Median FU Research Articles

Abstract P4-02-20: Utility of the 70-gene signature and 10 year follow up in patients with early-stage breast cancer in a single institution study

Abstract Introduction: Genomic tests are routinely used by clinicians to guide treatment decisions in early-stage breast cancer (EBC). The 70-gene MammaPrint assay (MP) assesses the risk of distant recurrence in untreated patients with EBC and categorizes the tumors as High Risk (HR, MP index: -1 to ≤0) or Low Risk (LR, >0 to +1). The LR category is further divided into Low but non-UltraLow (LNUL; >0 to ≤0.355) and UltraLow Risk (UL; >0.355 to 1). Here, we report the risk of distant recurrence by MP and 10-year outcomes in patients with EBC diagnosed at Magee Women’s Hospital of the University of Pittsburgh Medical Center. Methods: In this retrospective analysis, 259 women diagnosed with EBC between 2005 and 2008, who received a MP result, were included. Patient clinical and tumor characteristics were collected. The median FU was 13.1 year among patients with clinical data. Treatment received, 10-year Distant Metastasis Free Interval (DMFI) and 10-year Breast Cancer Specific Survival (BCSS) are reported according to the MP groups. Differences in DMFI and BCSS between MP risk groups were assessed by log-rank. Patients were treated at the physician’s discretion. Treatment was started prior to obtaining MammaPrint results. Results: Among the 259 patients, 69% were post-menopausal women (mean [range] age: 58 [31-81] years) and diagnosed with hormone receptor-positive HER2-negative tumors (90%), grade 1 or 2 (64%), and without lymph node invasion (93%). In this cohort, 69% (n = 159) had a MP LR result and 31% (n = 100) had a MP HR result. Overall, 14% (n = 35) of patients had a MP UL risk of recurrence of whom 74% (n = 26/35) were post-menopausal women. Substantially more patients received chemotherapy in the HR group (57%, n = 57) compared with the LR group (15%, n = 24) (table). Considering that treatment was initiated before MammaPrint results were known, MP results might have allowed chemotherapy de-escalation in in 15% (n = 24) of patients with a MP LR. Similarly, in the 39% (n = 39) of women with a MP HR treated with endocrine therapy only, knowledge of MP results could have provided important information to add chemotherapy to the treatment plan.. In the MP UL group, 74 % (n = 26) of patients were treated with endocrine therapy only compared with those who received chemotherapy (9%, n = 3) and no adjuvant treatment (9%, n = 3). The 10-year DMFI and 10-year BCSS were higher in the LR compared with the HR group (table). When further stratifying the MP LR group in LNUL and UL, the 10y DMFI was 0.97 (95% CI; 0.94 – 1.00) and 1.00 for the MP LNUL and UL groups, respectively. Within the first 10 years, 8 of the 10 distant recurrences observed were in the MP HR group, and 2 were in the MP LNUL group. Among the 18 recorded deaths, 5 were breast cancer-related, 4 in the MP HR and 1 in the MP LR (LNUL) groups. Discussion: In this single-institution retrospective analysis, all patients showed excellent BCSS and DMFI outcomes confirming the ability of MP to correctly predict the good prognosis (LR) and poor prognosis (HR) in patients with EBC. In this analysis, as observed in other cohorts, women with a MP UL risk result had an excellent prognosis at 10 years while being treated mostly with endocrine therapy only. Taken together, with the low endocrine therapy adherence reported in the literature, these data suggest that patients with a MP UL result may be candidates for further treatment de-escalation to optimize the risk/benefit ratio of endocrine therapy in future studies. Table 1. Clinical outcomes and treatment received in patients stratified by MammaPrint results * Patients were treated at the physician’s discretion a p = 0.011, MP LR vs MP HR. b p = 0.032, MP UL vs LNUL vs HR. c p = 0.061 MP LR vs MP HR. d p = 0.170, MP UL vs LNUL vs HR. Citation Format: Azadeh Nasrazadani, Juan L. Gomez Marti, Margaret Q. Rosenzweig, Meghan McGuire, Katie Quinn, Josien Haan, Alexandre Houzelle, Rohit Bhargava, William Audeh, Adam M. Brufsky. Utility of the 70-gene signature and 10 year follow up in patients with early-stage breast cancer in a single institution study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-20.

