Kaplan-Meier Estimates Of Overall Survival Research Articles

How Median Follow-up Time Informs Survival Outcomes: Lessons from a Trial of Acute Myeloid Patients Treated with Venetoclax and Azacitidine

Background: Follow-up time in clinical trials must leverage conflicting aims. To ensure patient safety, investigators often assess toxicity and efficacy endpoints at various times throughout a trial. Yet accurate analysis requires stable estimates of time-to-event outcomes, which can require longer follow-up than is observed in interim analyses. While median follow-up is routinely reported in clinical trials, the stability of time-to-event estimates and their relationship to follow-up times are rarely discussed. However, the potential follow-up of study participants who are censored in a clinical trial can impact time-to-event estimates (Betensky 2015). Methods: A clinical trial of venetoclax + azacitidine in 33 newly diagnosed older patients with AML was conducted at our institution and is described in detail elsewhere (Pollyea 2018). Trial data consisting of follow-up from January 2015 through February 2018 established promising results (overall response rate = 91%; median response duration, progression-free survival, and overall survival (OS) were not yet reached). Due to ongoing interest in median time-to-event patient outcomes that were not reached and thus could not be reported at the time of publication, the data have been re-analyzed on repeated occasions as follow-up has continued, with OS of particular interest. Median follow-up was calculated using the reverse Kaplan-Meier method. Median OS was calculated using Kaplan-Meier product limit estimates. Analysis of trial data has occurred at 6 different censoring time points: December 4, 2017; February 28, 2018; October 3, 2018; December 31, 2018; March 8, 2019; and May 20, 2019. Upper and lower limits of the Kaplan-Meier OS estimate were calculated to explore the stability of OS estimates over time (Betensky 2015). Analyses were performed using SAS version 9.4 (SAS Institute). Results: Median OS was not reached until analysis was conducted as of October 3, 2018. At this analysis the median OS (1130 days) exceeded the median follow-up time (867 days). This phenomenon also occurred for data censored on December 31, 2018, with the median OS (1130 days) also exceeding the median follow-up time (956 days). In the most recent two analyses of the data (March 8, 2019 and May 20, 2019), the median OS settled at a consistent value (880 days) that did not exceed the median follow-up times (1023 days and 1096 days, respectively). Exploration of the stability of OS estimates revealed that a single patient enrolled early in the study and died after 1130 days of follow-up skewed the median OS estimate upward. Conclusions: Interest in our clinical trial results motivated numerous follow-up analyses of our data. As such, we encountered a peculiar result in which median OS exceeded median follow-up. In investigating the stability of the OS K-M estimates, a single patient's study data was found to skew results in these instances. Removal of this patient's data in these instances (when the relationship between median follow-up and median OS suggest estimate instability) results in a median OS consistent with subsequent analyses at later censoring dates (880 days for the modified analysis). We therefore conclude that time-to-event estimate stability is informative and should be incorporated into survival analysis of clinical trial data. Disclosures Pollyea: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

798P - Regorafenib in combination with paclitaxel for beyond first-line treatment of advanced esophagogastric cancer (REPEAT): A phase Ib trial with expansion cohort

BackgroundAdvanced esophagogastric cancer (EGC) has a dismal prognosis of less than one year. Survival has improved with second line therapies, such as the combination of the angiogenesis inhibitor Ramucirumab and Paclitaxel (PTX). Monotherapy with Regorafenib (Reg), a multikinase inhibitor of angiogenic, stromal, and oncogenic kinases, demonstrated an improved progression-free survival (PFS) in advanced gastric cancer. In the REPEAT trial, we assessed the tolerability of Reg in combination with PTX for beyond first-line treatment of patients (pts) with advanced EGC. MethodsPts with metastatic EGC who progressed after first-line treatment, received PTX 80mg/m2 i.v. on day 1, 8, and 15 of a 28-day cycle, and 120mg Reg on day 1-21 of a 28-day cycle, as determined in phase Ib. Toxicity was assessed using CTCAE version 4, and Kaplan-Meier estimates of overall survival (OS) and PFS were done. In tumour biopsies, the effect of Reg on PTX uptake and Reg targets will be assessed, and the effect of Reg on PTX pharmacokinetics will be evaluated. ResultsReg 120mg on day 1-21 combined with PTX was well tolerated in the Ib phase (N=14), and 33 pts were enrolled in the expansion cohort (total 47 pts, 81% received 120mg). The majority of pts received treatment as second-line (60%); the remainder as third line or beyond. Most common grade 1/2 toxicities included fatigue (11%), peripheral sensory neuropathy (9%), diarrhea (5%), and alopecia (5%). Hypertension (10%), diarrhea (7%), and peripheral sensory neuropathy (5%) were the most common grade 3/4 toxicities. Median number of cycles was 4 (IQR 2-6), with 5 pts still on treatment (median follow-up 6.9 months). Best responses achieved were partial response (26%), stable disease (51%), and progressive disease (15%), with 4 patients not evaluable. Reasons for treatment discontinuation were progression (n=36), toxicity (n=5), or patient decision (n=1). Median PFS and median OS were 4.1 months and 7.8 months, respectively. ConclusionsThe combined treatment of Reg with PTX is tolerable and shows promising effects on survival in beyond first-line treatment of advanced EGC. PK analyses and biomarker analyses on biopsies of metastatic lesions are ongoing. Clinical trial identification2014-005433-31 Release date: 10th December 2014. Legal entity responsible for the studyThe authors. FundingBayer. DisclosureJ. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies, Outside submitted work: Servier; Advisory / Consultancy: Shire. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Nordic. M. Bijlsma: Research grant / Funding (institution), Outside submitted work: Celgene; Research grant / Funding (institution), Outside submitted work: Servier. H.W.M. van Laarhoven: Honoraria (self), Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy, Research grant / Funding (institution): Nordic Group; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Bayer Schering Pharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Philips Healthcare; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck Sharp & Dohme. All other authors have declared no conflicts of interest.

