bluuebunny/crossref_metadata_2025 huggingface dataset:
CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML).
Authors: Wang Victoria , Mannis Gabriel N. , Olin Rebecca Leah , Logan Aaron , Martin Thomas G. , Damon Lloyd Earl , Kilayko Danielle , Munster Pamela N. , Andreadis Charalambos
Published: September 2018

7040

Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2nddose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.
Impact of early landmark responses with ponatinib on 4-yr outcomes in CP-CML patients (pts) in PACE, a pivotal phase II trial.
Authors: Mueller Martin , Baccarani Michele , Deininger Michael W.N. , Guilhot Francois , Hochhaus Andreas , Hughes Timothy P. , Shah Neil P. , Talpaz Moshe , Lustgarten Stephanie , Santillana Sergio , Rivera Victor M , Clackson Timothy Piers , Cortes Jorge E.
Published: September 2018

7050

Background: Ponatinib is approved for pts with refractory CML or Ph+ ALL for whom no other TKI therapy is indicated, or for patients with T315I. Previously (Mueller ASCO ‘16), we reported the positive association of early landmark responses with ponatinib on survival at 3 yrs in heavily pretreated pts with CP-CML in PACE (NCT01207440). Here, we provide an update with survival outcomes at 4 yrs. Methods: The association of molecular (assessed in a central lab) and cytogenetic responses (CyR) at 3, 6 and 12 mo with 4-yr post-landmark PFS and OS was evaluated in CP-CML pts (n = 267). P values: calculated using log-rank test. Data cutoff: 3 Oct ‘16. Results: At baseline, median time from diagnosis: 7 (range, 0.5–27) yrs; median age: 60 (18–94) yrs; median %Ph+: 100% (3–100), ≤10% Ph+: 19 pts (7%); 61% of pts had ≥3 prior TKIs. Among evaluable pts at 3, 6 and 12 mo, MCyR/CCyR was achieved in 48%/39%, 62%/52% and 71%/56% and MMR in 14%, 29% and 39% of pts, respectively. Greater reductions in BCR-ABL1 levels (Table) and CyR at most landmark time points were associated with improved 4-yr post-landmark PFS and OS. Deeper responses at all landmark time points were associated with achievement of MR4.5 over time. Conclusions: As with the 3-yr landmark analysis, CyR and deep reductions in BCR-ABL1 transcripts at early time points correlated with improved 4-yr post-landmark survival in this refractory population. These data continue to demonstrate the prognostic value of early cytogenetic and molecular responses with ponatinib in heavily pretreated pts with CP-CML. Clinical trial information: NCT01207440. [Table: see text]
Implementation of a screening program for identification of unrecognized inherited marrow failure syndromes.
Authors: Lachowiez Curtis Andrew , Meyers Gabrielle
Published: September 2018

7055

Background: Inherited marrow failure syndromes (IMFS) are considered diseases of childhood, but testing adults with atypical presentations of diseases associated with IMFS is critical for establishing an optimal treatment protocol. The most common IMFS, Fanconi Anemia and Telomere Biology Diseases, are associated with MDS and aplastic anemia (AA), head and neck cancers, skin, and cervical cancer. Such patients can have profound toxicity with standard chemotherapy regimens. Methods: We implemented a screening protocol in patients at highest risk of an undiagnosed IMFS (MDS under age 60, AA patients under age 65, and head and neck cancers under age 60) with chromosome breakage analysis and telomere length testing. Results: Our protocol diagnosed nine patients (estimated ~10% of patients < age 60 with these diseases) with IMFS. The features of these patients are described in the table. Only three (33%) patients had the classic physical characteristics of IMFS. Three patients were over age 50 when diagnosed with an inherited disorder. Most importantly, in all patients the treatment approach was modified significantly, including minimizing conditioning for BMT, utilizing danazol as first line treatment for AA, as well as aggressive cancer and endocrinopathy screening. Outcomes with modified treatment have been favorable, and occult malignancies were detected through screening in two patients. Conclusions: Inherited marrow failure syndromes are uncommon yet under recognized disorders that significantly impact treatment decisions in addition to implementation of surveillance programs for both the affected individual and their relatives alike. Through this approach of thoughtful screening of patients presenting to our institution with marrow failure we identified an unrecognized IMFS in an estimated 10% of patients. [Table: see text]
A genetic risk-stratified, randomized phase 2 intergroup study of fludarabine/antibody combinations in symptomatic, untreated chronic lymphocytic leukemia (CLL): Results from Cancer and Leukemia Group B (CALGB) 10404 (Alliance).
Authors: Ruppert Amy S. , Byrd John C. , Heerema Nyla A. , Smith Mitchell Reed , Godwin John E. , Couban Stephen , Fehniger Todd A. , Thirman Michael , Halvorson Alese E. , Tallman Martin S. , Appelbaum Frederick R. , Stone Richard M. , Robinson Sue , Chang Julie E. , Mandrekar Sumithra J. , Larson Richard A.
Published: September 2018

