Radiologic response as a prognostic factor in advanced hepatocellular carcinoma with macroscopic vascular invasion after transarterial chemoembolization and radiotherapy

Introduction: We evaluated the radiologic response rate of combined transarterial chemoembolization (TACE) plus radiotherapy (RT) in treatment-naïve patients with liver-confined hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI) and analyzed its clinical importance in overall survival (OS) outcomes. Methods: Patients who were treated with TACE plus RT as a first-line treatment for HCC with MVI between January 2010 and December 2015 were retrospectively reviewed. Radiologic response was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) at 2- and 4-months after completion of RT. Landmark analysis at 2- and 4-months and time-dependent Cox regression analysis using response as a time-dependent covariate were performed for univariable and multivariable analyses. Results: The 2-month landmark analysis included 427 patients, and the 4-month landmark analysis included 355 patients after excluding patients without imaging studies for response evaluation at 4 months. Radiologic responses were observed in 210 (49.2%) patients at 2 months and 181 (51.8%) at 4 months. In multivariable analyses, radiologic response was identified as an independent prognosticator for OS at 2 months (median OS: responders, 23.1 months vs. non-responders, 8.0 months; hazard ratio [HR], 3.194; P < 0.001) and 4 months (median OS: responders, 26.5 months vs. non-responders, 9.3 months; HR, 4.534; P < 0.001). Conclusion: Radiologic response assessed by mRECIST was a significant prognostic factor for OS in patients with advanced-stage HCC showing MVI treated with combined TACE plus RT.

Non-Intensive Continuous Treatment with a Tyrosine Kinase Inhibitor (TKI) Followed By Allo-HSCT Is an Effective Therapeutic Strategy for Adult Ph-Positive Acute Lymphoblastic Leukemia: Outcomes of the Russian Prospective Multicenter RALL Study