The impact of age on the outcome of patients treated with radiotherapy for mucoepidermoid carcinoma (MEC) of the salivary glands in the head and neck: A 15-year single-center experience

IntroductionData regarding treatment and survival outcome of patients with mucoepidermoid carcinoma of the head and neck are limited to case reports and case series. As a consequence of lacking evidence, treatment guidelines do not exist. We aimed to analyze the effect of modern radiotherapy in form of intensity modulated radiotherapy (IMRT) either with simultaneously integrated boost or carbon ion boost on local control and survival for a relatively large patient collective. Materials and methodsPatient records of 62 consecutive patients treated with postoperative (n = 53, 85%) or definitive (n = 9, 15%) radiotherapy between 2004 and 2019 were analyzed retrospectively. Kaplan-Meier estimates for overall survival (OS), distant progression-free survival (PFS), local control (LC) and locoregional control (LRC) were statistically calculated and prognostic factors were identified using the log-rank test. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE). ResultsThe median follow-up was 47 months (range, 4–188 months). The 3-year OS, DPFS, LC and LRC, estimated by Kaplan-Meier curves, were 82%, 87%, 89% and 92%, the estimated 5-year OS, DPFS, LC and LRC were 78%, 87%, 84% and 88%, respectively. In univariate analysis, age >56 years (vs. age ≤56 years) was identified as the only independent negative prognostic factor for decreased OS (HR = 1.078; 95%-CI = 1.029–1.130; p = 0.001), DPFS (HR = 1.055; 95%-CI = 1.000–1.114; p = 0.051) and LC (HR = 1.087; 95%-CI = 1.022–1.157; p = 0.008). Treatment was well tolerated without any grade ≥4 toxicity. Acute and late grade 3 toxicities were rare with 16% acute (n = 10) and 13% late toxicities (n = 8). ConclusionRadiotherapy with intensity modulated radiotherapy including either simultaneously integrated photon boost or active raster-scanning carbon ion boost for mucoepidermoid carcinomas of the head and neck resulted in excellent survival outcome and locoregional control with moderate toxicity. However, patients older than 56 years seem to have a disadvantage in all calculated endpoints (OS, DPFS, LRC) due to frequent local and distant relapses. Condensed abstractModern radiotherapy with intensity modulated radiotherapy including either a simultaneously integrated photon boost or carbon ion boost for mucoepidermoid carcinoma results in excellent survival outcome and locoregional control with moderate toxicity. The 5-year OS, DPFS, LC and LRC, estimated by Kaplan-Meier curves, were 89%, 75%, 84% and 80%, respectively. Patients older than 56 years seem to have a disadvantage in all calculated endpoints (OS, DPFS, LRC).

Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary?

Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases in patients with limited stage small cell lung cancer (LS-SCLC). However, PCI is associated with significant neurocognitive sequelae. In prior studies assessing the role of PCI in SCLC, patients have not been consistently staged with pretreatment magnetic resonance imaging (MRI). Modern improvements in staging imaging continue to enhance the ability to detect early brain metastases. We sought to determine if PCI was associated with improved overall survival (OS), progression free survival (PFS), and cumulative incidence (CI) of brain metastases in LS-SCLC patients in the modern era of MRI staging. We identified patients with LS-SCLC treated with curative intent between 2006-2018 staged initially with MRI and no progression of disease after initial therapy. Kaplan-Meier estimates of OS and PFS were calculated and multivariate Cox proportional hazards models were generated. The cumulative incidence of brain metastases was estimated using competing risks methodology. In total, 96 patients were identified, 39 (41%) of whom received PCI. Median follow-up was 39 months. The median OS for the cohort was 34.0 months (95% CI 23.9-55.2) and PFS was 18.3 months (95% CI 10.3-29.9). Median OS in those treated with PCI versus those not treated with PCI was 35.8 months (95% CI 31.8-NR) versus 30.5 months (95% CI 16.1-56.1, p=0.09) while median PFS was 24.4 months (95% CI 19.1-NR) versus 10.6 (95% CI 9.2-29.9, p=0.04). At 2 years, the CI of brain metastases was 12% with PCI and 33% without PCI; this increased to 39% and 33% by 4 years (p=0.68). Multivariate analysis revealed age ≥70 (HR 1.97) and partial response/stable disease after initial therapy (PR/SD) versus complete response (CR; HR 4.26) as significant factors influencing OS. Patients with a PR/SD had an increased of HR 4.99 for PFS whereas patients treated with PCI had a reduced HR for PFS. Stratified by disease response, patients with CR did not benefit from PCI (p=0.67), while those with PR/SD had improved PFS (p=0.02). Overall, PCI was associated with improved PFS and reduced cumulative incidence of brain metastases in the MRI era. Patients who achieved a CR to initial therapy did not experience a significant PFS benefit with the addition of PCI. This data is hypothesis generating and may indicate that subsets of LS-SCLC patients may potentially be spared from the significant neurotoxic sequelae of PCI in the era of modern imaging. Further prospective studies are needed.

Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma: A Comparison of Three Platinum-based Regimens

Concurrent chemoradiotherapy (CRT) improves outcomes for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) and high-risk postoperative patients. Current data support cisplatin at a dose of 100 mg/m2 every 3 weeks (Q3WC). Other regimens including weekly cisplatin (QWC) and weekly carboplatin/paclitaxel (CP) have been reported. We aim to compare survival, disease control, and post-treatment nutritional status between these regimens. We identified patients with HNSCC treated with CRT between 2010 and 2017. Patient, tumor, and treatment factors were abstracted from the medical record. Severe comorbidity was defined as Charlson comorbidity index ≥3. Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) and cumulative incidence (CI) of locoregional (LRF) and distant failure (DF) with death as a competing risk were generated from the date of RT completion. Multivariate models adjusting for baseline factors were performed. Gastrostomy tube dependence (GTD) at 6 months was defined as a Functional Oral Intake Scale ≤3. In total, 236 patients were treated with definitive (78%) or postoperative (28%) CRT with Q3WC (n=63), QWC (n=127) and CP (n=46). The Q3WC group had fewer patients >65 years old (10% v. 20% QWC v. 37% CP) or severe comorbidity (32% v. 39% v. 57%) and more frequent use of induction chemotherapy (3% v. 8% v. 20%). Primary sites included oropharynx (56%), larynx (27%), oral cavity (12%), and hypopharynx (5%) and 95% had stage III-IV disease. There were no baseline differences in gender, ECOG performance status, tobacco/alcohol use, clinical or pathologic stage, HPV status, extracapsular extension, or margin status. Cumulative dose ≥200 mg/m2 was achieved in 89% with Q3WC versus 73% with QWC (p=0.02). Twelve Q3WC patients converted to QWC due to one or more toxicity: nausea/vomiting (8), cytopenia (4), acute kidney injury (3), dehydration/weight loss (2), mucositis (1) and dermatitis (1). Median follow-up was 27 months. Three-year OS and DFS were 84%, 62% and 59% (p=0.01) and 74%, 58% and 48%, respectively (p=0.01). Compared to Q3WC, QWC (aHR 2.77) and CP (aHR 3.04) were associated with worse OS on multivariate analysis. Disease-specific survival also favored Q3WC (p=0.05). At 3 years, CI of LRF was 14% for Q3WC, 17% for QWC and 20% for CP (p=0.63); 3-year DF was 10%, 15% and 17%, respectively (p=0.81). No differences in weight change (mean -13% v. -12% v. -10%, p=0.29) or GTD (32% v. 20% v. 31%, p=0.31) were observed. Every-3-week cisplatin was associated with improved survival in patients treated with chemoradiotherapy for HNSCC. No significant differences were detected in locoregional or distant control. This may be related to cumulative dose, competing comorbidity and/or selection biases. There were no significant differences in nutritional outcomes.

Treatment Outcome of a Combined Dose-Escalated Treatment Regime With Helical TomoTherapy® and Active Raster-Scanning Carbon Ion Boost for Adenocarcinomas of the Head and Neck.

