Superior OS Research Articles

Race as a prognostic factor in high-risk prostate cancer: An NCDB analysis.

e16611 Background: It is commonly held that race serves as a significant prognosticator in prostate cancer. However, it is unclear if race affects all risk groups similarly. We sought to analyze whether race, either African American (AfA) or Caucasian (C), impacted overall survival of men receiving standard of care treatment using a large national database. Materials and Methods: All data was obtained from the NCDB (National Cancer Database), a collaborative effort between the American Cancer Society and Commission on Cancer. The database initially contained 1,294,126 cases of prostate cancer diagnosed between 2004 and 2014. Those with documented race and minimum follow up of 4 years were analyzed in this study. Patients were eliminated from the study if they had metastatic or nodal disease, received chemotherapy, or had non-invasive disease. Patients were grouped into two cohorts as per NCCN criteria: favorable risk and unfavorable risk. All patients received definitive therapy appropriate for their risk group. AfA and C men were matched 1:1 within each risk cohort using propensity scores, and multivariate analysis was conducted on these matched cohorts. Results: The final analyzed cohort included 75,217 patients with median follow-up time of 5 years. 10-year OS for favorable risk and unfavorable risk cohorts were 78% and 73% respectively (log rank, p < 0.001). In the favorable risk cohort, 5,422 C cases were matched to 5,422 AfA cases. C men had superior OS compared to AfA men, 89% versus 86% at 8 years and 79% versus 79% at 10 years (HR 0.688, 95% CI 0.571-0.872, p = 0.0025). In the unfavorable risk cohort, 3,870 C cases were matched to 3,870 AfA cases. Race was not a significant prognostic factor for OS, 83% versus 83% at 8 years and 73% versus 71% at 10 years in C and AfA men, respectively (HR 0.961, 95%CI 0.837-1.103, p = 0.572). Conclusions: Race has no effect on overall survival in unfavorable disease while AfA race is a predictor for worse survival in favorable risk prostate cancer, independent of socioeconomic and demographic factors. This suggests that the biology of disease plays a significant role in favorable risk cohorts, but with more advanced higher risk disease, other factors besides race may play a more significant role.

A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS)

Hypomethylating agent (HMA) failure myelodysplastic syndrome (MDS) patients have poor outcomes and urgent need for novel therapies. Hedgehog pathway signaling upregulation plays a central role in myeloid neoplasm pathogenesis and leukemia stem cell survival. We evaluated the efficacy and safety of the smoothened inhibitor glasdegib in HMA-failure MDS (n = 35, median age 73 years). According to the International Prognostic Scoring System and the MD Anderson Global Risk Model, 54% and 77% had higher risk disease, respectively. Overall response was 6% (n = 2), and best response was marrow complete remission with hematologic improvement in both patients. Median OS and median follow-up were 10.4 and 42.8 months, respectively. Drug response/stable disease (SD) resulted in better OS than treatment failure (20.6 [95% CI, 10.4-] vs 3.9 months [95% CI, 0.7–9.1]; P< .0001). Response/SD was confirmed to be an independent covariate for improved OS (P < .0001). Grade 3 or higher infections occurred in 11% of patients (n = 4); non-hematologic toxicities were rare. Early mortality (< 30 days) occurred in 11% of patients (n = 4). Glasdegib was well tolerated among HMA-failure MDS patients, although single-agent activity was limited. SD or better resulted in notably superior OS. These results support further investigation of glasdegib, potentially in novel drug combinations, in MDS patients.

Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).

547 Background: N+I showed superior OS v S in ITT (IMDC any risk) and intermediate/poor-risk (I/P) pts with aRCC in CheckMate 214 at 17.5 mo min follow-up. Methods: Pts with clear cell aRCC were randomized 1:1 to N3 mg/kg + I1 mg/kg Q3W×4 and then N3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Co-primary endpoints were OS, RECISTv1.1 ORR and PFS per IRRC in I/P pts. PFS and ORR were assessed by investigator (inv) at 30 mo. Results: At 30 mo min follow-up, OS remains significantly improved in ITT and I/P pts with N+I v S; the HR for OS in favorable (fav) risk pts has improved for N+I v the previous analysis (1.22 [95% CI 0.73–2.04] v 1.45 [99.8% CI 0.51‒4.12]). Per previous IRRC ORR (N+I, 42% [95% CI 37‒47]; S, 27% [95% CI 22‒31]), ORR per inv was higher with N+I v S in ITT and I/P pts. ORR CIs overlapped in fav pts, CR was doubled with N+I v S. Increasing PFS benefit with N+I v S is emerging in ITT and I/P pts; PFS CIs between arms remain overlapping in fav pts (Table). 15% v 9% of N+I and S ITT pts remain on therapy, and 48% v 61% have received 2nd-line systemic therapy; 39% of S pts received subsequent immune-checkpoint inhibitor therapy. Among pts who were alive with CR, 50% v 10% remain on treatment with N+I (n = 56) v S (n = 10). 5 N+I and 7 S additional pts developed Gr 3–4 drug-related AEs; 1 N+I and 3 S additional pts had AEs leading to discontinuation. No new drug-related deaths occurred. Conclusions: At 30 mo min follow-up, OS and ORR remain improved with N+I v S in ITT and I/P CheckMate 214 pts. No new safety signals emerged with longer follow-up. Clinical trial information: NCT02231749. [Table: see text]

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study.