7503

Background: Prior to use of novel targeted agents for CLL, debate existed regarding the best chemoimmunotherapy regimen to build upon in patients (pts) with non-del(11q) disease. The role of lenalidomide (L) was also not defined. CALGB 10404 was a randomized phase 2 study addressing these questions. Methods: Pts with untreated CLL requiring therapy were randomized to treatment with fludarabine + rituximab (FR), FR + 6 monthly consolidative treatments of L (5 mg days 1-21/28 x 1 then 10 mg days 1-21/28 x 5) (FR+L), or FR + cyclophosphamide (FCR). Based on pretreatment central interphase cytogenetic screening, pts with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, testing whether 2-year progression-free survival (PFS) rate was improved in non-del(11q) pts within each arm. A target accrual of 103 non-del(11q) pts per arm provided at least 84% power to detect an increase in 2-year PFS rate from 60% to 73%; the critical value was 69% using a single stage design and type I error rate of 4%. Results: A total of 342 non-del(11q) CLL pts were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. Two-year PFS rates with exact 90% CIs were 64% (57-71%) (FR), 71% (63-78%) (FR+L), and 74% (66-80%) (FCR). Median PFS was significantly shorter with FR compared to FR+L (p = 0.03) and FCR (p < 0.01): 43 (95% CI: 33-50), 66 (95% CI: 45-not reached), and 78 (95% CI: 58-not reached) months respectively. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across arms, although there was a plateau in OS with no events beyond 41 months in the FR+L arm, different from FR/FCR where events continued to occur. The most common adverse events were cytopenias and infections. Conclusions: FR+L and FCR met the protocol defined primary endpoint. FR+L extended PFS relative to FR and a plateau in survival differentiated this arm from the FR/FCR arms. Future studies comparing FR+L to FCR or incorporating L into other novel treatment regimens are justified. Support: U10CA180821, U10CA180882, Celgene. Clinical trial information: NCT00602459.
Autologous (auto) versus matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic (allo) hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) patients (pts) with early chemoimmunotherapy failure (ECF): A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.
Authors: Godfrey James K. , Smith Sonali M. , Ahn Kwang Woo , Digilio Alyssa , Fenske Timothy S , Sureda Anna M. , Hamadani Mehdi
Published: September 2018

7508

Background: Contrary to most FL, high-risk FL pts with ECF (i.e. relapse within 2 yrs of frontline chemoimmunotherapy) have a 5 yr OS of only 50%. (Casulo, JCO 2015). We used the CIBMTR database to compare autoHCT versus either MSD or MUD alloHCT as the first transplant approach in FL pts with ECF. Methods: Adult FL pts (age ≥18) undergoing autoHCT or alloHCT between 2002-2014 and receiving first line rituximab-based chemoimmunotherapies with evidence of ECF (defined as disease relapse or progression within 2 yrs of treatment initiation) were included. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS), relapse and non-relapse mortality (NRM). Results: 440 pts had ECF (auto = 240, MSD = 105, MUD = 95) (Table 1). The 5 yr adjusted probabilities (AjP) of NRM were significantly lower with autoHCT (5%), versus MSD (17%) or MUD (33%) HCT (p<0.0001). 5 yr AjP of relapse were significantly lower with MSD (31%) or MUD HCT (23%), versus autoHCT (58%; p<0.0001). AjP of 5 yr PFS following auto, MSD and MUD HCT were 38%, 52% and 43% (p=.006) respectively. The AjP of 5 yr OS was significantly higher following autoHCT (70%) or MSD HCT (73%) versus MUD HCT (49%; p=0.004). Conclusions: AutoHCT for FL pts with ECF has low NRM and 5 yr OS rates (70%) that are provocatively higher than historical data (~50%). MSD HCT had the lowest relapse rate with similar survival. A prospective trial confirming the role of HCT in ECF FL is warranted. [Table: see text]
Tolerability and activity of chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib in patients with advanced CLL and NHL.
Authors: Nastoupil Loretta J. , Lunning Matthew Alexander , Vose Julie , Schreeder Marshall T. , Siddiqi Tanya , Flowers Christopher , Cohen Jonathon Brett , Burger Jan Andreas , Wierda William G. , O'Brien Susan Mary , Sportelli Peter , Miskin Hari P. , Purdom Michelle A , Weiss Michael S. , Fowler Nathan Hale
Published: September 2018