Introduction: Data regarding treatment and survival outcome of patients with adenocarcinoma of the head and neck are limited to case reports and case series. As a consequence of lacking evidence, treatment guidelines do not exist. We aimed to analyze the effect of a bimodal irradiation regime with intensity modulated radiotherapy (IMRT) and carbon ion boost on local control (LC) and survival in adenocarcinoma patients for a large patient collective.Materials and Methods: Patient records of eighty consecutive patients treated between 2009 and 2018 were analyzed retrospectively and Kaplan-Meier estimates for LC, overall survival (OS) and progression-free survival (PFS) were compared among patients with salivary gland adenocarcinoma (SGAC), salivary duct adenocarcinoma (SDAC), and intestinal-type adenocarcinoma (ITAC) according to the World Health Organization (WHO). Prognostic factors were identified using the log-rank test and cox-regression modeling. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE).Results: Median follow-up was 41 months. The 3-year and estimated 5-year Kaplan-Meier rates for all patients were 83 and 75% for LC, 74 and 50% for OS and 60 and 53% for PFS, respectively. While bimodal RT for ITAC resulted in a significantly decreased 3-year LC rate of 50 vs. 93% for each SGAC and SDAC (p < 0.01), no statistical significant survival differences could be identified across the three groups regarding OS (p = 0.08) and PFS (p = 0.063). 3-year OS was 88% for SGAC, 78% for SDAC and 67% for ITAC and 3-year PFS was 72% for SGAC, 53% for SDAC and 44% for ITAC, respectively. Nevertheless, in subgroup analysis, OS for ITAC was significantly worse compared to SGAC (p = 0.024). In multivariate analysis, bilateral tumor side (vs. unilateral) solely could be identified as independent negative prognostic factor for LC (p < 0.01). Treatment was well-tolerated with 21% acute (n = 17) and 25% (n = 20) late grade ≥3 toxicities.Conclusion: Radiotherapy including active raster-scanning carbon ion boost for relatively radio resistant adenocarcinomas of the head and neck resulted in favorable survival outcome for salivary gland and salivary duct adenocarcinomas with moderate toxicity. However, local control and prognosis for bilateral intestinal-type adenocarcinomas (ITAC) seem to remain low even after dose-escalation.

Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary?

PurposeProphylactic cranial irradiation (PCI) reduces the incidence of brain metastases in patients with limited stage small cell lung cancer (LS-SCLC). However, PCI is associated with neurotoxicity. Previous studies have not consistently used pretreatment magnetic resonance imaging. Modern imaging improvements continue to enhance early metastasis detection, potentially decreasing the utility of PCI. We sought to determine whether PCI was associated with improved outcomes in LS-SCLC patients with modern imaging. Methods and MaterialsWe identified LS-SCLC patients with no intracranial disease who were treated between 2007 and 2018. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated and multivariate Cox proportional hazards models were generated. The cumulative incidence of brain metastases was estimated using competing risks methodology. ResultsNinety-two patients were identified without intracranial disease at initial staging, 39 of whom received PCI. Median follow-up was 56.7 months. The median OS for the cohort was 35.5 months (95% CI, 25.8-49.3), and median PFS was 19.1 months (95% CI, 12.3-30.5). Median OS with PCI versus observation was 37.9 months (95% CI, 31.8-not reached) versus 30.5 months (95% CI, 14.6-56.1; P = .07), whereas median PFS was 26.3 months (95% CI 19.1-not reached) versus 12.3 months (95% CI, 8.5-30.5; P = .02), respectively. Overall, at 2 years, the cumulative incidence of brain metastases was 10% with PCI and 29% without; this increased to 32% and 29% by 4 years (P = .66). In those patients who had negative magnetic resonance imaging of the brain after completing initial treatment, the 1-year cumulative incidence of brain metastasis was not significantly different at 8% versus 11% (P = .46) respectively. Both PCI and treatment response were independent predictors for PFS on multivariate analysis. Stratified by disease response, patients with a complete response did not benefit from PCI (P = .50), whereas those with partial response or stable disease experienced improved PFS (P = .01). ConclusionsOverall, PCI was associated with improved PFS and reduced early incidence of brain metastases. Patients achieving a complete response to initial therapy did not experience a PFS benefit with PCI. This may indicate that subsets of LS-SCLC patients can potentially be spared from PCI in the era of modern imaging.

PF767 PHASE 2 STUDY EVALUATING THE SAFETY AND EFFICACY OF ONE OR TWO DOSES OF DONOR LYMPHOCYTES DEPLETED OF HOST ALLOREACTIVE T‐CELLS (ATIR101) FOLLOWING T‐CELL‐DEPLETED HAPLOIDENTICAL HSCT