543 Background: A phase 1b study of pembro (anti–PD-1) plus axi (VEGFR-TKI) showed promising antitumor activity and manageable safety in patients (pts) with previously untreated mRCC. The global, open-label, phase 3 KEYNOTE-426 study assessed the efficacy and safety of pembro + axi vs sunitinib as first-line therapy for mRCC (NCT02853331). Methods: Eligible pts with clear-cell mRCC, no previous systemic therapy for mRCC, and KPS ≥70% were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID or sunitinib 50 mg orally QD (4-wk on/2-wk off schedule). Treatment was given until PD, intolerable toxicity, or pt/investigator decision. Randomization was stratified by IMDC risk group and geographic region. Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR was the key secondary endpoint. At the protocol-specified first interim analysis, the superiority thresholds were P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS and PFS were significant). Results: 861 pts were randomized: 432 to pembro + axi, 429 to sunitinib. After a 12.8-mo median follow-up, 59.0% of pts in the pembro + axi arm and 43.1% in the sunitinib arm remained on treatment. Pembro + axi significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P &lt; 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P &lt; 0.0001). Duration of response was prolonged with pembro + axi (median not reached vs 15.2 mo). The pembro + axi benefit was observed in all subgroups tested, including all IMDC risk and PD-L1 expression subgroups. Treatment-related AEs were grade 3-5 in 62.9% of pts in the pembro + axi arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%. Conclusions: Pembrolizumab + axitinib provided superior OS, PFS, and ORR compared with sunitinib and had manageable safety in pts with previously untreated, advanced or metastatic clear-cell RCC. These data suggest that pembrolizumab + axitinib should be a new standard of care for this population. Clinical trial information: NCT02853331.

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCTat 2years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

The cervix: is last century's paradigm more fitting than today's?

Predicting delivery has always been an obstetrical conundrum. Nobody understands why or how the cervix opens when it does. A debate about cervical structure and function has been continuing for a century, changing as imaging and staining techniques evolve, and the cervix has been seen variously as the primary driver or passive bystander in the process of parturition. Today's dogma is that the cervix is largely a downstream responder to signals that cause alterations to its collagen scaffolding, while other components - e.g. smooth muscle - play relatively minor roles. This was not always true. From the mid-1800s to mid-1900s, parturition was generally thought to be dictated by the cervix, perhaps via a specific region at the junction of the cervix and uterus. In the 1920s, a Viennese obstetrician obsessed with ‘the problems of the isthmus’ proposed that the terms isthmus and internal os not be used interchangeably, because the isthmus ‘lives its own life’ as opposed to being a simple circular borderline between the uterus and cervix (Frankl Br J Obstet Gynaecol 1933;40:397; see Figure 1). He detailed his work and that of others on the morphology of the isthmus, a ‘hollow space’ in the proximal cervix, bordered by superior ‘anatomic’ and inferior ‘histologic’ ostia. He described how, by the second trimester, the superior os disappears as it coincides with the ‘so-called contractional ring of the gravid uterus’ and the inferior os becomes the internal os. Twenty years later, a British pathologist obsessed with cervical muscle set out to counteract the growing theory that collagen alone determines cervical function (Hughesdon Br J Obstet Gynaecol 1952;59:763). He explored dozens of samples from fetuses, girls and women aged from 6 days to 91 years, many of whom were pregnant, defining epithelium, glands, muscle, collagen, etc. He found that cervical muscle bundles are evident by 180 days post-conception and persist throughout life, with temporal ‘elaborations’ (e.g. during pregnancy). He suggested that if contemporaneous investigators found muscle to be sparse or random, in contrast to collagen, it was because their processing and staining techniques had distorted the anatomy. He also noted that, even if the bundles were random, the fact that they were arranged in a ring meant they could act as a ‘compressor’. Decades later, a study in labouring women demonstrated that the cervix itself contracts, suggesting an active role in parturition (Olah et al. Br J Obstet Gynaecol 1994;101:341). Recently, interest in the proximal cervix has once again been reinvigorated. With diffusion tensor magnetic resonance imaging, Nott et al. identified a circumferential ‘occlusive structure’ in this region (BJOG 2018;125:812), and with immunohistochemistry techniques and functional organ baths, Vink et al. found a dense ring of smooth muscle cells that demonstrate integrated force generation upon exposure to oxytocin (AJOG 2016;215:478.e1). New techniques like these are furthering the debate about cervical structure and function. Perhaps such studies will finally bring us closer to predicting the timing of birth. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Ganglion cell complex loss in patients with type 1 diabetes: A 36-month retrospective study.