Abstract P6-01-47: Stromal tumor infiltrating lymphocytes and pathological complete response in patients with inflammatory breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Inflammatory breast cancer (IBC) is a rare (1-5%), but aggressive form of breast cancer (BC), accounting for ~10% of BC mortality. In early setting (M0), standard of care is neoadjuvant chemotherapy (NACT), followed by surgery. Nevertheless, outcome is still relatively poor. Pathological complete response (pCR) after NACT is prognostic in BC in general, and can be predicted by a high percentage of stromal tumor infiltrating lymphocytes (sTIL) in the primary tumor. The predictive value of sTIL in IBC has only been sporadically investigated, often in smaller series. Our aim was to determine which variables, including sTIL, are associated with pCR and to determine the prognostic value of pCR in IBC in a large multicentric, retrospective cohort. Patients & Methods: We included patients with IBC treated with NACT+/- anti-Human Epidermal growth factor Receptor 2 (HER2) therapy, followed by surgery from 10/1996 to 10/2021 in 7 different European hospitals. Clinicopathological variables were collected and central pathological review was performed, including sTIL scoring. This study focused on M0 cases. Considered clinicopathological variables were: age, histology, tumor grade, estrogen receptor status (ER), HER2 status, focality (unifocal vs not), and baseline locoregional nodal status (Table 1). Associations between pCR, clinicopathological variables and sTIL were assessed using Firth’s logistic regression models: Model 1 was adjusted for center, Model 2 additionally included all variables of interest. Similarly, linear regression was used to investigate the association between sTIL and clinicopathological features. Univariable and multivariable Cox regression was used to evaluate the role of pCR on disease free survival (DFS), distant recurrence free survival (DRFS) and overall survival (OS). DFS and DRFS were analyzed considering death without the respective event as competing risk. Results: 494 patients were included. The distribution according to receptor status was: ER-/HER2- (24.3%), ER+/HER2- (34.4%), ER+/HER2+ (13%) and ER-/HER2+ (20.2%). pCR rate was 26% and per receptor status: ER-/HER2- (28%), ER+/HER2- (10%), ER+/HER2+ (42%) and ER-/HER2+ (45%). pCR was associated with grade (G3 vs G1/2, OR =2.79 (1.70 − 4.74), p < .001), ER-status (positive vs negative, OR = 0.39 (0.26 − 0.60), p < .001) and HER2 status (positive vs negative, OR = 3.74 (2.43 − 5.81), p < .001) in Model 1. Only the association with HER2 status remained significant in Model 2 (OR = 5.34 (2.83 − 10.47), p < .001). sTIL was scored for 385 patients. Median sTIL was 5.3% [IQR 2.0%;16.7%] and according to receptor status: ER-/HER2- (10%), ER+/HER2- (2.5%), ER+/HER2+ (6.7%) and ER-/HER2+ (8.3%). Higher sTIL was associated with NST (p = .032), grade 3 (p = .015), and ER-negativity (p = .007) in Model 1. This was no longer significant in Model 2, but the direction of the trends was preserved. sTIL was associated with pCR (5% increment, OR = 1.13 (1.05 − 1.22), p = .002), but no longer after adjustment. No association between pCR and sTIL was found stratifying by receptor status. The median FU was 9.4 years and multivariable Cox regression models revealed that ER+ and HER2+ status and achieving pCR were significantly associated with better DFS, DRFS, and OS (Table 1). Conclusion: Our results indicate that patients with HER2+ tumors have a higher probability of achieving pCR and that pCR has an independent prognostic role in IBC. This is the largest IBC study with centrally scored sTIL, demonstrating that sTIL is associated with pCR but its role as an independent predictor of pCR is still not certain. Citation Format: Maxim De Schepper, Ha-Linh Nguyen, François Richard, Florence Lerebours, Roman Vion, Florian Clatot, Anca Berghian, Marion Maetens, Sophia Leduc, Edoardo Isnaldi, Chiara Molinelli, Matteo Lambertini, Frederica Grillo, Gabriele Zoppoli, Luc Dirix, Hilde Wuyts, Kevin Punie, Hans Wildiers, Chantal Remmerie, Ann Smeets, Ines Nevelsteen, Patrick Neven, Anne Salomon, Denis Larsimont, Caroline Duhem, Patrice Viens, François BERTUCCI, Elia Biganzoli, Peter Vermeulen, Giuseppe Floris, Christine Desmedt. Stromal tumor infiltrating lymphocytes and pathological complete response in patients with inflammatory breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-47.

Abstract P4-01-25: Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer

Abstract P4-01-25: Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer

Outcomes of Surgical Treatment for Extradural Benign Primary Spinal Tumors in Patients Younger than 25 Years: An Ambispective International Multicenter Study.

Extradural primary spinal tumors were retrospectively analyzed from a prospective database of 1495 cases. All subjects with benign primary tumors under the age of 25 years, who were enrolled between 1990 and 2012 (Median FU was 2.4 years), were identified. Patient- and case-related characteristics were collected and statistically analyzed. Results: 161 patients (66f;95m; age 17.0 ± 4.7 years at time of diagnosis) were identified. The most common tumors were osteoblastomas n = 53 (32.9%), osteoid osteomas n = 45 (28.0%), and aneurysmal bone cysts n = 32 (19.9%). The tumor grade, according to the Enneking Classification S1/S2/S3, was 14/73/74 (8.7/45.3/46.0%), respectively. Tumor-related pain was present in 156 (96.9%) patients. Diagnosis was achieved by biopsies in 2/3 of the cases. Spinal fixation was used in >50% of the cases. Resection was Enneking appropriate in n = 100 (62.1%) of cases. Local recurrence occurred in 21 (13.1%) patients. Two patients died within a 10-year follow-up period. Conclusion: This is one of the largest international multicenter cohorts of young patients surgically treated for benign spinal tumors. The heterogenic young patient cohort presented at a mid-term follow-up without a correlation between the grade of aggressiveness in resection and local recurrence rates. Further prospective data are required to identify prognostic factors that determine oncological and functional outcomes for young patients suffering from these rare tumors.