Background:The use of ex vivo T‐cell‐depleted haploidentical hematopoietic stem cell transplantation (haplo HSCT) minimizes the risk of severe graft‐versus‐host disease (GVHD). However, delayed immune reconstitution increases the risk of serious infections and relapse. ATIR101 is a donor‐derived, T‐cell‐enriched leukocyte preparation depleted ex vivo of host‐alloreactive T cells. When administered as an adjunctive infusion after T‐cell‐depleted haplo HSCT, ATIR101 aims to deliver donor T cells that can facilitate early immune protection and provide anti‐leukemic activity while minimizing the risk of GVHD.Aims:In a previous Phase 2 study of a single ATIR101 infusion of 2 × 106 T cells/kg in patients with AML/ALL, overall survival (OS) at 1 year was 61% with no cases of Grade III/IV acute GVHD (aGVHD; Ref). It was hypothesized that two doses may improve efficacy further; therefore, a Phase 2 exploratory study was conducted (CR‐AIR‐008; NCT02500550).Methods:Seventeen patients with hematologic malignancies (who provided informed consent) received myeloablative conditioning followed by a CD34‐selected stem cell graft. Two ATIR101 infusions of 2 × 106 T cells/kg derived from the same donor were planned for 28–32 and 70–74 days post HSCT. Patients did not receive GVHD prophylactic immunosuppression. The protocol allowed for evaluation of the safety of the double dose in the initial 6 patients, permitting an adjustment to a single dose in the case of dose‐limiting toxicity (Grade III/IV aGVHD within 120 days post HSCT). The primary endpoint was the incidence of Grade III/IV aGVHD up to 180 days post HSCT and patients were followed for 1 year for secondary endpoints, including: transplant‐related mortality (TRM), relapse‐related mortality (RRM), GVHD‐free relapse‐free survival (GRFS), and OS.Results:Two of the first 6 patients that who received a double dose of ATIR101 (4 AML, 2 MDS) experienced Grade III/IV aGVHD within 120 days of HSCT (1 Grade III at 25 days, 1 Grade IV at 18 days after the second dose). In accordance with the protocol, the remaining 11 patients were scheduled to only receive a single 2 × 106 T cells/kg dose on Days 28–32 (5 AML, 3 ALL, 3 MDS). Nine of these 11 patients received ATIR101 (2 did not receive ATIR101 due to an early death and a batch rejection); 2/11 developed Grade III aGVHD within 180 days. There were 2 cases of chronic GVHD in double‐dose and none in single‐dose patients. Table 1 shows secondary outcomes at 1 year. For double‐dose patients, TRM was 67%, RRM was 0%, and the 1‐year Kaplan–Meier (KM) estimate of OS was 33% and of GRFS was 17%. For single‐dose patients, TRM was 36%, RRM was 9%, and 1‐year KM estimates of OS and GRFS were 55% and 46%, respectively.Summary/Conclusion:Administration of a single dose of ATIR101 showed a favorable safety profile. There were 2 cases of Grade III aGVHD but no Grade IV aGVHD or chronic GVHD. OS and GRFS in this study confirmed results from the larger Phase 2 study of a single ATIR101 dose, and disease relapse and TRM were limited in both studies. Based on the observed Grade III/IV aGVHD, the safety profile of a second dose at the time point evaluated does not align with previous single‐dose data with ATIR101. Further investigation is needed to clarify the cell number for a second dose of ATIR101 that can be administered safely post HSCT. Based on the two Phase 2 studies with ATIR101, a large, randomized, Phase 3 trial has been initiated, comparing a single dose of ATIR101 with PTCy in haplo HSCT (HATCY; NCT02999854).image

Survival prediction in patients with chronic limb-threatening ischemia who undergo infrainguinal revascularization

Accurate survival prediction critically influences decision-making in caring for patients with chronic limb-threatening ischemia (CLTI). The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial demonstrated that in patients who survived >2years, there was a significant advantage to infrainguinal bypass compared with endovascular intervention, which increased with time. Validated survival models for patients with CLTI are lacking. The Vascular Quality Initiative was interrogated for patients who underwent infrainguinal bypass or endovascular intervention for CLTI (January 2003-February 2017). Cox survival models were generated using only preoperative variables. Survival at 30days, 2years, and 5years was modeled separately. Patients were defined as low risk (30-day survival >97% and 2-year survival >70%), medium risk (30-day survival 95%-97% or 2-year survival 50%-70%), and high-risk (30-day survival<95% or 2-year survival<50%). Among 38,470 unique CLTI patients, 63% (n= 24,214) underwent endovascular intervention and 37% (n= 14,256) underwent infrainguinal bypass. Kaplan-Meier estimates of overall survival at 30days, 2years, and 5years were 98%, 81%, and 69%, respectively. The proportion of patients in the low-, medium-, and high-risk groups was 84%, 10%, and 6.5%, respectively. Patients in the low-risk group were significantly less likely to undergo endovascular intervention compared with those in the high-risk group (low risk, 59% endovascular; high risk, 75% endovascular; P< .0001). Independent predictors of death were similar in all three models, with greatest magnitude of effect associated with age >80years, oxygen-dependent chronic obstructive pulmonary disease, stage 5 chronic kidney disease, and bedbound status. The C index for the 30-day model, 2-year model, and 5-year model was 0.76, 0.72, and 0.71, respectively. Procedure type (open or endovascular) was not significant in any models and did not have an impact on C indices. These survival prediction models, derived from a large U.S. cohort of patients who underwent revascularization for CLTI, demonstrated good performance and should be validated. Most CLTI patients considered candidates for limb salvage were of average perioperative risk and were predicted to survive beyond 2years. These models can differentiate patients into low-, medium-, and high-risk groups to facilitate evidence-based revascularization recommendations that are consistent with current treatment guidelines.

Neutrophil-to-lymphocyte ratio and subsequent recurrence of non-small cell lung cancer patients in remission.