BACKGROUND:To analyze changes over a 3-year period in ganglion cell complex (GCC) thickness in individuals with type 1 diabetes mellitus (T1DM) using spectral-domain optical coherence tomography (Optovue, Fremont, CA, USA).METHODS:Thirty-seven individuals from “Friends for Life Conference” with T1DM and a 3-year history of GCC thickness measurements were included in the study. Data analysis using SPSS 22 and Excel StatPlus was completed to note the subgroups that had a significant change.RESULTS:Significant decreases were noted in the following subgroups with slope in parenthesis. Overall: GCC superior thickness OD (−0.48)Male: GCC thickness OD (−0.86), GCC superior thickness OD (−0.735)Body mass index (BMI) 25.0–29.9: GCC thickness OD (−0.48), GCC superior thickness OS (−0.915), GCC inferior thickness OD (−0.43)Ages 10–20 years: GCC superior thickness OD (−0.635)Duration of diabetes 10–20 years: GCC thickness OD (−1.055), GCC superior thickness OD (−0.99). CONCLUSION:GCC loss was noted in individuals who were males, those with BMIs of 25.0–29.9, and those who had diabetes for 10–20 years. Ganglion cell loss was also noted before the presence of any diabetic retinopathy, suggesting onset of neuronal loss before any vasculature changes.

Tumor Abnormal Protein Level Predicts Disease Response and Progression of Diffuse Large B-Cell Lymphoma in the Rituximab Era.

Changes of glycoprotein are hallmarks for various malignancies; however, the prognostic impact in diffuse large B-cell lymphoma (DLBCL) has not been well elucidated. Here we used serum tumor abnormal protein (TAP) level, a lectin-based agglutination assay, to investigate the clinical value of circulating glycoprotein level in DLBCL. One hundred and thirty-one newly diagnosed DLBCL patients treated by rituximab combined chemotherapy were retrospectively enrolled, all with data available for TAP level at initial diagnosis. Additionally, TAP levels during and after initial treatments were measured in 97 cases. Our results showed elevated pre-treatment TAP level was significantly associated with shorter progression-free survival (PFS, p = 0.019) and overall survival (OS, p = 0.025), especially in the high-risk subgroups. In the multivariate Cox regression analyses, pre-treatment TAP level was an independent predictive factor for PFS (p = 0.048). Moreover, ≥ 25% decrease of TAP level indicated superior PFS (p = 0.006) and OS (p = 0.024) in patients with elevated TAP levels at diagnosis. In cases which achieved complete or partial remission, TAP levels were significantly reduced during treatment, but not in non-responsive or progressed patients. TAP level is a strong prognostic tool for predicting disease progression and monitoring individual response for DLBCL in the rituximab era.

Better treatment outcomes in patients with actively treated therapy-related myeloid neoplasms harboring a normal karyotype.

We analyzed treatment outcomes and prognostic factors in adult patients with therapy-related myeloid neoplasms (t-MNs) to select patients who would be benefited by active anticancer treatment. After excluding 18 patients who received palliative care only and 13 patients with acute promyelocytic leukemia, 72 t-MN patients (45 with acute myeloid leukemia and 27 with myelodysplastic syndrome) were retrospectively evaluated. Among them, 10 (13.9%), 32 (44.4%), and 30 patients (41.7%) had favorable, intermediate- and adverse-risk cytogenetics, respectively. Among patients with intermediate-risk cytogenetics, patients with a normal karyotype (NK; N = 20) showed superior allogeneic stem cell transplantation-censored overall survival (AC-OS) and OS compared to those with non-NK-intermediate-risk cytogenetics (P < 0.001). In the multivariate analysis, male sex, age ≥ 70 years, and unfavorable cytogenetics (non-NK-intermediate plus adverse risk cytogenetics) were associated with inferior AC-OS. Those results suggest that a more-refined subdivision of risk stratification would be necessary in patients with intermediate-risk cytogenetics.

Prognostic Significance of Total Lymphocyte Count, Neutrophil-to-lymphocyte Ratio, and Platelet-to-lymphocyte Ratio in Limited-stage Small-cell Lung Cancer