7511

Background: Novel targeted agents are emerging for B-cell malignancies, but few studies have safely combined these agents. Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily PI3Kδ inhibitor, demonstrating a favorable safety profile compared to prior inhibitors, including in long-term follow up (Burris, 2016). This Ph 1 trial evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb + PI3Kδ + BTK inhibitor (ibrutinib) in pts with B-cell malignancies. Methods: Eligible pts had CLL or rel/ref NHL w/o limit to prior therapies, including those ref to prior PI3Kδ or BTK inhibitors. UTX dosed on D1, 8, 15 of C1; D1 of C2-6, and C9 & 12. TGR-1202 dose escalated (400/600/800mg QD), ibrutinib dosed at 420mg (CLL) or 560mg (NHL), both on C1D1. Results: 38 pts were enrolled: 20 CLL/SLL and 18 NHL, including 6 follicular (FL), 6 DLBCL, 4 mantle cell (MCL) and 2 marginal zone (MZL). Med age 65 yrs (range 32-85); 29 M/9 F; med prior tx = 3 (range 0-6). 2 pts were ref to prior PI3Kδ and 2 were prev treated with ibrutinib (1 ref/1 rel). MTD was not reached. Most common ( > 20%) all causality AE’s were fatigue (42%), diarrhea (39%), dizziness (34%), nausea (32%), neutropenia, pyrexia, rash, infusion reaction, insomnia (each at 29%), thrombocytopenia, cough (each at 26%), anemia (24%) and sinusitis (21%). GR 3/4 AE’s were minimal, the only event > 10% was neutropenia (16%). ORR amongst 36 evaluable pts is shown in the table below. 53% of evaluable CLL pts had high-risk cytogenetics and 4/6 DLBCL pts were non-GCB. One CLL pt (17p/11q del) ref to both PI3Kδ and ibrutinib achieved a CR. Med time on study is 10 mos (range 1 – 27+ mos). Med DOR not reached (range 3 – 24+ mos). Conclusions: This is the first known triple combination of an anti-CD20 mAb + PI3Kδ + BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies. Expansion cohorts at the highest dose (800mg TGR-1202 + full dose ibrutinib) are underway. Future trials for the triplet are warranted. Clinical trial information: NCT02006485. [Table: see text]
Ibrutinib vs chlorambucil: Immunophenotypic and quantitative impacts on circulating immune cells in chronic lymphocytic leukemia (CLL).
Authors: Solman Isabelle , You Hana , Taylor Marlene , Dubovsky Jason A. , Kipps Thomas J. , Burger Jan Andreas , Lal Indu , Chang Betty Y. , James Danelle Frances , Hill John Stephen
Published: September 2018

7524

Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by FDA for treatment (Tx) of patients (pts) with CLL. Following the outcome of the RESONATE-2 trial, ibr was approved as the first chemotherapy-free Tx option for treatment-naïve (TN) pts. In this study, ibr reduced the risk of progression or death by 84% compared with chlorambucil (chl). To assess the impact of ibrutinib vs this traditional chemotherapeutic agent on the immune system, quantitative changes in circulating cells were studied throughout the first year of Tx. Methods: Immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of TN CLL pts who received 420 mg ibr once daily (n=50) or 0.5-0.8 mg/kg chl twice a month (n=30). Medians of statistically significant changes (p<0.05, Wilcoxon test) in absolute counts of 1-year paired samples (pre-dose vs 1-year) are reported. Results: Chl progressively reduced circulating B, T, NK, NKT cells, myeloid derived suppressor cells (MDSC), and monocytes by 69%-99%. All development stages of CD4+ and CD8+ T cells, except stem cell memory T cells (TSCM), decreased by 51%-90%. Regulatory T cells (Treg) and PD1+ T cells also decreased similarly; however, long-term activated T cells (TLA) were not impacted. On the other hand, ibr mainly reduced B cells (90%), MDSC (61%) and some T cells, specifically TLA, PD1+ T cells, Treg and effector T cells (27-52%). Naïve T cells, TSCM, central memory T cells and NK cells were spared throughout the full year of Tx. Classical monocytes were increased (+187%), while non-classical monocytes and intermediate monocytes remained relatively steady. Conclusions: Chl, a traditional chemotherapy, affected non-specifically most immune cell subsets in circulation, although surprisingly it did not affect TLA which have been reported as dysfunctional in CLL. Ibr represents a more targeted Tx approach than cytotoxic chemotherapy; essentially B cells, abnormal T subsets (TLA, PD1+T, Treg) and pro-tumor MDSCs were reduced. However, ibr preserved naïve T cells, NK cells and monocytes, which are important for mounting anti-tumor responses. Clinical trial information: NCT01722487.
Whole body diffusion-weighted MRI to predict treatment outcome after one cycle of immunochemotherapy in aggressive non-Hodgkin lymphoma.
Authors: De Paepe Katja , De Keyzer Frederik , Bechter Oliver , Van Keerberghen Ciska-Anne , Gheysens Olivier , Wolter Pascal , Dierickx Daan , Janssens Ann , Verhoef Gregor , Oyen Raymond , Vandecaveye Vincent
Published: September 2018