Introduction. As Ph-positive (Ph+) ALL in adults remains less favorable in prognosis than other ALL, and by expert opinion needs non-intensive chemotherapy protocols and new generation TKI with the majority of pts undergoing allo-HSCT, the results of treatment based on the different approach: de-escalated but continuous treatment with the change of TKI according to the molecular response and allo-HSCT may be of interest and provide new insights to the treatment of Ph+ ALL. Aim. To evaluate survival and outcomes in different risk groups in pts with Ph+ ALL in the RALL-study (Ph+ALL-2009, Ph+ALL-2012 and Ph+ALL-2012m protocols). Patients and methods. Between January 2010 and June 2021, 74 new Ph+ ALL cases were diagnosed in 6 centers of the RALL-group and 63 of them were evaluable for analysis (median age 37 years (17-73), m/f 32(43%)/42(57%), CNS disease in 13(21%) pts, WBC&gt;30*10 9/l in 27(43%) pts, bcr/abl transcript p190/p210/p190+210 in 31(60%)/12(23%)/9(17%) cases). Standard cytogenetic was performed in all 63 pts, 1 had no mitosis, 6(10%) monosomy 7 and 2 (3%) complex karyotypes were detected. All pts were treated according to RALL protocols with continuous Imatinib. Ph+ALL-2009 protocol included 600 mg Imatinib with prednisone, VNCR, L-asp, Dauno, Cph, followed by 6-MP and MTX. Imatinib had to be changed to Dasatinib (140 mg) after non-achievement of molecular complete response (MolCR) on day 70. MolCR was defined as bcr/abl chimeric transcript &lt;0,01% by PCR with 10 -4 sensitivity. In protocols Ph+ALL-2012 and Ph+ALLm, we de-intensified chemotherapy: reduced Dauno, Cph and L-asp doses, accordingly. All pts were considered as candidates for allogeneic HSCT in CR1 if HLA-identical donor was available. 36 (57%) pts underwent HSCT in the first-line therapy: 2(6%) autologous, 9 (25%) matched related, 20 (56%) matched unrelated and 5 (13%) haplo-HSCT. Results. Hematological complete remission (CR) was achieved in 60 (95%) of 63 pts (1 early death and 2 refractory cases occurred). On day 70, MolCR was achieved in 21(38%) of 56 pts. Death on therapy in CR (within 5 months of induction/consolidation) was registered in 4 (6%) cases. The major causes of the non-relapsed mortality in unrelated allo-HSCT (n=9) were aGVHD and severe infections, at a median +4 months after HSCT. The 5-year overall survival (OS) and disease-free survival (DFS) for all 63 pts were 58% and 45%, respectively. The long-term outcome on different protocols (Ph+ALL-2009, Ph+ALL-2012 and Ph+ALL-2012m) were similar: 3-year OS - 55% vs 51% vs 75% (p=0,27), 3-year DFS - 56% vs 44% vs 50% (p=0,54), respectively. The 5-year OS was 65% vs 61% (p=0,84), and DFS was 57% vs 31% (p=0,24) in transplanted vs non-transplanted patients by landmark analysis with a median 5,3 month of CR. Landmark analysis of 5-year OS for transplanted and non-transplanted pts depending on age showed no significant difference for both groups: &gt;45y 40% vs 80%; and ≤45y 70% vs 49%, respectively (p=0,1625), although data for 5-year OS was still not mature at the time of analysis. DFS was significantly different in transplanted vs. non-transplanted pts: &gt;45y 40% vs 71%; ≤45y 61% vs 0%; respectively (p=0,0439). In a multivariate analysis for Ph+ ALL among common risk factors (age &gt; 45y, WBC&gt;30, LDH&gt;2N, immunophenotype, late MolCR &gt;70d, CNS leukemia) WBC&gt;30, HSCT were significant risk factors for OS and DFS. Conclusions. Our data demonstrate that de-intensification of chemotherapy does not affect the efficacy of Ph+ ALL therapy in the era of TKIs. We confirmed that patients older than 45y old could be treated by chemotherapy with TKI (new generation TKI if needed) only, but all pts younger than 45y should be considered for HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Post-Relapse Survival after Haploidentical Hematopoietic Cell Transplantation (Haplo) with Post Transplant Cyclophosphamide (PTCY): Potential Impact of DLI Post-Relapse