8533 Background: Baseline neutrophil-lymphocyte ratio (NLR), a surrogate marker for systemic inflammation and immunosuppression, is a well-established prognostic marker in non-small cell lung cancer (NSCLC). This study tests if interim NLR is prognostic in NSCLC patients in remission. Methods: This single-center, retrospective cohort study analyzed 131 NSCLC patients treated from 2010-2015 who achieved complete remission. Patient data included demographics, histologic subtypes, stage, and treatment type. NLR was calculated at baseline and from the first available blood sample during remission. Kaplan-Meier estimates of overall survival (OS) and time to recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox proportional hazards model. Results: Of 131 cases, 63 had subsequently recurred at the last follow up. Mean age was 64 ± 10 years. Histology: adenocarcinoma (60%), squamous cell (33%), and unspecified (7%). Ninety percent were smokers. Thirty-five percent had stage I, 24% had stage II, and 41% had stage III disease. Treatment modalities varied from surgery (28%), chemotherapy (2%), or radiation therapy (10%) alone, or combined (50%). The time from end of treatment, median (range), to the interim NLR was 9.2 months (2.2, 66.7). The baseline and interim median NLR were 2.6 (0.6, 34.0) and 3.1 (0.5, 20.5), respectively. The median follow-up duration was 44 months (5.9, 101). For the univariate analysis interim NLR was binned into tertiles. In multivariable analysis remission NLR remained strongly prognostic for OS (P&lt;0.001) as did patient’s age (P=0.002), but not stage, race, sex, and baseline NLR. Conclusions: Our study found that interim NLR, obtained in remission, was strongly prognostic for OS and recurrence. The results may indicate that even subclinical disease promotes immunosuppression or alternatively that immunosuppression increases recurrence risk. NLR during remission may help identify NSCLC patients at high risk of recurrence and may thus be of value in surveillance of lung cancer survivors. [Table: see text]

Influence of tumor size and Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline on patient (pt) outcomes in lenvatinib-treated radioiodine-refractory differentiated thyroid cancer (RR-DTC).

6081 Background: In SELECT, lenvatinib significantly improved progression-free survival (PFS) of pts with RR-DTC versus placebo (18.3 v 3.6 months; hazard ratio [HR]: 0.21 [99% CI: 0.14, 0.31]; P&lt;0.001). Here we examine the treatment of RR-DTC with lenvatinib in relation to tumor size (sum of all targeted lesions) and ECOG PS. Methods: In this post hoc analysis of SELECT with pts randomized to receive lenvatinib, Kaplan-Meier estimates of time to ECOG PS ≥2 were calculated for subgroups of pts according to baseline ECOG PS or tumor size. Objective response rate (ORR) and Kaplan-Meier estimates of overall survival (OS) and PFS according to ECOG PS (0 or 1) at baseline were calculated. Correlations between ECOG PS at baseline (0 or 1) and maximum tumor shrinkage were calculated using one-way analysis of variance. Results: Pts with ECOG PS 0 or 1 at baseline had similar demographic and disease characteristics. ORR was 78.5% and 51.0% for pts with ECOG PS 0 and 1 at baseline, respectively (odds ratio [95% CI]: 3.508 [2.018, 6.097]). Mean maximum percent decrease in tumor size was significantly greater in pts with baseline ECOG PS 0 (-46.13%) versus pts with ECOG PS 1 (-37.16%; P=0.0017). For pts with ECOG PS 1 at baseline, time to ECOG PS ≥2 was numerically shorter with tumor size &gt;60 mm versus tumor size ≤60 mm (HR [95% CI]: 1.450 [0.708, 2.967]). Additional results are summarized in the table. Conclusions: Among pts with RR-DTC, PFS, OS, ORR, and time to ECOG ≥2 were generally better for patients with lower ECOG PS or smaller tumor size at baseline. These results may indicate that it is beneficial to start lenvatinib in pts with RR-DTC early, before ECOG PS worsens and tumor size increases. Clinical trial information: NCT01321554. [Table: see text]

Benefit of second-line systemic chemotherapy for advanced biliary tract cancer: A propensity score analysis

Whether 2nd-line-chemotherapy (2LCTX) + best-supportive-care (BSC) benefits patients with advanced biliary tract cancer (aBTC) more than BSC alone is unclear. We therefore conducted a propensity-score-based comparative effectiveness analysis of overall survival (OS) outcomes in 80 patients with metastatic, recurrent, or inoperable aBTC, of whom 38 (48%) were treated with BSC + 2LCTX and 42 (52%) with BSC alone. After a median follow-up of 14.8 months and 49 deaths, the crude 6-, 12-, and 18-month Kaplan-Meier OS estimates were 77%, 53% and 23% in the BSC + 2LCTX group, and 29%, 21%, and 14% in patients in the BSC group (p = 0.0003; Hazard ratio (HR) = 0.36, 95%CI:0.20–0.64, p = 0.001). An inverse-probability-of-treatment-weighted (IPTW) analysis was conducted to rigorously account for the higher prevalence of favorable prognostic variables in the 2LCTX + BSC group. After IPTW-weighting, the favorable association between 2LCTX and OS prevailed (adjusted HR = 0.40, 95%CI: 0.17–0.95, p = 0.037). IPTW-weighted 6-, 12-, and 18-month OS estimates were 77%, 58% and 33% in the BSC + 2LCTX group, and 39%, 28% and 22% in the BSC group (p = 0.037). Moreover, the benefit of 2LCTX was consistent across several clinically-relevant subgroups. Within the limitations of an observational study, these findings support the concept that 2LCTX + BSC is associated with an OS benefit over BSC alone in aBTC.

Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study

The anti-programmed death 1 monoclonal antibody pembrolizumab has shown antitumour activity and is a first-line and second-line treatment option for patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer. We report updated 3-year safety and efficacy outcomes from the phase 1 study, KEYNOTE-001. KEYNOTE-001 is a multicohort, open-label, phase 1 study of pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in treatment naive or previously treated patients with locally advanced or metastatic non-small-cell lung cancer with measurable disease at baseline. Two cohorts were randomly assigned to a pembrolizumab dose by use of a computer-generated randomisation schedule at cohort-dependent ratios, and a further four cohorts were assigned to a pembrolizumab dose without randomisation. We present 3-year outcomes for the full analysis set of patients who received at least one dose of study treatment, pooled for all pembrolizumab doses. The primary efficacy endpoint was proportion of patients with objective response, analysed here as investigator-assessed response according to immune-related response criteria. Secondary efficacy endpoints included overall survival, duration of response, and progression-free survival. Safety endpoints included incidence of adverse events. This study is registered at ClinicalTrials.gov, number NCT01295827, and is ongoing. Between May 8, 2012 and July 13, 2014, 550 patients (101 treatment naive and 449 previously treated) were enrolled. Median follow-up was 34·5 months at data cutoff (Sept 1, 2016). At 36 months, investigator-assessed objective response according to immune-related response criteria was achieved for 41 of 101 treatment naive patients (41% [95% CI 30·9-50·8]; median duration of response was 16·7 months [95% CI 12·6-not reached]) and 102 of 449 previously treated patients (23% [18·9-26·9]; 33·3 ([22·5-not reached]). The Kaplan-Meier estimate of overall survival at 36 months was 26·4% (95% CI 14·3-40·1) for treatment naive patients and 19·0% (15·0-23·4) for previously treated patients, with median overall survival of 22·3 months (95% CI 17·1-31·5) and 10·5 months (8·6-13·2). PD-L1 tumour proportion score ≥50% was associated with longer median overall survival (95% CI) versus tumour proportion score 1-49% (treatment naive: 34·9 [20·3-not reached] vs 19·5 [10·7-26·3] months; previously treated: 15·4 [10·5-18·5] vs 8·5 [6·0-12·7] months). Grade 3-5 treatment-related adverse events occurred in 66 patients (12%), and 30 (6%) discontinued owing to a treatment-related adverse event. The most frequent grade 3-4 treatment-related adverse events were pneumonitis (10 [2%] of 550) and fatigue (5 [1%] of 550). Overall, 227 patients (41%) of 550 had serious adverse events, of which 50 (9%) were treatment related. Pembrolizumab provides durable response and long-term effects on overall survival, with tolerable safety, for treatment naive and previously treated patients with advanced non-small-cell lung cancer expressing PD-L1. Merck Sharp & Dohme Corp.

Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background

BackgroundCardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated. Methods and resultsOf 137 children with mitochondrial disease whose genetic diagnosis was made between 2004 and 2018, 29 had mitochondrial cardiomyopathy (21%). After a median follow-up of 35 months, the overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001). Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively. Among the 21 cardiomyopathy patients who died, two died within one month of birth (COQ4 in one patient, and COX10 in one patient), ten died within one year (BOLA3 in three patients, QRSL1 in two patients, large chromosomal deletions in two patients, MT-ATP6/8 in one patient, MT-TL1 in one patient, and TAZ gene in one patient), and nine died after one year (MT-ND5 in three patients, MT-TL1 in three patients, ACAD9 in one patient, KARS in one patient, and MT-TV in one patient). In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age) and m.3243A>G (90 and 80%, died at 12 and 13 years of age, respectively). ConclusionsIn children with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. Genetic analysis coupled with detailed phenotyping could be useful for prognosis.

Efficacy and Feasibility of Allogeneic Hematopoietic Stem-Cell Transplantation in the Treatment of Refractory Acute Myeloid Leukemia

BackgroundRefractory acute myeloid leukemia (AML) includes AML includes failure of disease to respond to standard induction chemotherapy, relapse within 6 months after first CR, and 2 or more relapses. The outcome of these patients is usually very poor; only a small proportion can be rescued by allogenic hematopoietic stem-cell transplantation (allo-HSCT). The aim of this study was to evaluate the efficacy and feasibility of allo-HSCT in patients with refractory AML. Patients and MethodsWe retrospectively analyzed the clinical outcome of 91 patients who were diagnosed with treatment-refractory AML at Hacettepe University Hospital between January 2002 and June 2018. Patients' disease status included refractory AML, defined as failure to respond to standard induction chemotherapy and relapse within 6 months after first complete remission. ResultsThe median follow-up was 12 months (range, 0.5-184 months) for the entire group. Kaplan-Meier estimates of the 3-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 67% and 12%, respectively. Additionally, the Kaplan-Meier estimates of 5-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 44% and 4%, respectively (P < .001). Complete remission was obtained in 25 patients (83.3%) who underwent allo-HSCT; however, the disease of only 3 patients (3.8%) exhibited complete response after salvage chemotherapy. ConclusionAllo-HSCT is still the best-known treatment option with curative potential in patients with treatment-refractory AML. Therefore, all efforts should be made in an attempt to find a suitable matched donor in order to perform allo-HSCT.