7534

Background: Treatment adaptation based on early identification of non-Hodgkin lymphoma (NHL) patients not responding to therapy might improve survival. The role of interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) after 2-4 cycles of immunochemotherapy (ICT) herein is experimental as it renders false positive results, due to a rituximab-induced inflammatory response. Whole body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) was evaluated as a radiation-free imaging technique to predict treatment outcome in NHL after one cycle ICT (2-3 weeks). Methods: 47 patients with aggressive NHL (35 DLBCL,2 primary mediastinal BCL,3 unclassifiable BCL, 2 Burkitt,2 MCL, 2 peripheral TCL and 1 extranodal NK-TCL) were enrolled. All had baseline and interim WB-DWI/MRI, and end-of-treatment PET/CT; 39/47 had interim PET/CT. International prognostic index (IPI), immunohistochemical (IHC) markers Ki-67, Bcl-6 and Bcl-2 were evaluated for their predictive value. WB-DWI/MRI was assessed quantitatively with histogram analysis (high b-value signal intensity (SI) and apparent diffusion coefficient (ADC)). Patients were categorized as non-responder when lesions had decreased ADC or insufficient SI decrease between scans. Kaplan-Meier survival analysis was performed with log rank, Cox hazard ratio calculation and multivariate analysis. Outcome measure was disease-free-survival (DFS). Results: Median follow-up time was 43 months (4-70 months). 33 patients had complete remission (CR), 5 progression and 9 recurrent disease. WB-DWI/MRI predicted DFS correctly in 45/47 (96%) [log rank p<0.001; hazard ratio (HR) 52, (CI 95% 6-401)]; end-of-treatment PET/CT was correct in 37/47 (79%) [p=0.003;HR 4.3, (1.5-12.4)], and interim PET/CT in 28/39 (72%) [p=0.016;HR 3.9, (1.2-12.5)]. IPI score and IHC parameters were not significantly predictive. Multivariate analysis showed WB-DWI/MRI as the only independent prognostic factor (p<0.001). Conclusions: WB-DWI/MRI can accurately predict treatment outcome in aggressive NHL after only one cycle of immunochemotherapy without the burden of radiation exposure. Clinical trial information: NCT01231269.
Phase II clinical trial of first-line combination of radiation followed by gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy for early-stage extranodal natural killer/T-cell lymphoma with unfavorable prognostic factors: The GREEN study (NCT02276248).
Authors: Qi Fei , Wang Wei-Hu , Li Ye-Xiong , Dong Mei , He Xiao-hui , Yang Jianliang , Yang Sheng , Fang Hui , Chen Bo , Qi Shunan , Qin Yan , Zhao Yuting
Published: September 2018

7540

Background: Currently concomitant or sequential chemotherapy with radiotherapy has been recognized as the standard treatment for extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). However, the optimal schedule has not been fully defined. Methods: We designed a phase II prospective study to investigate the efficacy and toxicity profile of sequential radiation followed by systemic GDP (gemcitabine, dexamethasone and cisplatin) chemotherapy on previously untreated early-staged (stage IE/IIE) ENKTL patients with at least one unfavorable prognostic factor. The primary endpoint was 2-year progression-free survival (PFS). Secondary endpoints were 2-year overall survival (OS), overall response rate (ORR), and toxicity. Results: A total of40 patients were enrolled and completed the entire course of treatment between June 2010 and June 2014. The median age was 38 (range 25-63) years old. All the enrolled patients presented with at least one unfavorable prognostic feature: age > 60 years (5.0%), B symptom (40%), elevated serum LDH (40.0%), regional lymph node involvement (32.5%) and primary tumor invasion (87.5%). At the completion of the whole treatment, ORR was 97.5% and the complete remission rate was 95.0%. Median follow-up time was 43.7 months (range 9.4-72.3 months). 2-, 3-, 5-year PFS rates were 84.7%, 82.1%, 77.5%, and OS rates were 89.9%, 87.1%, 79.7%, respectively. Recurrence within the RT field was observed in four patients and systemic failure in three individuals. Grade 1-2 skin reaction and mucositis were the main toxicity related to radiation. Grade 3-4 neutropenia (12/40), thrombocytopenia (7/40) and anemia (2/40) were observed during GDP chemotherapy. No clinically significant late toxicities were observed during follow-up visits. Conclusions: The current results indicates that first-line radiation followed by GDP chemotherapy can be one of the most effective and feasible treatment schedule for early-stage ENKTL patients, especially those with poor prognostic factors. Clinical trial information: NCT02276248.
MYC+ relapsed and refractory (R/R) diffuse large b-cell lymphoma (DLBCL): Impact of additional hits and outcomes with subsequent therapy.
Authors: Epperla Narendranath , Maddocks Kami J. , Salhab Mohamed , Chavez Julio C. , Reddy Nishitha M. , Karmali Reem , Umyarova Elvira , Bachanova Veronika , Glenn Martha Jane , Xavier Ana Carolina , Zhou Zheng , Hernandez-Ilizaliturri Francisco J. , Barta Stefan K. , Lansigan Frederick , Mehta Amitkumar N. , Flowers Christopher , Cohen Jonathon Brett , Fenske Timothy S , Hamadani Mehdi , Costa Luciano J
Published: September 2018