Molecular Characterization of Response/Loss-of-Response to Ruxolitinib in Patients with Myelofibrosis

Background. Ruxolitinib (RUX) is standard of care for most patients (pts) with primary (PMF) and secondary (sMF) myelofibrosis. However, about half of responders lose benefits at 3-5y, associated with clonal progression, and have a dismal outcome thereafter. The molecular bases for response/loss of response to RUX have not been clarified yet. Aim. To explore genetic variables associated with response/loss of response to RUX in MF pts. Patients and Methods. All consecutive pts with WHO2016/IWG-MRT diagnosis of PMF/sMF, treated with RUX at our Center, were included. To the purpose of the study, response was stringently defined as achievement of spleen lenght reduction from LCM of >50% at any time point; non-responders (NR) were all the others. Loss-of-response was defined as the reappearance of >5cm splenomegaly, if the nadir under RUX was <5cm, and >50% increase if the nadir was >5cm. A custom NGS panel including complete CDS of 552 genes, selected for putative involvement in RUX response (belonging to JAK/STAT, MAPK, ERK pathways, inflammatory reactions, apoptosis) or associated with myeloid neoplasms, was designed. For RNAseq analysis, we used the R package DOSE and performed Over Representation Analysis (ORA) to identify over-represented biological functions/processes. Results. Baseline characteristics. A total of 171 pts were included, 52.1% PMF (15.8% prePMF, 36.5% overtPMF) and 82 sMF (46.9%; 29.2% PPV-, 17.7% PET-MF). DIPSS at RUX start was Int-1: 43.8%, Int-2: 39.8%, high: 16.4%. Median FU from RUX start was 3.5y (0.8-17.3y), median time on RUX was 2.4y (0.2-12y). Sixty-eight pts (39.8%) died, 39 (22.8%) while on RUX. AML developed in 13 pts (7.6%), 10 of which while on RUX. OS from RUX start was 5.8y (4.4-7.3y). JAK2V617F mut in 72.3%, MPLW515 7.6%, CALR 19.3% (12.8% Type1/like, 6.4% Type2/like), TN 2.3%. 68 pts (39.8%) were High Molecular Risk (HMR; ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1). Response to RUX. 93/171 pts (54.4%) were NR. Of the 78 responders (45.6%), 45 (57.7%) lost response (hence, R/L) after a median of 22.7 mo from RUX start, and 33 pts (43.3%) maintained response (hence, R/M) at last FU. Response outcome was influenced by RUX dose: 75.2% of NR and 64.4% of R/L had received <20 mg/die, compared with 63.6% of R/M who had received >30 mg/die. RUX stop (any reason) occurred in 24.2% of R/M, 62.2% R/L, 55% of NR (P=0.02). Baseline molecular predictors. Baseline molecular variables found to correlate with response/loss of response included: (i) HMR status, found in 51.1% R/L vs 24.2% R/M and 40.2% NR (P=0.04); (ii) >1 RAS pathway mutated gene (CBL, NRAS, KRAS, PTPN11), found in 30% NR, 5% R/L and 13.8% R/M (P=0.016); (iii) isolated CBL (n=8, 10.5%; P=0.02) and U2AF1 (n=5,6.7%; P=0.05) mutation, found exclusively in NR pts. Nor type nor variant allele frequency (VAF) of driver mutations impacted on response/loss of response. Serial mutational analysis. Among JAK2V617F mut pts, a partial molecular response (PMR, >50% VAF reduction; IWG-MRT criteria) was achieved by 18.6% of pts, after a median of 1.7y (1-5y). Median VAF reduction under RUX of pts with PMR was 71.3% (51-100%). A PMR occurred in 44.4% of R/M vs 14.8% of (R/L+NR), P=0.03. In 14 responder pts who were on stable dose of RUX since >1y and later became R/L, target NGS sequencing for 552 genes was performed using granulocyte DNA, collected at baseline (T0), at the time (+6mo) of response adjudication (T1) and at R/L (T2). A total of 91 mutated genes were acquired at T2 (mean gene number/pt, 2.5, range 1.0-16). Of these, 22 genes belonged to categories of "transcription regulator", 19 "cytokine mediator signaling", 14 "spliceasome/RNA processing", 11 "EGFR/TKI resistance" and 8 "chromatin regulators" (GO, KEGG, Reactome, Wikipathway). Serial, single cell analysis to interpret clonal hierarchy is ongoing, results will be presented at meeting. Pairwise RNAseq was performed in 4 pts with purified PB CD34+ cells collected at T1 and T2. By using a stringent FDR<0.1 value, enriched transcripts belonged to "RHO-GTPase" (n=88), "spliceasome" (n=40), "Type-2 interferon responses" (n=20), "IL12 stimulated gene and proteins" (n=14) categories. Conclusions. This study adds to the understanding of molecular mechanisms of response/loss of response to RUX by identifying baseline predictors and highlighting a set of involved genes/pathways, that remain to be validated.

Optimizing the Supportive Care of Intensive Chemotherapy in AML : Impact of Vitamin C and D Supplementation in Patients with NPM1 Mutation. a Dataml Registry Study