Relapse of malignancy remains a major cause of mortality among patients receiving allogeneic hematopoietic cell transplantation. We have previously published our center experience showing that patients who relapse after haplo had a worse 1 year post-relapse survival (PRS) compared to relapses after matched related or unrelated donors (17%, 46% and 40% respectively , p&lt;0.05)(Solh et al, BMT 2016). We hypothesized at that time that relative lack of donor lymphocyte infusion (DLI) use following haplo relapses could have contributed to the difference in outcomes between donor types, and commenced incorporation of DLI into the management strategy for relapse after haplo transplantation. To assess this hypothesis, we investigated the post-relapse survival among consecutive 392 patients who received their haplo transplant at our center between January of 2008 and January of 2020 and assessed for factors contributing to improved PRS. Methods: A total of 392 patients who received their first haplo at our center were included in this analysis. Patient, disease, and transplant related factors were retrieved from our data base where they were prospectively entered. All transplants were performed in the outpatient setting with admissions reserved for complications that required inpatient care. GVHD prophylaxis for all patients was tacrolimus (till day 180), mycophenolate (stop at day 35) and cyclophosphamide 50mg/kg on days 3 and 4. Supportive care and GVHD management were per our programmatic standards. Endpoints included OS, DFS, NRM, relapse and post-relapse survival was assessed as survival from time of relapse. A landmark analysis for patients surviving more than 4 months post haplo was performed to assess for treatment factors affecting long term survival. Results: out of 392 transplant recipients, 109 experienced relapse of malignancy after receiving their first haplo transplant with a median time from transplant to relapse of 194 days (range 43-1268) and median age at relapse of 53 years (20, 74). The patient characteristics for relapsing patients were as follows: diagnosis (AML 37%, ALL 21%, MDS 20%, Lymphoma 16%), prior auto (16%), HCT-CI 0-2 (45%), Disease risk (high/very high 51%). Transplant characteristics included myeloablative regimen (42%), peripheral blood cell source (75%), HLA match (5/10 in 72%, 6/10 in 16%, 7/10 in 12%), and female donor -male recipient in 23%. Post relapse remission induction with disease specific therapy was given to 102 out of 109 patients. Additionally, seventeen patients received DLI (cell dose (1x10 5 to 5x10 6 CD3+ cells/kg)and 10 patients received a second transplant post relapse. 3 patients developed GVHD (aGCVD 2, moderate severe cGHVD 1) after DLI infusion. 1 year and 3-year endpoints for the whole 392 patients were OS (79% and 63%), DFS (70% and 56%), NRM (11% and 15%) and relapse (19% and 29%). 1-year and 3-year post-relapse survival were 37% and 19%. IN a landmark analysis at 4 months, receiving DLI had significantly better OS than no DLI p=0.015(figure 1). On a multivariable analysis for OS, factors associated with improved OS included time from transplant to relapse (&gt;=1 year vs &lt;6 months, HR 0.29, 95% CI 0.16-0.54, p&lt;0.001)), DLI ( yes versus no, HR 0.61, p=0.015)) and patient sex ( male vs female, HR 1.74, 95% CI 1.07-2.81, p=0.025). In conclusion, some patients who relapse after Haplo with PTCY can still achieve long term remissions. The use of DLI in our experience is safe and contributed to improved survival. DLI should be considered in relapse management of haplo recipients. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy.

Predictors and clinical outcomes of poor symptomatic improvement after transcatheter aortic valve replacement

ObjectiveTranscatheter aortic valve replacement (TAVR) improves clinical symptoms in most patients with severe aortic stenosis (AS). However, some patients do not benefit from the symptom-reducing effects of TAVR. We assessed the predictors and clinical outcomes of poor symptomatic improvement (SI) after TAVR.MethodsA total of 1749 patients with severe symptomatic AS undergoing transfemoral TAVR were evaluated using the Japanese multicentre TAVR registry. Poor SI was defined as readmission for heart failure (HF) within 1 year after TAVR or New York Heart Association (NYHA) class ≥3 after 1 year. A logistic regression model was used to identify predictors of poor SI. One-year landmark analysis after TAVR was used to evaluate the association between poor SI and clinical outcomes.ResultsAmong the overall population (mean age, 84.5 years; female, 71.3%; mean STS score, 6.3%), 6.6% were categorised as having poor SI. Atrial fibrillation, chronic obstructive pulmonary disease, Clinical Frailty Scale ≥4, chronic kidney disease and moderate to severe mitral regurgitation were independent predictors of poor SI. One-year landmark analysis demonstrated that poor SI had a higher incidence of all-cause death and readmission for HF compared with SI (p<0.001). Poor SI with preprocedural NYHA class 2 had a worse outcome than SI with preprocedural NYHA class ≥3.ConclusionsPoor SI was associated with worse outcomes 1 year after the procedure. It had a greater impact on clinical outcomes than baseline symptoms. TAVR may be challenging for patients with many predictors of poor SI.Trial registration numberThis registry, associated with the University Hospital Medical Information Network Clinical Trials Registry, was accepted by the International Committee of Medical Journal Editors (UMIN-ID: 000020423).