7541

Background: Translocations involving MYC are a hallmark of poor prognosis among patients with newly diagnosed DLBCL. The impact of MYC translocations with or without additional “hits” involving BCL2 or BCL6 in response to salvage therapy and survival in R/R DLCBL is not well defined. Methods: We performed a multicenter retrospective study of 176 patients with R/R DLBCL failing to achieve CR or relapsing within 6 months after completion of upfront chemoimmunotherapy and for whom FISH information on MYC, BCL2 and BCL6 was available. The objectives were to examine the response to salvage therapy, utilization of hematopoietic cell transplantation (HCT) and survival outcomes in MYC- (n = 120), MYC+ single hit (SH, n = 28), and MYC+ double hit (DH, n = 36) R/R DLBCL. Results: Overall response rate to first salvage therapy and utilization of HCT was comparable between the 3 cohorts (Table). 2-year OS was 0% in MYC+ SH, 8.8% in MYC+ DH and 29.9% in MYC- cases (p = 0.001) without difference in OS between SH and DH (P = 0.8). The higher risk of death for MYC+ SH (HR 1.79, 95% C.I. 1.03-3.11, P = 0.03) and MYC+ DH (HR 1.93, 95% C.I. 1.23-3.00, P = 0.004) persisted after adjustment for covariates. For patients who underwent auto-HCT, 2-year OS was 0% in MYC+ SH, 29.3% in MYC+ DH and 55.4% in MYC- cases (p < 0.001) without significant difference between SH and DH (P = 0.8). All 4 MYC+patients who underwent allo-HCT relapsed in < 4 months. Conclusions: MYC+ R/R DLBCL have similar response to salvage therapy than the MYC- counterparts but dismal survival irrespective of additional “hits” and even if HCT can be performed. MYC+ R/R DLBCL represents an unmet medical need and should be prioritized for clinical trials with novel agents and innovative cellular therapies. [Table: see text]
Treatment patterns among elderly follicular lymphoma patients diagnosed between 2000 and 2011: An analysis of linked SEER-Medicare data.
Authors: Onukwugha Ebere , Nagarajan Madhu , Albarmawi Husam , Gardner James F. , Keating Karen N. , Valderrama Adriana , Malacan Jean , Yaldo Avin , Yared Jean
Published: September 2018

7563

Background: There are multiple treatment regimens approved for the management of follicular lymphoma (FL). However, there is limited information available to describe the course of therapy (COT) that patients receive following FL diagnosis. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER) registry & Medicare claims dataset, we analyzed patients 66 years and older diagnosed with FL from 2000 to 2011. In order to characterize FL treatments, we identified first, second and subsequent-lines of therapy listed in the National Comprehensive Cancer Network guidelines 2.2016. We identified the first COT (COT1) as the first regimen that a patient receives after diagnosis. We identified the second and third COT (COT2 and COT3) as new treatment received following/interrupting COT1 or COT2, respectively. Using visual analytics software, we investigated and reported the proportion of patients receiving each COT, the top three regimens within each COT, and the median time to starting a COT from diagnosis or end of a previous COT. Results: 10,836 FL patients were identified after applying the inclusion/exclusion criteria. Sixty-two percent (N=6,756) of the patients received FL-directed treatment. Among patients receiving COT1, 65% received COT2. Among patients receiving COT2, 79% received COT3. The table below provides additional information on the COT received. Conclusions: Analysis of real-world data indicates that almost 4 out of 10 elderly FL patients do not receive the listed FL-directed treatments. In contrast to rituximab, there was limited use of RCHOP and RCVP after COT1 during the study period. Additional research is needed to understand the differences across demographic groups and associated health outcomes. [Table: see text]
Efficacy of daratumumab in combination with lenalidomide plus dexamethasone (DRd) or bortezomib plus dexamethasone (DVd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk status.
Authors: Weisel Katja C. , San Miguel Jesus , Cook Gordon , Leiba Merav , Suzuki Kenshi , Kumar Shaji , Cavo Michele , Avet-Loiseau Herve , Quach Hang , Hungria Vania , Lentzsch Suzanne , Hajek Roman , Sonneveld Pieter , Wu Kaida , Qin Xiang , Chiu Christopher , Soong David , Qi Ming , Schecter Jordan Mark , Dimopoulos Meletios A.
Published: September 2018

8006

Background: In 2 randomized phase 3 trials of RRMM patients (pts), DRd (POLLUX) or DVd (CASTOR) significantly improved PFS and deepened responses compared with Rd or Vd alone, respectively. The novel mechanism of action of daratumumab (D) may improve the poor prognosis associated with high-risk cytogenetic abnormalities in RRMM. Therefore, we examined the efficacy of DRd and DVd among RRMM pts with standard (std) or high cytogenetic risk status. Methods: Bone marrow aspirates were collected at screening and assessed centrally via next generation sequencing (NGS). Pts with high-risk cytogenetics included those who had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p; std-risk pts were defined as those confirmed negative for these abnormalities. Efficacy analyses included PFS and ORR. Results: Samples from 311/569 pts in POLLUX and 353/498 pts in CASTOR were assessed via NGS. In POLLUX, the median duration of follow-up was 17.3 months. Significantly longer median PFS and numerically higher ORR were observed with DRd vs Rd among high-risk patients, and significant improvements in these outcomes were observed in std-risk patients (Table). In CASTOR, the median duration of follow-up was 13.0 months. Significantly longer median PFS and higher ORR were observed with DVd vs Vd among both high- and std-risk pts (Table). Concordance rates for t(4;14), t(14;16), and del17p were high (88%-98%) between NGS and FISH. Updated data, including subgroup analyses, will be presented. Conclusions: In RRMM pts, the addition of D to standard-of-care regimens improved outcomes regardless of cytogenetic risk status. Targeting CD38 by combining D with Rd or Vd appears to improve the poor outcomes associated with high-risk cytogenetic status. See table. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]
The impact of body mass index on the risk of early progression of smoldering multiple myeloma to symptomatic myeloma.
Authors: Gonsalves Wilson I. , Rajkumar S. Vincent , Dispenzieri Angela , Lacy Martha , Buadi Francis , Dingli David , Go Ronald S. , Kapoor Prashant , Hayman Suzanne R. , Lust John Anthony , Leung Nelson , Russell Stephen J. , Zeldenrust Steven R. , Lin Yi , Hwa Yi Lisa , Kourelis Taxiarchis , Kyle Robert A. , Gertz Morie A. , Kumar Shaji
Published: September 2018