Background Vitamin (vit) deficiencies are frequently observed in patients (pts) with newly diagnosed AML (ND-AML). A lower level of vit D is associated with a worse prognosis in pts treated with intensive chemotherapy (IC) (Lee HJ, Cancer 2014). Similarly, a pretransplant vit D deficiency is associated with a higher risk of relapse (Radujkovic JCO, 2017). Moreover, preclinical studies demonstrated the antileukemic activity of vit D through the modulation of cell cycle, differenciation and apoptosis even though the clinical translation has not been successful (Cao H, Exp Hematol 2017 ; Paubelle E, Cell Rep 2020). More recent data have highlighted the role of vit C in AML. Vit C is a cofactor and increases the activity of TET2 enzyme, inducing DNA demethylation, stem cell differentiation and antileukemic activity (Agathocleous M, Nature 2017; Cimmino L, Cell 2017). Cases of remission following vit C supplementation have been reported (Foster M, Antioxidants, 2018 ; Das A, Blood Cancer J, 2019) and a small study showed that the addition of vit C to decitabine/AraC/aclarubicin/G-CSF improved outcome compared to DCAG (Zhao H, Leuk Res 2018). Based on these data, we modified our practice by adding vit C and D to the supportive care (SC) of IC. Methods The study population included all pts with ND-AML treated by IC and registered in Toulouse DATAML from 01/2015 to 05/2020. As of March 2018, as part of the SC for AML pts treated by IC and in the absence of contra indication (renal lithiasis, renal insufficiency, G6PD deficiency, hypercalcemia), vit C (1g x 2/d, three times a week ; IV) and vit D (100,000 IU/week ; PO) have been administered from d10 until hematologic recovery of induction and consolidation. The principal objective of this retrospective study was to assess the impact of the vit supplementation on EFS. Secondary objectives were response to induction, early death, OS, RFS, incidence of relapse, vitamin levels during treatment and safety. Results 431 pts were included, 262 without (from 01/2015 to 02/2018 ; control group) and 169 with vit C/D supplementation (03/2018-05/2020 ; vitC/D group). Data were updated on 03/03/2022. The median FU was 45.6 months. Pt characteristics were well balanced except for age, PS and creatinine (Table 1). In the vitC/D group, the median plasma level of vit C was 3.20 mg/L (range, 0.47-15.42) at diagnosis and 4.62 mg/L (range, 0.18-18.1) at time of hematologic recovery from induction (P=0.18). The level of vit D at diagnosis was 16 ng/mL (range, 4-56) and 18 ng/mL (range, 4-42) in the control and vitC/D groups, respectively. Upon recovery from induction, vit D levels significantly increased compared to diagnosis in the vitC/D group (median, 39 ng/ml, range, 5-93 ; P<0.0001). CR/CRi rate was 84.4% (control) and 84% (vitC/D) (P=0.93). Day-30 death rate was 4.2% (control) and 2.4% (vitC/D) (P=0.31). During induction, the rates of grade 3-4 bacterial infections (vitC/D, 27.2% vs control, 35.1%, P=0.086), fungal infections (10.1 vs 18.3%, P=0.019), hemorrhages (1.8 vs 5.7%, P=0.045) or macrophage activation syndrome (1.8 vs 8.8%, P=0.002) were lower in the vitC/D group. Median level of day-21 calcemia was higher in the vitC/D group (2.48 mmol/L vs 2.44, P=0.003). Grade 2 hypercalcemia was observed in only 1 patient of the control group. Allo-SCT was performed in 37 (26.1%) and 75 (33.9%) pts of the vitC/D and control groups, respectively. Median pretransplant vit D levels were significantly higher in the vitC/D group (33 vs 19 ng/mL, P<0.0001). There was no significant difference in EFS (vitC/D, median 13.9 vs 17.4 months, P=0.26), RFS (15.5 vs 23.5, P=0.24) and OS (30.8 vs 34.5, P=0.80) between both groups. However, multivariate analysis for OS showed a significant interaction between vitC/D and NPM1 mutation meaning that vitC/D supplementation was significantly and independently associated with better OS in pts with NPM1 mutations (HR, 0.52 ; 95%CI: 0.30-0.90, P=0.019) but not in NPM1 wildtype pts (HR, 1.01 ; 95%CI: 0.68-1.51, P=0.95). MV analysis for EFS, RFS and CIR did not find any significant interactions. Conclusion Vit C and D supplementation is feasible and safe in AML pts during IC. Normal Vit D levels can be restored before transplant, which may be important. The potential impact of vit C/D supplementation in AML with NPM1 mutations needs further studies and pave the way for exploratory analyses to explain how the VDR pathway and/or vit C activity may interact with the biology of NPM1 mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

JAK2V617F Molecular Response to Ruxolitinib in Patients with PV and ET Is Associated with Lower Risk of Progression to Secondary Myelofibrosis