BackgroundWe sought reliable markers of survival and disease control among patients treated for limited-stage small-cell lung cancer (LS-SCLC). Patients and MethodsSubjects were 122 patients given (chemo)radiotherapy for LS-SCLC at MD Anderson in 2002 through 2015. Pretreatment total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were analyzed for associations with overall (OS) and progression-free survival. Optimal cutoff values were identified with receiver operating characteristic curves and survival probabilities with the Kaplan-Meier method. ResultsPretreatment TLC was 1.86 × 103/μL (±0.88); NLR, 3.44 (±3.69); and PLR, 170.53 (±101.56); corresponding cutoffs were 1.9, 2.9, and 140.1. Higher TLC was associated with superior median and 2-year OS (17.4 vs. 15.7 months and 33% vs. 29%; P = .029), and higher NLR and PLR with worse median and 2-year OS (NLR: 14.9 vs. 17.8 months, 29% vs. 31%; P = .026; PLR: 14.8 vs. 18.9 months, 24% vs. 37%; P = .009). Multivariate Cox regression adjusted for age, disease stage, number of chemotherapy cycles, and use of prophylactic cranial irradiation confirmed the links between high TLC and superior OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.32-0.94; P = .028) and between high NLR and PLR and inferior OS (NLR: HR, 1.86; 95% CI, 1.15-3.01; P = .011; PLR: HR, 1.72; 95% CI, 1.06-2.82; P = .030). ConclusionsBaseline lymphopenia was an indicator of poor prognosis in patients with LS-SCLC.

Subgroup Analyses of the Randomized GMMG Phase III Multicenter Trial Relapse Suggest Survival Benefit of Salvage Autologous Transplant Primarily in Low Risk Multiple Myeloma

Subgroup Analyses of the Randomized GMMG Phase III Multicenter Trial Relapse Suggest Survival Benefit of Salvage Autologous Transplant Primarily in Low Risk Multiple Myeloma

Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia

Abstract Outcome of persons &gt;65 years with acute myeloid leukemia (AML) is poor. Allogeneic transplant can cure some of these patients but is associated with substantial transplant-related mortality (TRM) and high relapse risk. We analyzed 185 consecutive patients &gt;65 years with high-risk AML between 2010 and 2015 who had measurable residual disease (MRD) and molecular risk assessments and who received myeloablative conditioning (MAC, n=42) or reduced-intensity conditioning (RIC, n=143) and a transplant from an HLA-identical sibling (n=66) or a 10/10 loci HLA-matched unrelated donor (MUD, n=119) in order to identify patients who would benefit from allotransplant. MRD was assessed by flow cytometry in bone marrow samples. AML cytogenetic and molecular risk were defined using the 2017 European Leukemia Net genetic risk stratification. The patients who were MRD-negative at time of transplant had a better 2-year cumulative incidence of relapse (CIR 17.6%) and a 2-year overall survival (OS, 69.4%) as compared to the patients in remission but MRD-positive (55.6% CIR, 21.5% OS) or the patients who had morphological evidence of leukemia prior to transplant (48.7% CIR, 19.9% OS), (p&lt;0.0001). Multivariate analysis for 2-year CIR showed that having detectable leukemia at time of SCT (defined as MRD-positive or morphological evidence of leukemia) (HR=14.5, CI=3.4-61.4, p&lt;0.0001), having received &lt;3 cycles of chemotherapy prior to SCT (HR=1.8, CI=1.1-2.8 p=0.01), and high-risk genetics were independent predictors of relapse. However, high-risk genetics only had a deleterious effect on outcomes for MRD-negative patients (HR=9.4, CI=2.0-43.6, p=0.004), and did not affect the outcome of patients with detectable leukemia (HR=1.1, CI=0.7-1.9, p=0.61). Patients who received RIC (Flu-Mel-RIC or Bu-Flu-RIC) or MAC (Bu-Flu-MAC) had similar proportion of MRD-negative patients (p=1.0). However, MRD-negative patients who received Flu-Mel-RIC had a superior OS than patients who received Bu-Flu-RIC (adjusted HR=1 vs 5.3, p=0.02) or patients who received Bu-Flu-MAC (HR=1 vs 5.093, p=0.04), which is explained by a significantly lower relapse rate in patients receiving Flu-Mel-RIC (adjusted HR=1 vs 4.8, p=0.03) and a significantly lower TRM as compared to patients receiving Bu-Flu-MAC (adjusted HR= 5.1, p=0.01). Patients who had major medical complications (MMC), defined as a medical event requiring admission to the intensive care unit for ventilatory or inotropic support or a medical event that prolonged the patient hospitalization for more than 2 weeks, during induction or consolidation chemotherapy preceding the transplant, had a higher day +100 mortality (30.6% vs 6.0%, p&lt;0.0001), 2-year TRM (55.6% vs 16.8%, p&lt;0.0001) and lower 2-year OS (8.3% vs 44.6%, p&lt;0.0001). Multivariate analysis for 2-year OS showed that history of delayed hematological recovery during induction or consolidation chemotherapy prior to transplantation (HR=1.5, CI=1.0-2.3, p=0.04), high risk genetics (HR=1.8 CI:1.2-2.6, p=0.006), donor-recipient HLA-DRβ3/4/5-DP mismatch (HR=2.2, CI=1.3-3.6, p=0.001), history of cardiovascular disease (HR=1.7, CI=1.1-2.6, p=0.02) were independent predictors for OS. Other variables such as secondary leukemia, CMV sero-status, FEV1 or creatinine clearance prior to SCT, sex mismatch, ABO group mismatch, donor type, or stem cell source did not have a significant impact on OS or TRM. Outcomes were also similar between patients transplanted in CR1 or in ≥ CR2 or in CR or CRi. We sought to identify those patients who may clearly benefit from a SCT. To that end, we classified patients according to the MRD status prior to transplantation and the presence or absence of the other prognostic factors identified in the multivariate analysis. As seen in the Figure, the High risk group which includes patients with detectable leukemia and &gt;1 additional adverse prognostic factors (or a MMC), had a 2-year OS of 7.7% (CI=3.1-17.8). In comparison, the Low risk group which includes MRD-negative patients with ≤3 other prognostic factors (and no MMC), had a 2-year OS of 76.2% (CI=63.3-85.6). Finally, the Intermediate risk group which constituted the remaining patients, had a 2-year OS of 32.2% (CI=22.1-44.3, p&lt;0.00001). These data indicate the possibility to identify persons &gt;65 years with high-risk AML likely to benefit from an allotransplant. Figure. Figure. Disclosures Rezvani: Affirmed GmbH: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy, Research Funding; AROG pharmaceuticals: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Circulating Tumor DNA Dynamics during Therapy Predict Outcomes in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma with striking variability in tumor biology and clinical behavior across patients. Noninvasive blood-based biomarkers that monitor disease and treatment response may guide clinical decisions throughout disease course. Circulating tumor DNA (ctDNA) is a highly tumor-specific biomarker detectable in the blood of virtually all MCL patients. Within a prospective clinical trial, we studied Adaptive's next-generation sequencing assay to detect and quantify ctDNA in serum throughout therapy. Previously, we reported that ctDNA clearance after induction predicts both PFS and OS (Roschewski et al. ASCO 2018). Bortezomib (BZ) is a proteasome inhibitor shown to improve PFS when added to combination chemotherapy (Robak et al. N Eng J Med 2015). Herein, we analyze the clinical significance of ctDNA dynamics during therapy in patients treated with BZ + DA-EPOCH-R without consolidation.Methods: Untreated MCL patients received BZ monotherapy x 1 cycle then induction with BZ + DA-EPOCH-R up to 6 cycles. After induction, patients were randomized to observation vs. BZ maintenance x 18m. Patients had serum prospectively collected pre-Tx, after BZ monotherapy, before each cycle, after induction, and with each surveillance visit. Surveillance visits were paired with CT scans q4mos x 2y, q6mos in years 2-4, then annually. Pre-treatment specimens (FFPE or frozen cells) were analyzed for tumor-specific clonotypes. Tumor DNA was amplified using locus-specific primer sets for the Ig heavy-chain and light-chain loci, CCND1, and BCL2 translocations. Amplified products were sequenced, and patients without a high-frequency tumor clonotype were excluded. Levels of ctDNA at baseline, after BZ monotherapy, and after 1, 2 cycles of induction were analyzed.Results: 53 untreated MCL patients received BZ + DA-EPOCH-R between September 2005 and January 2016. After median potential f/u of 10y, median PFS is 29.3m and the 5-yr OS is 78.2%. BZ maintenance had no impact on PFS or OS. Of 52 patients w/available biopsies, 50 (96%) had a tumor-specific clonotype identified. Of 48 patients w/pre-treatment serum, 46 (96%) had detectable ctDNA. ctDNA was successfully tracked in 625 of 647 (97%) serum samples. The median level of baseline ctDNA was 742.98 cell equivalents/mL (range 0 to 101,008.58). Baseline ctDNA correlated with total metabolic tumor volume on PET scan (rs=0.74) but was not associated with PFS (p=0.45) or OS (p=0.22). Of 42 patients who received BZ monotherapy, 26 (62%) had decreases in ctDNA, 15 (36%) had increases, and 1 (2%) had no change. The median absolute decrease in ctDNA was 35 cell equivalents/ml (range -20,901 to +6,667) and the median relative decrease was 24% (range -100% to +530%). Notably, lower absolute ctDNA levels after BZ window were associated with improved PFS compared to patients with ctDNA above the median (34m vs 22m, p=0.02)(Figure 1). Clearance of ctDNA after 1 cycle of DA-EPOCH-R + BZ was strongly associated with a superior median PFS (76.4m vs 20.7m, p=0.0037)(Figure 2) and a trend towards superior 4-yr OS (92.3% vs 73.0%, p=0.23). Clearance of ctDNA after 2 cycles of DA-EPOCH-R + BZ was also associated with a superior median PFS (32.4m vs 21.4m, p=0.015) and a trend towards superior median OS (82.2m vs 73.2m, p=0.15).Conclusions: Circulating tumor DNA is detectable in nearly all patients with MCL. Dynamic changes that occur very early during therapy may predict clinical outcomes and may be an early readout for the activity of targeted agents. Given its broad applicability, ctDNA should be prospectively studied as part of response-adapted approaches in MCL.This work was supported by the Intramural Research Program of NCI and Adaptive Biotechnologies, Inc. [Display omitted] DisclosuresJacob:Adaptive Biotechnologies: Employment, Equity Ownership. Yusko:Adaptive Biotechnologies: Employment, Equity Ownership. Wiestner:Pharmacyclics LLC, an AbbVie Company: Research Funding.