8032

Background: Human adipocytes can contribute directly to the in vitro growth and progression of multiple myeloma (MM) cell lines. Clinically, an elevated body mass index (BMI) has been associated with an increased risk of MGUS and a shorter time to progression (TTP) of MGUS to MM. However, the impact of BMI on the risk of early progression to MM from a more advanced plasma cell disorder such as smoldering MM (SMM) remains unknown. Methods: This study included patients (pts) with a known or new diagnosis of SMM evaluated at the Mayo Clinic, Rochester from January 2000-December 2010. Pts were classified based on their BMI as: normal (< 25) and elevated (>/= 25) BMI. Progression to symptomatic MM was defined by the development of hypercalcemia, renal insufficiency, anemia or lytic bone lesions. Results: There were 306 pts with a diagnosis of SMM who were included in this analysis. The median follow up was 106 months. There were 203 (66%) pts who progressed to symptomatic MM at last follow up. The median BMI of the group was 27.5 (Range: 17.2 – 56.4). There were 228 (75%) pts with an elevated BMI. There were 76 (28%) pts who had myeloma defining events (MDEs) such as a serum free light chain ratio > 100 or > 60% clonal bone marrow plasma cells at initial evaluation. MDEs were present in 17% and 33% of pts with a normal and elevated BMI respectively (P = 0.011). The median TTP of SMM to MM in pts with a normal and elevated BMI was 64 and 36 months respectively (P = 0.0006). The 2-year progression rate of SMM to symptomatic MM in pts with a normal and elevated BMI was 16% and 42% respectively (P < 0.0001). Upon limiting the analysis to only SMM pts without MDEs at initial evaluation (N =187), the 2-year progression rate to symptomatic MM with a normal and elevated BMI was 15% and 33% respectively (P = 0.013). In a multivariable model, only elevated BMI (P = 0.004) and increasing clonal bone marrow plasma cells (P = 0.001) was statistically significant in predicting for a 2-year progression to MM. Conclusions: SMM pts with an elevated BMI appear to have a higher risk of early progression to MM than those with a normal BMI. This study provides evidence of a potentially modifiable risk factor for the progression of SMM to MM and warrants confirmation in larger studies.
Treatment approaches and outcomes in extramedullary plasmacytomas.
Authors: Goyal Gaurav , Bartley Adam C. , Gonsalves Wilson I. , Kumar Shaji
Published: September 2018

8050

Background: There is a lack of contemporary studies analyzing the optimum radiation dose and prognostic factors for outcomes of extramedullary plasmacytomas. In this study, we aim to answer these questions by utilizing the National Cancer Data Base (NCDB). Methods: This is a retrospective study of patients with histologically confirmed diagnosis of plasmacytoma from 2000-2011 using NCDB. Patients who had bone marrow involvement were excluded from the analysis. Hazard ratios were calculated using the Cox-proportional hazard method. In addition, we utilized survival trees as a novel tool for assessing prognostic effect of factors among four age quartiles (Q): Q1: 18-52, Q2:52-62, Q3:62-72, and Q4: ≥72 years. Results: A total of 5,056 patients were included in the study (median age 62 years; range, 52-72 years). Of these, 63% were males. Radiation therapy was received by 3,905 patients, with a median radiation dose of 45 Gy. A radiation dose of ≥40 Gy was associated with improved overall survival (OS) as compared to <40 Gy. Factors associated with worse OS included older age (≥65 years) and bone disease (Table). In survival tree analysis, radiation dose ≥44.5 Gy was associated with better OS in Q1 as compared to lower dose. For Q2 and Q3, disease location played a major role, with improved survival seen in upper aero-digestive and lymph node disease as compared to bone and soft tissue. In Q3, among the bone and soft tissue disease, radiation dose ≥ 43.5 Gy was associated with the better survival as compared to ≤43.5 Gy. In Q4, soft tissue and upper aerodigestive plasmacytomas had better outcomes as compared to bone and lymph node disease. Among the latter group, a radiation dose ≥30.3 Gy was associated with improved OS as compared to lower dose. Conclusions: This is the largest study of extramedullary plasmacytomas in the United States. This study shows that dose of radiation has a significant impact on outcomes, in addition to disease location and age. [Table: see text]
Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts).
Authors: Gadgeel Shirish M. , Ventimiglia Jaclyn , Kalemkerian Gregory Peter , Fidler Mary J. , Chen Wei , Sukari Ammar , Halmos Balazs , Boerner Julie , Wozniak Antoinette J. , Galasso Cathy , Pennell Nathan A.
Published: September 2018