Introduction. Ruxolitinib (RUX) is approved for patients (pts) with Polycythemia Vera (PV) who are refractory or intolerant to hydroxycarbamide, based on composite endpoint of spleen volume reduction and Hct control (RESPONSE-1 trial) and Hct control (RESPONSE-2). Conversely, studies in pts with Essential Thrombocythemia (ET) were inconclusive, and the drug is not approved in that indication. Aim. The aim of current study was to analyze changes of JAK2V617F variant allele fraction (VAF) in PV and ET pts who were long-term treated with RUX, and the clinical correlates and outcome of molecular responses. Patients and Methods. The study included 65 PV and 12 ET pts; the latter had been enrolled in phase-2 studies and were still on RUX owing to continuing clinical benefits. Median time from diagnosis to RUX was 5.9y (0.6-24y), age 58y (25-87y), 50.6% were male, history of thrombosis in 21 pts (27%). A JAK2V617F mutation was found in 75 pts (97.4%), JAK2ex12 and MPLW515L in 1 pt each. At circa-annual intervals, JAK2V617F VAF was measured in granulocytes by digital PCR or highly sensitive (threshold <0.01%) RTQ-PCR. MPLW515L was measured by digital PCR. IWG-MRT criteria were used for clinical and molecular response assignment. The latter included partial (PMR: a >50% VAF reduction) and complete (CMR; JAK2V617F undetectable) molecular response, confirmed at >1y. We also considered a deep molecular response (DMR) as a confirmed VAF<2%. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate. Results. Median FU on RUX was 8.8y (1.3-14.1). The median RUX dose was 20 mg die (5-50mg). RUX was discontinued in 23 pts for AE (n=7, 9.1%), disease progression (n= 12, 15.6%), refractoriness/loss of response (n=3, 3.8%) or pt decision (n=1, 1.3%), after a median of 5.0y (0.8-13y). While on RUX, there were 3 thrombosis and 4 bleedings. Progression to secondary MF (sMF) occurred in 24 pts (31.1%) after a median of 6.0y (2-11.5); of these, 22 (92%) were PV, accounting for 34% of all PV compared to 16.6% of ET. Three pts (3.9%) transformed to AML after 9.2y (1.3-13.7y) and died, and 2 pts (2.6%) died after evolution to sMF while on RUX. A IWG-MRT response was reached in 92% for Hct, 59% for platelet count, 73% for leukocyte count, 77% for spleen volume (<50% palpatory). The median JAK2V617F VAF was 47% (21-98%) and 68% (15-99%) at diagnosis and RUX start, respectively. The overall mean VAF decrease was 64.6%+27.5%. A PMR was observed in 33 pts (44.2%), after a median time of 3.3y (1-7.6y), 51% and 50% of PV and ET; the baseline JAK2V617F VAF was 61.3±27.7% for PV and 32.3±10.4% for ET. A CMR (confirmed) was declared in 5 JAK2V617F mutated pts (6.5%; median baseline VAF 44.7±36.8%) of which 3 were PV, and in the MPLW515L mutated ET pt (baseline VAF 33%). A DMR was confirmed in 9 pts (11.7%; median baseline VAF 30.5±16.0), of which 6 were PV. Median time to CMR and DMR was 4.6y (1.1-7.6y) and 5.0y (2.1-12.1y), respectively. Mean duration of CM + DMR was 8y (7-12y). There was no correlation between any category of molecular response and response of Hct, platelets and spleen length, while normalization of leukocytes occurred more frequently in pts with PMR (93.8% vs 62.5%, P=0.02). Of the pts who progressed to sMF, 21 of 24 pts (87.5%) had not attained an at least PMR (P<0.0001). The HR of sMF evolution was 19.9 (95%CI, 2.4-166.7) for those who did not obtain any molecular response and 3.56 (95%CI, 0.37-34.6) for those who obtained PMR, using CMR+DMR as reference (P<0.0001) (Figure 1). By ROC analysis, a cutoff level of <60% JAK2V617F VAF at baseline (involving 35 pts, 45.5% of the entire population) was associated with a significantly greater likelihood to obtain CMR+DMR (37.1% vs 2.4%; P<0.0001) as well as PMR (60% vs 38.2%, P=0.01). All 3 pts who transformed to AML had not obtained any molecular response. Discussion. In this study, 18% of PV and ET pts receiving RUX developed sustained JAK2V617F complete plus deep molecular response (JAK2V617<2%) over long term treatment, that were associated with lower risk of progression to secondary MF; also pts attaining a PMR had reduced probability to develop sMF compared to those who did not show any changes in JAK2V617 VAF, overall reinforcing that attainment of molecular response may be a surrogate of disease modification. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combined Treatment with Ibrutinib and Anti-CD38 Monoclonal Antibody Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia with TP53 Aberrations: Results of the Filo Phase II Study IDA53