Outcomes of Older Patients (≥ 70 Years) Treated With Targeted Therapy in Metastatic Chemorefractory Colorectal Cancer: Retrospective Analysis of NCIC CTG CO.17 and CO.20

BackgroundThe safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated. Patients and MethodsOutcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included. ResultsA total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03). ConclusionOS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients.

532P - KEYNOTE-189 study of pembrolizumab (pembro) plus pemetrexed (pem) and platinum vs placebo plus pem and platinum for untreated, metastatic, nonsquamous NSCLC: Does choice of platinum affect outcomes?

Background: In KEYNOTE-189 (NCT02578680), pembro plus pem and platinum provided superior OS (HR 0.49, P < 0.00001) and PFS (HR 0.52, P < 0.00001) and had manageable safety vs placebo plus pem and platinum as first-line therapy for metastatic nonsquamous NSCLC. In an exploratory analysis, we assessed outcomes by investigator’s choice of carboplatin (carbo) or cisplatin (cis). Methods: 616 patients (pts) with untreated metastatic nonsquamous NSCLC regardless of PD-L1 TPS without sensitizing EGFR or ALK alteration were randomized 2:1 to 4 Q3W cycles of pembro 200 mg or placebo + pem 500 mg/m2 + carbo AUC 5 or cis 75 mg/m2 followed by maintenance pembro or placebo + pem. Randomization was stratified by TPS (<1% vs ≥ 1%), platinum (carbo vs cis), and smoking status (current/former vs never). Primary end points were OS and PFS; ORR and safety were secondary. Results: Carbo was chosen for 72% of pts in both arms. OS, PFS, and ORR were improved in the pembro plus pem and platinum arm in both carbo and cis recipients (Table). In the pembro vs placebo arm, 83% vs 72% received 4 carbo doses and 81% vs 79% received 4 cis doses. 76% vs 65% and 78% vs 72%, respectively, received ≥5 pem doses. Grade 3-5 AE rates for pembro vs placebo were 70% vs 66% with carbo and 59% vs 65% with cis. Rates of the most common any-grade AEs were generally similar for carbo and cis: nausea 54% with pembro vs 48% with placebo for carbo and 60% vs 63% for cis, anemia 45% vs 48% and 50% vs 44%, and fatigue 44% vs 43% and 33% vs 26%. Rates of acute kidney injury in the pembro arm were 5.1% with carbo and 5.4Table532PCarboCisPembro + Chemo N = 297Placebo + Chemo N = 148Pembro + Chemo N = 113Placebo + Chemo N = 58OS, medianNR (NR-NR)11.3 (8.0-NR)NR (NR-NR)10.8 (8.1-NR)(95% CI), moHR (95% CI)0.52 (0.39-0.71)0.41 (0.24-0.69)PFS, median8.6 (7.1-9.2)4.9 (4.6-5.6)9.2 (6.9-11.1)4.8 (4.7-6.0)(95% CI), moHR (95% CI)0.55 (0.44-0.70)0.44 (0.30-0.65)ORR, % (95% CI)47 (41-53)18 (12-25)49 (39-58)21 (11-33) Open table in a new tab % with cis. Conclusions: Pembro plus pem and platinum improved efficacy and was generally tolerable compared with placebo plus pem and platinum regardless of the chosen platinum. These data support the use of both carbo and cis in combination with pembro and pem as first-line therapy for metastatic nonsquamous NSCLC. Editorial acknowledgement: Sheri Arndt. Clinical trial identification: MK-3475-189, NCT02578680. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: M.C. Garassino: Personal fees as a consultant, advisor: AZ, BI, BMS, Lilly, MSD, Roche; Travel support: Lilly, MSD, Pfizer; Research funding to the institution: AZ, AZ/MedImmune, BMS, MSD, Roche/Genentech. E. Felip: Personal fees as a consultant, advisor: AZ, BMS, BI, Celgene, Guardant Health, Lilly, MSD, Novartis, Pfizer, Roche,Takeda; Speaker: AZ, BI, BMS, MSD, Novartis, Pfizer, and Roche. S. Powell: Personal fees as a consultant, advisor: BMS; Research funding to the institution: BMS, Genentech/Roche, Incyte, MSD, Novartis, Pfizer,Vyriad. S.Y-S. Cheng: Personal fees as a consultant, advisor: Merck, Roche. N. Peled: Grants, personal fees, honoraria for serving as an advisor: AZ, BI, BMS, Lilly, MSD, Novartis, Pfizer, Roche, NovellusDx, FMI, Gaurdant360. R. Hui: Advisor: MSD, AZ, Roche, BMS,Novartis; Speaker honoraria: MSD, Novartis, AZ, Roche, BMS. M. Reck: Personal fees for lectures, consultant: Roche, Lilly, AZ, BI, BMS, Celgene, MSD, Merck, Novartis, Pfizer, AbbVie. E.B. Garon: Institution research funding: AZ, BI, BMS, Genentech, Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer. M. Boyer: Travel funds: BI, BMS, Genentech/Roche (G/R),MSD; To institution: AZ, BMS, MSD, Amgen, Ascentage Pharma, BeiGene, BI, G/R, Lilly, OncoMed, Peregrine Pharmaceuticals, Pfizer. F. Grossi: Personal fees for serving as a consultant, advisor, lectures: MSD, BMS, AstraZeneca, Pierre Fabre, Roche, Pfizer; Research funding: BMS. J. Yang, M.C. Pietanza: Full-time employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S. Gadgeel: Personal fees: Ariad, AZ, BMS, Genentech/Roche (G/R), Pfizer, Takeda; To Institution: ACEA Biosciences, Acerta, AZ, BMS, Five Prime Therapeutics, G/R, Halozyme, Incyte, Janssen Oncology, Merck, Millennium, Novartis, OncoMed, Pfizer. All other authors have declared no conflicts of interest.

