufficient to render a cure. The addition of AC to SR extends life-expectancy and is cost-effective compared to SR alone. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes, though a cost-conscious approach is needed when selecting an AC regimen. This represents a novel change in the treatment of stage IB NSCLC.