Background: Despite significant improvement with BTK inhibitors, long-term disease control of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with TP53 abnormalities remains challenging. CD38 expression is an independent adverse prognostic factor in CLL. This has been related to the involvement of CD38 in CLL cells migration, proliferation, tissue invasion and BCR signaling (Vaisiti 2015; Matas-Cespedes 2016). Daratumumab is the first in class anti-CD38 monoclonal antibody approved in multiple myeloma in both relapse and frontline settings. Preclinical studies have shown daratumumab to induce significant effect on viability and migration of patient-derived CLL cells (Matas-Céspedes et al, 2016). Moreover, the combination of daratumumab and ibrutinib demonstrated synergistic effect on both in vitro CLL cells killing and in vivo tumor burden reduction and survival prolongation in a CLL xenograft model (Manna et al, 2019). We therefore hypothesized that daratumumab would improve ibrutinib efficacy in R/R CLL patients with TP53 aberrations. Methods: This phase 2 trial enrolled patients with R/R CLL and TP53 abnormalities regardless of cell surface CD38 expression. Treatment consisted of ibrutinib (420 mg/d) alone for one month then combined to intravenous daratumumab (16 mg/kg/d) administered weekly for 8 weeks, every other week for the subsequent 4 months then monthly until intolerance or disease progression. The primary endpoint was the complete response (CR) rate according to iwCLL criteria after 12 months (M12) of combined therapy. We estimated a 20% CR rate at M12 to be the target threshold for treatment efficacy and 7% the minimum acceptable. We planned to recruit 44 patients. Results: Between December 2018 and May 2022, 29 patients have been enrolled. The study prematurely closed due to drop in patient accrual and failure to achieve the primary endpoint. Median age was 69 years [45-86] and sex ratio M/F was 18/11. Median number of previous lines was 1 [1-4]. Four patients (14%) had bulky adenopathy. Median lymphocytosis was 55 G/L (4.5-385). Median hemoglobin level and platelet count were 13.2 g/dL (8.1-17.3) and 127 G/L (37-188) respectively. All patients had TP53 disruption with 17p deletion in 16 cases (55%), TP53 mutations in 26 (93%), both in 14 (48%). Five had 11q deletion (18.5%). IGHV was unmutated in 16 patients (62%) and 2 additional patients had subset#2 stereotyped BCR. Eighteen patients had complex karyotype (72%) of whom 9 (36%) had very complex karyotype. Elevated b2microglobulin was present in 19 patients (73%). CD38 expression ranged from 0 to 87%. At data cutoff (18 JUL 2022), 21 patients have reached M12 and 15 are still on treatment. Fourteen patients went off study of whom 6 before M12. Reasons of discontinuation were progressive disease (PD) in 4 patients (at month 4, 13, 19 and 25) of whom 2 Richter transformation (RT), related adverse event (AE) in 3 (grade 3 infusion related reaction (IRR), recurrent cutaneous carcinoma, atrial fibrillation), COVID-19 in 3, pandemic context in 1, death of unknown cause in 1, and consent withdrawal in 2 patients. Five patients died (1 RT, 3 COVID-19, 1 unknown cause). AEs and serious AEs (SAE) were reported in 29 and 19 patients, respectively. Grade ≥3 AEs were hematological (n=9), infections (n=7), metabolism disorder (n=5), IRR, renal deficiency, myalgia, urologic disorder, death of unknown cause (all n=1). Grade 1-2 AEs reported in ≥ 10% of patients included gastrointestinal disorder (n=16), metabolism disorder (n=10), cardiovascular disorder (n=7), cutaneous neoplasms (n=6), ENT infections (n=5), COVID 19 (n=5), bleedings (n=4) and skin disorders (n=3). No tumor lysis syndrome occurred. At M12, one patient achieved CR, 20 patients achieved PR. Overall response and CR rate were 78% and 3.7% in intend-to-treat calculation, and 95% and 4.5% in per protocol calculation, respectively. With a median FU of 20.2 months, median progression free and overall survival were 27.1 [95%CI 23.4-NR] and 33.5 [95%CI 27.1-NR] months, respectively. Although not significant, there was a trend toward shorter PFS in CD38+ patients that daratumumab did not reverse. Conclusions: Daratumumab was safely combined with ibrutinib without unexpected toxicity in CLL. However, this combination did not provide any clear improvement of complete response rate in this very high-risk CLL population, as compared with ibrutinib alone. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lenalidomide-Rituximab or Lenalidomide-Rituximab-Bendamustine in Patients with Relapsed/Refractory Follicular Lymphoma: Priimary Analysis of the Randomized Phase II HOVON110/Rebel Trial

Introduction The R2 regimen (lenalidomide-rituximab) is effective in treatment-naive and relapsed/refractory follicular lymphoma (R/R FL). Combining R2 with bendamustine (R2B) is feasible (Stevens WBC et al., Hemasphere 2020) and hypothesized to deepen remission and prolong event-free survival (EFS) compared to historic controls. We performed a randomized phase II trial of R2 and R2B, aiming at identifying the most promising arm to take forward to a randomized phase III trial. Methods In the multicenter, prospective, randomized, non-comparative phase II part of the HOVON110/ReBeL study (Dutch Clinical Trial Register NTR3028), patients (pts) with FL relapsed after ≤5 prior therapies were randomized 1:1 to R2 (Arm A) or R2B (Arm B). Stratification factors used were FLIPI score (0-2 vs 3-5), number of prior treatments (1 vs 2-5), prior bendamustine use and relapse during rituximab maintenance (RM). Arm A pts received 6 cycles of R2 q28 days (lenalidomide 20 mg day 1-21, rituximab 375 mg/m2 day 1); Arm B pts received 6 cycles of R2B q28 days (lenalidomide 20 mg day 3-21, rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 day 1,2). In both arms, pts with partial or complete remission (PR/CR) received 2 years of RM treatment, once every three months. Subcutaneous rituximab was allowed. Thrombosis prophylaxis was advised during induction; antimicrobial prophylaxis with valaciclovir and cotrimoxazole was mandatory in arm B. Arms A and B were separately evaluated for efficacy and toxicity. Co-primary endpoints were CT-based CR rate according to Cheson 2007 criteria at end of induction (EOI) and incidence of severe toxicities (ST), defined as grade ≥ 3 non-hematological toxicity, specified grade 4 hematologic toxicity (neutropenia lasting ≥ 7 days despite GCSF, febrile neutropenia, thrombocytopenia) or non-lymphoma related death. An event for event-free survival was defined as induction failure, progression, relapse or death from any cause. PET-CT was performed before and after induction. Central pathology and blinded central PET-CT review (Lugano classification) were performed. Results Between 2014 and 2019, 92 of 150 planned pts were randomized. The trial was stopped early because of slow accrual. Two pts (1 in each arm) were ineligible. Baseline characteristics were comparable between Arms A/B in terms of gender and median age (64/62 years). Most pts had stage III/IV disease (85%/80%), an intermediate/high risk FLIPI score (78%/89%) and had undergone 1 prior treatment (75%/76%; range 1-5). For pts in arms A/B, 80%/76% completed all 6 induction cycles and 41%/43% completed 8 cycles of RM. Main reasons for discontinuation during induction were progressive disease (PD) (n=4 per arm) and toxicity or other reasons in 5/7 patients. Severe toxicity (ST) occurred in 3 pts in arm A (6.8%; 2 fatal pneumonia cases) and in 6 pts in arm B (13.0%; no fatalities), while 43%/66% of pts experienced any grade 3-4 AE (2%/7% grade 4). These comprised mainly skin toxicity, infections and gastrointestinal toxicity. In the R2B arm, 1 pt had Pneumocystis carinii pneumonia during RM. Based on intention to treat (ITT) and local CT assessment (efficacy co-primary endpoint), 16% of R2 and 22% of R2B treated pts achieved a CR at EOI; the overall response rate (ORR) was 70% and 72%, respectively. The complete metabolic remission rate (CMR) by central PET-CT review at EOI was 48% and 54%. At a median follow-up of 48 months (mo), EFS was 39% and 61%; median EFS was 24.6 mo and not reached (NR). Importantly, median time to next treatment (TTnT) was 9.2 mo and NR. There were 7 second primary malignancies (SPM) in 5 pts in Arm A) and 5 SPM in 4 pts in Arm B). Overall survival was excellent in both arms with 72% and 91% of pts alive at 48 months. Causes of death during the study were progression of FL (n=8) and toxicity (n=3) in Arm A; FL (n=3), toxicity (n=1) and suicide (n=1) in Arm B. Conclusions This randomized non-comparative phase II trial of R2 and R2B in R/R FL patients showed high CT-based OR rates and PET-CT CMR rates, but low CT-based CR rates for both treatments. At a median FU of 48 months, 39% of R2 treated patients and 61% of R2B treated patients were still alive and in remission; this compares favorably with historic real world controls (Batlevi et al, Blood Cancer J 2020). Both regimens were associated with less severe toxicity than expected (pre-set acceptability threshold of 20% ST), supporting further investigation of R2 combinations in randomized phase III trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Follow-up of Clinical Outcome Determinants and Correlative Biological Features from the Nordic NLG-T-01 Trial