8504

Background: The median progression free survival (PFS) and overall survival (OS) following initial chemotherapy in ES-SCLC pts are 2 and 7 months, respectively (Ready N, J Clin Oncol 2015). We evaluated the benefits of maintenance pembro in ES-SCLC pts who had response/stable disease after 4-6 cycles of platinum/etoposide. Methods: Pts were required to begin pembro within 8 weeks of completion of chemotherapy, with restaging scans no more than 3 weeks prior to start of pembro. Prophylactic cranial radiation was permitted. Pts were treated with pembro 200 mg I.V. every 3 weeks for a maximum of 2 years. Disease assessment was done every 2 cycles for the first 6 cycles and then as per investigator discretion. Primary end point of the study was PFS. PFS according to immune related response criteria (irPFS) and OS were also assessed. Tumor tissue was analyzed for PD-L1 expression by the DAKO 22C3 antibody. Any level of expression was considered as positive for PDL1. Blood for circulating tumor cells (CTCs) was collected prior to first, second and third cycle of pembro. Results: Of the 45 pts enrolled, 55% were males and 22% had brain metastases. Median age was 66 years. The median time from end of chemotherapy to start of pembro was 5 weeks. Median number of pembro cycles was 4 (1-20 cycles). 35 pts had measurable disease at study entry. The disease control rate with pembro was 42% (1 CR, 3 PR, 15 SD). At a median follow up of 6 months, the median PFS was 1.4 months (90% CI-1.3-4.0) and the irPFS was 4.7 months (90% CI- 1.8-6.7). The median OS was 9.2 months (90% CI-6.1-15.2). 11 pts are still on therapy (3-20 cycles). The median CTC prior to pembro was 1 (0-256, n=37 pts). Each unit increase in baseline CTC correlated with worse PFS (p = 0.052; adjusted for brain mets, age and sex). PDL1 could be assessed in 35 pts and was positive in 1 pt. Most common adverse events were fatigue, nausea, cough and dyspnea. One pt developed atrio-ventricular conduction block and 1 pt type 1 diabetes. Conclusions: Maintenance pembro did not improve PFS in these patients but favorable OS suggests that some SCLC patients can benefit from maintenance pembro. Biomarkers to identify patients most likely to benefit from pembro need to be defined. Clinical trial information: NCT02359019.
Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
Authors: Awad Mark M. , Leonardi Giulia Costanza , Kravets Sasha , Dahlberg Suzanne Eleanor , Drilon Alexander E. , Noonan Sinead , Camidge D. Ross , Ou Sai-Hong Ignatius , Costa Daniel Botelho , Gadgeel Shirish M. , Steuer Conor Ernst , Forde Patrick M. , Zhu Viola Weijia , Fukuda Yoko Korenaga , Clark Jeffrey W. , Janne Pasi A. , Mok Tony , Sholl Lynette M. , Heist Rebecca Suk
Published: September 2018

8511

Background: Dramatic responses to MET inhibitors have been reported in patients with NSCLC harboring activating mutations that cause MET exon 14 ( METdel14) skipping. We conducted a multicenter retrospective analysis of pts with METdel14 NSCLC to determine if treatment with MET inhibitors impacts survival. Methods: We collected clinicopathologic data on pts with METdel14 NSCLC. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. Results: Of the 148 pts with METdel14 mutant NSCLC, the median age was 72 (range 43-88); 57% were women, and 41% were never smokers. The most common histologies were adenocarcinoma (77%) and pulmonary sarcomatoid carcinoma (14%). Overlap with oncogenic driver mutations in other genes was rare. At the time of diagnosis, 70% of pts had stage I-III disease, and 30% had stage IV disease. Of the 34 pts with metastastic disease who never received a MET inhibitor, the median overall survival (mOS) was 8.1 months. In this cohort, cancers that also had concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 pts with metastatic disease who received at least one MET inhibitor (including crizotinib, glesatinib, capmatinib, and ABBV-399), the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04). Among 22 patients treated with crizotinib, the median progression-free survival (PFS) was 7.36 months. Conclusions: Forpts with METdel14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival. The prognosis of pts who never received treatment with a MET inhibitor appears to be poor, particularly among METdel14 cancers with concurrent MET amplification.
PD-L1 expression and response to immunotherapy in patients with MET exon 14-altered non-small cell lung cancers (NSCLC).
Authors: Sabari Joshua K. , Montecalvo Joseph , Chen Ruqin , Dienstag Jordan A. , Mrad Chebli , Bergagnini Isabella , Lai Wei-Chu Victoria , Arbour Kathryn Cecilia , Shu Catherine A. , Hellmann Matthew David , Riely Gregory J. , Kris Mark G. , Rudin Charles M. , Rekhtman Natasha , Drilon Alexander E.
Published: September 2018