Blinatumomab for Minimal Residual Disease (MRD) in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Median Overall Survival (OS) Is Not Reached in Complete MRD Responders at a Median Follow-up of 53.1 Months

Blinatumomab for Minimal Residual Disease (MRD) in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Median Overall Survival (OS) Is Not Reached in Complete MRD Responders at a Median Follow-up of 53.1 Months

Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT.Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis.Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT.The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome.Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. DisclosuresChiesa:Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

Survival prediction in patients with chronic limb-threatening ischemia who undergo infrainguinal revascularization

ObjectiveAccurate survival prediction critically influences decision-making in caring for patients with chronic limb-threatening ischemia (CLTI). The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial demonstrated that in patients who survived >2 years, there was a significant advantage to infrainguinal bypass compared with endovascular intervention, which increased with time. Validated survival models for patients with CLTI are lacking. MethodsThe Vascular Quality Initiative was interrogated for patients who underwent infrainguinal bypass or endovascular intervention for CLTI (January 2003-February 2017). Cox survival models were generated using only preoperative variables. Survival at 30 days, 2 years, and 5 years was modeled separately. Patients were defined as low risk (30-day survival >97% and 2-year survival >70%), medium risk (30-day survival 95%-97% or 2-year survival 50%-70%), and high-risk (30-day survival <95% or 2-year survival <50%). ResultsAmong 38,470 unique CLTI patients, 63% (n = 24,214) underwent endovascular intervention and 37% (n = 14,256) underwent infrainguinal bypass. Kaplan-Meier estimates of overall survival at 30 days, 2 years, and 5 years were 98%, 81%, and 69%, respectively. The proportion of patients in the low-, medium-, and high-risk groups was 84%, 10%, and 6.5%, respectively. Patients in the low-risk group were significantly less likely to undergo endovascular intervention compared with those in the high-risk group (low risk, 59% endovascular; high risk, 75% endovascular; P < .0001). Independent predictors of death were similar in all three models, with greatest magnitude of effect associated with age >80 years, oxygen-dependent chronic obstructive pulmonary disease, stage 5 chronic kidney disease, and bedbound status. The C index for the 30-day model, 2-year model, and 5-year model was 0.76, 0.72, and 0.71, respectively. Procedure type (open or endovascular) was not significant in any models and did not have an impact on C indices. ConclusionsThese survival prediction models, derived from a large U.S. cohort of patients who underwent revascularization for CLTI, demonstrated good performance and should be validated. Most CLTI patients considered candidates for limb salvage were of average perioperative risk and were predicted to survive beyond 2 years. These models can differentiate patients into low-, medium-, and high-risk groups to facilitate evidence-based revascularization recommendations that are consistent with current treatment guidelines.

Outcomes of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphomas: A Retrospective Multicenter Experience by the Rete Ematologica Pugliese (REP)

BackgroundHodgkin lymphoma (HL) is a potentially curable disease, and modern therapy is expected to successfully cure more than 80% of the patients. However, patients progressing after intensive treatments, such as autologous stem cell transplantation (SCT), have a very poor outcome. Allogeneic SCT offers the only strategy with a curative potential for these patients. This study reports a retrospective multicenter experience of the Rete Ematologica Pugliese (REP) over the past 17 years, aiming to define the impact of each patient’s disease and transplant-related characteristics on outcomes. Patients and MethodsWe retrospectively studied 72 patients with HL who received allogeneic SCT from 2000 to 2017. At the time of allogeneic SCT, 33 (46%) patients had chemosensitive disease, and 39 (54%) were chemo-refractory. All patients received reduced-intensity conditioning, 50% received grafts from a matched sibling donor, and 50% from a matched-unrelated donor. ResultsWith a median follow-up of 48 months (range, 3-195 months), 30 patients are alive, and 42 have died. The Kaplan-Meier estimates of overall survival and progression-free survival at 5 years were 35% and 34%, respectively. Following transplantation, 12 (17%) patients died of non-relapse mortality at a median of 90 days (range, 1 day-20 months). The causes of death included infection (n = 7), graft-versus-host disease (n = 3), and multi-organ failure (n = 2). ConclusionsAllogeneic SCT results extend survival in selected patients with relapsed/refractory HL, showing low treatment-related mortality. Patients with active disease at the time of allogeneic transplantation have poor outcomes. Allogeneic SCT may be an effective salvage strategy for patients who relapse after an autologous SCT.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.