Introduction The Nordic NLG-T-01 was a large phase II trial evaluating the efficacy of bi-weekly etoposide-containing chemotherapy consolidated by autologous transplant in newly diagnosed patients with systemic peripheral T-cell lymphomas (PTCL) (d'Amore et al, JCO 2012). The final analysis of the trial showed female sex and anaplastic large cell (ALCL) histology to be predictive of a favourable outcome. Here, we present a long-term follow-up evaluating the outcome of NLG-T-01 patients according to clinico-pathological parameters and biological features, in particular rearrangements of the dual specificity phosphatase 22 (DUSP22-IRF4) and the TP63 gene. Methods A cohort of 160 adult PTCL patients aged 18 to 67 years were enrolled. Anaplastic lymphoma kinase (alk)-positive anaplastic large-cell lymphoma (ALCL), primary cutaneous and primary leukemic PTCL were excluded. Considering the high median age of the study population at the time of enrolment (57 yrs) and the length of follow-up, we analyzed, in addition to overall (OS) and progression-free survival (PFS), also disease-specific survival (DSS). Time-to-event end points were calculated by means of Kaplan-Meier estimates. Log-rank tests and Cox regression models were used to analyze prognostic factors. A trial-specific tissue micro-array (TMA) was constructed with those pre-therapeutic biopsies, where sufficient tissue was still available for analysis (n=87). Fluorescent in situ hybridization (FISH) was performed on TMA slides or whole sections using break apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation for rearrangements was performed without knowledge of the specific PTCL diagnosis, clinical course, or outcome. Results At a median FU of 10.7 years (range: 7-14 yrs), 71 of 160 (44,4%) intention-to-treat population patients were still alive and in remission. Causes of death for the 89 deceased patients were: lymphoma (76%), toxicity (10%), second malignancy (6%), other causes (8%). The 10-year OS, PFS and DSS for the whole ITTP were 41%, 38% and 51%, respectively (all CI95% within +/- 10% range). The multivariate analysis for long-term outcome-related parameters confirmed that female patients had a significantly better outcome than their male counterparts (10 yr OS: 68% vs 47%; HR 0.60 - CI95% 0.37-0.97; p=0.039). Elevated International Prognostic Index (IPI) parameters also retained their adverse prognostic impact, in particular age (pr year) (OS: HR 1.03 - CI95% 1.00-1.06; p=0.004 and PFS: HR 1.03 - CI95% 1.01-1.06; p=0.03) and poor performance score (PS ≥2) (OS: HR 1.71 - CI95% 1.08-2.72; p=0.023 and PFS: HR 1.84 - CI95% 1.18-2.86; p=0.009). DUSP22 analysis revealed presence of a classical DUSP22-IRF4 rearrangement in six patients. All of them achieved a complete remission (CR), four stayed in continuous CR for all the follow-up period, one experienced a late relapse approximately 5 years after end of 1st line treatment and responded to 2nd line treatment with a new sustained ongoing CR, and one died of sepsis after high-dose therapy while in CR. TP63 rearrangement was found in one patient, who responded to trial therapy and was in long-term CR at the time of follow-up analysis Fig.1 shows OS according to histological subtypes among the 87 patients analyzed for DUSP22 and TP63 rearrangements. Conclusions Long-term follow up of the Nordic NLG-T-01 trial, confirmed a superior outcome for female patients and an adverse prognosis for elevated IPI parameters, in particular age (per year) and PS ≥ 2. A correlative biological analysis showed a favourable outcome for ALCL patients with DUSP22/IRF4 rearrranged tumours compared to other histological subtypes, including triple negative ALCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in MRD+ AML-Patients Results in MRD Conversion, Improved Relapse-Free Survival and Vaccine Induced Immune Responses to Tumor Antigens