Combination of DC/CIK adoptive T cell immunotherapy with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients: a prospective patients' preference-based study (PPPS).

Advanced non-small cell lung cancer (NSCLC) has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with chemotherapy (CT) in this malignancy. We have developed a new clinical trial design termed as the prospective patient's preference-based study (PPPS). Consecutive patients (n = 135) with advanced NSCLC were treated with DC-CIK administered with CT or mono-therapy (CT or DC-CIK alone). For all the patients, the median PFS was 5.7months and the median OS was 17.5months. The 1-year PFS and OS rates were 29.4% and 58.2%, respectively. The 1-year PFS and OS rates for DC-CIK plus CT were significantly higher than that in the group of patients who received DC-CIK alone and CT alone (P < 0.05). The number of adoptively infused DC-CIK cells was associated with clinical efficacy. After adjusting for competing risk factors, DC-CIK combined with CT and infused number of CIKs remained independent predictors of PFS and OS. Phenotypic analysis of peripheral blood mononuclear cells showed that CD8+CD28+, and CD8+CD28- T cells, changed significantly in all groups (P < 0.01). The CD3+ T cells increased in the chemotherapy plus immunotherapy and the immunotherapy alone group (P < 0.01), while CD3-CD16+CD56 T cells decreased in the chemotherapy plus immunotherapy and the immunotherapy alone group (P < 0.01). DC-CIK combined with chemotherapy administration resulted in numerically superior PFS and OS compared with monotherapy in advanced NSCLC.

The association of physical activity before and after lymphoma diagnosis with survival outcomes.

The impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma-specific (LSS) and event-free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002-2012). We calculated Leisure Score Indexes (mLSI) from the self-reported usual adult PA (baseline) and at 3-years post-diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72-0.94); LSS 0.74 (0.61-0.90); EFS 0.92 (0.82-1.02)] and FU3 [HR (CI): OS 0.64 (0.46-0.88); LSS 0.32 (0.18-0.59); EFS 0.82 (0.61-1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49-1.00) and LSS (HR = 0.49, CI 0.26-0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.

Programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocytes in advanced non-small cell lung cancer treated with microwave ablation and chemotherapy

Background: Programmed death-ligand 1 (PD-L1) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with non-small cell lung cancer (NSCLC). We conducted this study to evaluate the correlation between PD-L1 or CD8+ TILs expression and MWA or survival in advanced NSCLC patients treated with microwave ablation (MWA) plus chemotherapy.Methods: Previously untreated, pathologically verified advanced NSCLC patients with adequate tissues for the analysis of PD-L1 expression and the presence of CD8+ TILs were retrospectively enrolled. None of the patients had sensitive mutations, and therefore, they were treated with MWA of the primary tumors followed by chemotherapy.Results: A total of 51 patients were enrolled. PD-L1 expression and the presence of CD8+ TILs were identified in 31 (60.8%) and 9 (17.6%) patients, respectively. PD-L1 expression and CD8+ TILs had no correlation with baseline characteristics, the response to chemotherapy or MWA. Patients with PD-L1 expression had similar progression-free survival (PFS: 7.9 months for PD-L1-positive vs. 5.8 months for PD-L1-negative; p = .660) and overall survival (OS: 18.7 months for PD-L1-positive vs. 15.2 months for PD-L1-negative; p = .901). Patients with CD8+ TIL expression did not show superior PFS (CD8+ TIL vs. CD8– TIL, 8.0 vs. 6.2 months, p = .435) or OS (CD8+ TIL vs. CD8– TIL, 20.5 vs. 16.9 months, p = .653).Conclusion: PD-L1 expression and the presence of CD8+ TILs could predict neither the patients’ response to chemotherapy or MWA nor survival in advanced NSCLC patients treated with MWA plus chemotherapy.