8512

Background: MET exon 14 skipping alterations ( METΔ14) are present in 4% of NSCLCs. Response to MET inhibition has been observed in ongoing prospective trials (44% response rate, phase 1 trial of crizotinib; Drilon et al ASCO 2016), however responses to other types or therapy, such as immunotherapy, is unknown. We evaluated the immunophenotype of METΔ14 lung cancers and response to PD-(L)-1-based immunotherapy. Methods: Pts with recurrent/metastatic NSCLC were eligible. METΔ14 was identified by broad hybrid capture-based next-generation sequencing (MSK-IMPACT). PD-L1 expression was determined by immunohistochemistry. Response to immune therapy was evaluated by RECIST v1.1. Results: 63 pts with METΔ14-positive non-small cell lung cancers were identified; 41 (65%) had sufficient tissue for PD-L1 analysis. Patient characteristics: median age 71 years, 58% female, median pack year smoking 5.85 years, histology: 73% (30/41) adenocarcinoma, 20% (8/41) pleomorphic carcinoma, 7% (3/41) squamous cell. Tumor PD-L1 expression was ≥50% in 44% (18/41, 95% CI 30-59%), 1-49% in 17% (7/41, 95% CI 8-32%), and < 1 in 39% (16/41, 95% CI 26-54%). The median age for patients with METΔ14 and PD-L1 positive (≥1%) tumors was 65 years (range 49-87); 60% (15/25) of patients were female; Histology: 72% (18/25) adenocarcinoma, 24% (6/25) sarcomatoid carcinoma, and 4% (1/25) squamous cell carcinoma. Immunotherapy was given to 15 pts: nivolumab (5), pembrolizumab (3), atezolizumab (2), durvalumab (1), and ipilimumab+nivolumab (4). The overall response rate to immunotherapy was 13% (2/15, 95% CI 3-39%). Overall response was 33% (1/3; 95% CI 6-80%) in patients with tumors PD-L1 ≥50%, and 20% (1/5, 95%CI 2-64%) in patients with tumors PD-L1 0%. Time on therapy ranged from 2 weeks to 9.6+ months. Conclusions: A substantial proportion of NSCLCs harboring METΔ14 alterations express PD-L1. Despite frequent PD-L1 expression, responses to immunotherapy were overall uncommon and lower than that observed with targeted therapy for this genomically defined subset of patients with lung cancers. Further exploration of this subset may reveal important mechanisms of immunotherapy resistance in PD-L1 expressing tumors.
Immune microenvironment in mesothelioma: Looking beyond PD-L1.
Authors: Thapa Bibhusal , Walkiewicz Marzena , Rivalland Gareth , Murone Carmel , Asadi Khashayar , Barnett Stephen , Knight Simon , Watkins Neil , Russell Prudence A , John Thomas
Published: September 2018

8515

Background: Studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise. Differences in response to PD-L1 and PD-1 inhibitors (10% vs 25%) have been reported. Also, expression of PD-L1 alone appears to be a limited predictor. As the roles of the multiple check point receptors and their ligands become defined, an understanding of their expression and interplay in the mm tumour microenvironment, which could affect suitability for checkpoint inhibition therapy, has become necessary. Methods: Tissue microarrays were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. Tumour infiltrating lymphocytes (TILs) were assessed in the stroma and expressed as a % of stromal area within invasive tumour. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. To quantify the immunosuppressive milieu, we combined our assessment of PD-L1, PD-L2 and TIM3 expression to derive an “Immune checkpoint score (ICS)” and explored its correlation with the tumour microenvironment and clinicopathological covariates. We are also exploring its predictive value in an independent cohort of mm patients who have received anti-PD-1 treatment. Results: Amongst 329 patients evaluated, PD-L1 was positive (+) in 41.7% and PD-L2+ in 24.5%. TIM3+ lymphocytes were found in 99.4% but LAG3+ lymphocytes in only 0.2%. 28/173 (16%) of PD-L1- patients were PD-L2+ and 31/136 (22%) PD-L1 and PD-L2 negative patients had high infiltration with TIM3+ lymphocytes. High ICS was associated with non-epithelioid histology, increased TILs and poorer survival. On multivariate analysis, high TILs, non-epithelioid histology and poor physiological status remained significantly associated with poorer survival. Data on the predictive role of ICS score will also be reported. Conclusions: While co-expression of PD-L1, PD-L2 and TIM3 can occur, their expression is mutually exclusive in a large proportion of patients. The expression of PD-L2 may explain differences in responses seen between PD-1 compared to PD-L1 inhibitors. A comprehensive assessment of these multiple immunosuppressive pathways may be necessary to truly gauge the immunosuppressive environment and tailor immunotherapy for individual cases.
A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.
Authors: Cho Jinhyun , Ahn Myung-Ju , Yoo Kwai Han , Lee Hansang , Kim Hee Kyung , Heo Mi Hwa , Hong Joo Hyun , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil
Published: September 2018

8521

Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631.