Effects of cardiac rehabilitation on the two-year prognosis of patients with heart failure: a multicentre prospective cohort study

Background Cardiac rehabilitation (CR) is a comprehensive disease management program highly recommended by heart failure (HF) guidelines. However, the prognostic effects of outpatient CR are inconsistent among recent meta-analyses which enrolled mainly younger HF with reduced ejection fraction (HFrEF). With an aging population, an increased importance of CR has been put on patients with HF with preserved ejection fraction (HFpEF). Purpose This study aimed to examine the prognostic effects of regularly undergoing CR for 6 months after discharge analysing nationwide cohort data including older population with HFrEF and HFpEF. Methods We analysed 2876 patients who hospitalised for acute HF or worsening chronic HF and capable of walking at discharge in the multicentre prospective cohort study. Frequency of outpatient CR participation of each patient was collected using medical records. We assessed CR frequency within 6 months of discharge since most collaborating hospitals conducted final follow-up examinations at 6 months. The CR group was defined as patients who underwent outpatient CR once or more per week for 6 months after discharge. The main study endpoint was a composite of all-cause mortality and HF rehospitalisation during a 2-year follow-up. We performed a propensity score-matched analysis to compare survival rates between the CR and non-CR groups. Propensity scores for each patient were produced by a logistic regression analysis with the CR group as the dependent variable and 33 potential confounders as independent variables. To evaluate events beyond 6 months, we also conducted landmark analyses at 6 months. Results Of the 2876 enrolled patients, 313 underwent CR for 6 months. After propensity score matching using confounding factors, 626 patients (313 pairs) were included in the survival analysis (median age: 74 years, men: 59.6%, median left ventricular ejection fraction [LVEF]: 42%). During 1006.1 person-years of follow-up, 137 patients were rehospitalised due to HF exacerbation, and 50 patients died in the matched cohort. In Cox proportional hazards model (Figure 1), CR was associated with a reduced risk of composite outcomes (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.48–0.91), all-cause mortality (HR 0.53; 95% CI 0.30–0.95), and HF rehospitalisation (HR 0.66; 95% CI 0.47–0.92). A subgroup analysis showed similar CR effects in patients with HFpEF (LVEF ≥50%) and HFrEF (LVEF &lt;40%). However, in a landmark analysis, CR did not reduce the adverse outcomes beyond 6 months after discharge (Figure 2). Conclusions The findings of this study demonstrate the needs that CR should become a standard treatment for HF regardless of HF type and the necessity of periodical follow-up after completing CR program to maintain its prognostic effects. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science Figure 1. Prognostic effects of CR Figure 2. Landmark analysis

12-month post-trial follow-up of participants in the Australian arm of the second low-dose colchicine trial

Background In the Australian arm of the LoDoCo2 trial, colchicine 0.5mg daily compared with placebo markedly reduced the risk of cardiovascular (CV) events in patients with chronic coronary disease (2.0 vs 3.9 events per 100 person years, HR 0.51; 95% CI 0.39–0.67). The purpose of this analysis was to explore CV and non-CV outcomes in the Australian cohort out to one year after cessation of trial medication. Methods Information was collected on all potential CV events and non-CV deaths as well as a range of other co-morbidities. All CV events were blindly adjudicated. The analysis examined the primary outcome (a composite of CV death, myocardial infarction, ischemic stroke, and unscheduled revascularization) and non-CV deaths by initial randomized treatment from the beginning of the trial up until one year after cessation of trial medication. A landmark analysis was then used to examine these outcomes from the date of last contact during the trial until one year after cessation of trial medication. Results The clinical status was confirmed in 1819/1824 (99.7%) participants who were alive at the end of the trial, and in 100% of those participants still taking trial medication at the end of the trial. During post-trial follow up, 515 patients (28.2%) were taking non-study colchicine, including 278 (30.5%) originally randomized to colchicine and 237 (25.9%) randomized to placebo. Over the entire follow-up period that included the 12-month period after the trial medication was ceased, the effect of prior exposure to colchicine on the primary CV outcome was still evident (2.2 vs 3.8 events per 100 person years, HR 0.58; 95% CI 0.45–0.74), however no post-trial CV benefit were apparent in the landmark analysis (3.3 vs 3.4 events per 100 person years, HR 0.97; 95% CI 0.56–0.1.69). Over the entire course of follow-up the incidence of new cancer (7.9% vs 7.2% RR 0.91; 95% CI 0.66–1.25) and non-CV death (0.9 vs 0.6 events per 100 person years, HR 1.44; 95% CI 0.92–2.27) was no different in the treatment groups. Conclusion Although the CV benefits of colchicine treatment that emerged during the trial were still evident in the year after stopping study treatment, no additional CV benefit accrued after it was ceased. These data suggest that colchicine should be continued long-term to maximize its CV benefits. FUNDunding Acknowledgement Type of funding sources: None.