Prediction of overall survival after re-irradiation with stereotactic body radiation therapy for pancreatic cancer with a novel prognostic model (the SCAD score)

PurposeTo develop a predictive model for stratification of patients with pancreatic cancer who may achieve survival benefits from re-irradiation with stereotactic body radiation therapy (SBRT). MethodsThe score was developed based on clinical predictors of OS in 31 patients receiving two courses of SBRT with Cox proportional hazards model. Results were then validated in another cohort with 11 participants to assess the performance of the score. ResultsIn the training cohort, the median BED10 of the first and second SBRT was 59.5 Gy (48–85.5 Gy) and 50.2 Gy (43.7–66.9 Gy) in 5–8 fractions, while in the validation cohort, the median BED10 of the first and second SBRT was 59.5 Gy (52.5–66.9 Gy) and 47.7 Gy (40.6–54.8 Gy) in 5–8 fractions. The interval between the first and second SBRT of the training cohort and validation cohort was 10.5 months (6.1–24.3 months) and 12.8 months (6.5–29.1 months), respectively. Multivariable analysis showed that tumor stage (P = 0.005), BED10 (P = 0.006) and CA19-9 response (P = 0.04) were significantly predictive of overall survival, which formed SCAD score (named after the initials of factors). Patients with the score < 3 points had a superior OS compared with those with the score ≥ 3 points in the validation cohort (median OS has not been reached vs. 15.9 months, P = 0.032). ConclusionsThe SCAD score may have the potential to identify individuals benefiting from re-SBRT and be a step toward more personalized medicine.

Abstract 2631: Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors

Abstract Background: We previously demonstrated that cancer associated macrophage-like cells (CAMLs) are cancer specific giant polyploid cells circulating in the blood of patients with solid tumors. Building on our initial discovery, others have shown that these hyperploidy cells are an innate immune response that is associated with decreased survival. However to date, no studies have been done to elucidate their clinical significance as in relation to the various stages of malignant disease. We established a 4 year prospective study of 315 patients from a variety of solid tumors (breast, prostate, lung, renal cell, pancreas, and esophageal) comparing the morphological properties of CAMLs in both early and late stage disease as they relate to progression free and overall survival (PFS/OS). These data suggest that CAML size appears have a strong negative correlation with progression and survival of cancer patients, irregardless of stage of disease, indicating their possible use as a non-invasive blood based biomarker in solid tumors. Methods: A prospective multi-institutional study used anonymized peripheral blood from 315 cancer patients [stage I (n=62), stage II (n=72), stage III (n=69) &amp; stage IV (n=106)] from subjects with breast (n=59), esophageal (n=27), lung (n=59), renal cell carcinoma (n=37), prostate (n=74), pancreas cancers (n=59). CAMLs were isolated by the CellSieve™ microfiltration technique at 5 institutions and stained for cytokeratin 8, 18, &amp; 19, CD14 and CD45. After imaging, a size based threshold ≥50µm was used to separate the patient cohorts, based on previously published assessments. Results: At least one CAML was found in 92% of cancer patients (n=289/315), with the lowest sensitivity in stage 1 (86%), followed by stage 2 (90%), stage 3 (97%) and stage 4 (95%). The property of CAML size was then evaluated. Overall, CAMLs of &amp;lt;50µm in size had superior PFS (HR: 3.8; 95% CI 2.8-5.3; p&amp;lt;0.001) and OS (HR=3.8; 95% CI 2.6-5.7;p&amp;lt;0.001) than those with ≥50 µm CAMLs. By each stage individually, stage 1 (PFS HR=7.5; 95% CI 3.2-17.7; p&amp;lt;0.001), stage II (PFS; HR=4.1; 95% CI 1.9-8.8; p&amp;lt;0.001), stage III (PFS HR=3.1; 95% CI 1.7-5.7; p=0.007), and stage IV (PFS HR=2.7; 95% CI 1.6-4.4; p&amp;lt;0.001). Conclusions: In this first large scale prospective study of the clinical utility of CAMLs, it appears that they are present in every stages of invasive solid tumor malignancies, with prevalence increasing with stage. Interestingly decreased CAML size was found to be associated with improved outcome and longer PFS. These data suggest that CAML detection and size assessment constitute a new real time predictor of progression, and survival in both early and late stage disease indicating the need for additional validation studies. Citation Format: Daniel L. Adams, Steven H. Lin, R. Katherine Alpaugh, Thai Ho, Jeffrey R. Marks, Stuart S. Martin, Susan Tsai, Saranya Chumsri, Cha-Mei Tang, Massimo Cristofanilli, Raymond Bergan. Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2631.