Impact of Early Pancreatic Graft Loss on Outcome after Simultaneous Pancreas–Kidney Transplantation (SPKT)—A Landmark Analysis

(1) Background: Simultaneous pancreas–kidney transplantation (SPKT) is a standard therapeutic option for patients with diabetes mellitus type I and kidney failure. Early pancreas allograft failure is a complication potentially associated with worse outcomes. (2) Methods: We performed a landmark analysis to assess the impact of early pancreas graft loss within 3 months on mortality and kidney graft survival over 10 years. This retrospective single-center study included 114 adult patients who underwent an SPKT between 2005 and 2018. (3) Results: Pancreas graft survival rate was 85.1% at 3 months. The main causes of early pancreas graft loss were thrombosis (6.1%), necrosis (2.6%), and pancreatitis (2.6%). Early pancreas graft loss was not associated with reduced patient survival (p = 0.168) or major adverse cerebral or cardiovascular events over 10 years (p = 0.741) compared to patients with functioning pancreas, after 3 months. Moreover, kidney graft function (p = 0.494) and survival (p = 0.461) were not significantly influenced by early pancreas graft loss. (4) Conclusion: In this study, using the landmark analysis technique, early pancreas graft loss within 3 months did not significantly impact patient or kidney graft survival over 10 years.

One‐Year Landmark Analysis of the Effect of Beta‐Blocker Dose on Survival After Acute Myocardial Infarction

Background Although beta‐blockers are recommended following myocardial infarction (MI), the benefits of long‐term treatment have not been established. The study's aim was to evaluate beta‐blocker efficacy by dose in 1‐year post‐MI survivors. Methods and Results The OBTAIN (Outcomes of Beta‐Blocker Therapy After Myocardial Infarction) registry included 7057 patients with acute MI, with 6077 one‐year survivors. For this landmark analysis, beta‐blocker dose status was available in 3004 patients and analyzed by use (binary) and dose at 1 year after MI. Doses were classified as no beta‐blocker and >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target doses used in randomized clinical trials. Age was 63 to 64 years, and approximately two thirds were men. Median follow‐up duration was 1.05 years (interquartile range, 0.98–1.22). When analyzed dichotomously, beta‐blocker therapy was not associated with improved survival. When analyzed by dose, propensity score analysis showed significantly increased mortality in the no–beta‐blocker group (hazard ratio,1.997; 95% CI, 1.118–3.568; P <0.02), the >0% to 12.5% group (hazard ratio, 1.817; 95% CI, 1.094–3.016; P <0.02), and the >25% to 50% group (hazard ratio, 1.764; 95% CI, 1.105–2.815; P <0.02), compared with the >12.5% to 25% dose group. The mortality in the full‐dose group was not significantly higher (hazard ratio, 1.196; 95% CI, 0.687–2.083). In subgroup analyses, only history of congestive heart failure demonstrated significant interaction with beta‐blocker effects on survival. Conclusions This analysis suggests that patients treated with >12.5% to 25% of the target dose used in prior randomized clinical trials beyond 1 year after MI may have enhanced survival compared with no beta‐blocker and other beta‐blocker doses. A new paradigm for post‐MI beta‐blocker therapy is needed that addresses which patients should be treated, for how long, and at what dose.

Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the randomized, phase 3 KEYNOTE-240 study.

e16122 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]