Background. Maintenance therapy in AML patients with measurable residual disease (MRD) remains challenging. Immunotherapy could be an effective way to induce durable disease control. This phase II study aims to show efficacy of priming the immune system, using an allogenic leukemia-derived dendritic cell vaccine (DCP-001), to induce an effective anti-leukemic response to control or kill remaining malignant cells (ADVANCE-II, Clintrials.gov: NCT03697707). Methods. A total of 20 evaluable AML patients in first complete remission (CR1) with MRD positivity and ineligible for HSCT received 4 biweekly doses of 25e6 or 50e6 cells per intradermal vaccination (cells/vc) and 2 doses as boosts at week 14 and 18 of 10e6 cells/vc. MRD, as primary endpoint, was assessed at baseline, week 14, 20 and 32 by flow cytometry and/or molecular analyses. Evaluation of secondary endpoints relapse-free (RFS) and overall survival (OS) was done at data cut-off (18th July 2022). Peripheral blood samples were taken before and during treatment for analysis of vaccine induced responses as measured by IFNγ ELISPOT and general immune profiles by flow cytometry using a 40-marker panel. Results. Patients aged 34-79 (median 60y) had a cytogenetic risk status assessed of 4 better, 15 intermediate and 1 poor-risk, with mutations in NPM1 (n=10), CBFB-MYH11 (n=4), IDH2 (n=2), RUNX1-RUNX1T1 (n=2), TP53 (n=1) and CEBPA (n=1). All 20 patients have received 4 initial vaccinations, 17 patients received all booster vaccinations and 1 patient received one booster. No serious adverse events (AE) or severe AE (grade 3 or higher) related to the treatment have been reported. Related AEs are mainly injection site reactions, such as redness, warmth and swelling, occurring within 48 hours after intradermal administration. To date, median RFS and OS have not yet been reached (Figure 1), with a median follow up period of 15.4 (range 6.6- 16.8) months for the entire study population. Estimated RFS and OS at 6 months is 83.9% (range 64-94%) and 97% (range 79-99%), respectively. Estimated RFS and OS at 12 months is 70% (range 48-85%) and 87% (67-95%), respectively. MRD response (conversion or >10-fold decrease of MRD) was observed in 7 patients: 5 patients converted to negative and 2 showed a MRD decrease. Responses were observed within 14-20 weeks and durable in 4 out of 5 patients, remaining MRD negative up to week 32. Seven patients remained in CR with stable MRD levels and 6 patients relapsed before week 32. Three patients with stable MRD became eligible for HSCT during study and were transplanted successfully. Immune responses were observed to tumor associated antigens expressed by DCP-001; WT1, RHAMM and PRAME, with specific vaccine induced responses (VIR) in the majority of patients (17/20) and highest number of VIR per antigen observed in patients with MRD responses (Figure 2). Differences in immune profiles at baseline were observed; relapsed patients had a high number of CD8RO+ cells, in particular CD8 CM. On the contrary, MRD responders had the highest level of CD8RA+ cells at baseline, with CD8 EMRA cells at the highest level. Patients with stable MRD had comparable, but slightly lower CD8RO+ levels than MRD responders. Conclusion/discussion. Vaccination with DCP-001 resulted in durable MRD responses with five patients converting to MRD negativity, remaining relapse-free and alive during follow up. This translates in promising survival data with the median RFS for the full patient population not reached to date, at a median FU time of 15.4 months. Highest level of vaccine-induced T-cell responses to leukemia specific antigens were detected in MRD responders. Baseline levels of CD8 memory profiles were markedly different in MRD responders, which might be indicative that lower number of memory cells, and thus especially higher number of CD8 EMRA could reflect the ability to induce a tumor specific cytotoxic T-cell response after vaccination. Relapse on study was limited, with an estimated RFS at 6 months of 83.7%, which is higher than expected for this MRD+ AML patient population, which would be around 45% as shown for placebo-treated patients from a recent phase III study in a similar patient population (Quazar AML001). Immunotherapy with DCP-001 as AML maintenance therapy is safe and effective in triggering immune responses and converting patients from MRD positive to MRD negative, leading to promising relapse-free survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

Pencil Beam Scanning (PBS) Proton Therapy for Children Requiring Radiotherapy with Anesthesia (GA) for Pelvic Rhabdomyosarcoma (RMS)

<h3>Purpose/Objective(s)</h3> Radiotherapy (RT) for pediatric pelvic RMS presents unique challenges, particularly for young children who require GA during RT, for whom bladder/rectal filling can be particularly variable. PBS may reduce dose to OARs and risk of second malignancy vs. double scatter (DS) protons; however, the precision of PBS requires highly reproducible daily setup. This study was undertaken to describe use of PBS in patients requiring RT for pelvic RMS with daily GA. <h3>Materials/Methods</h3> Pts with RMS of pelvic soft tissues treated with PBS from 1/2013-6/2020 with GA were included in this IRB-approved retrospective analysis. PBS proton plans were developed for all. DS plans were generated for all, and photon (VMAT) backup plans for 9/11 pts. Statistical analyses used 2-sided Student's t-tests. <h3>Results</h3> 11 total pts, median age 2.4 y (R 9 m – 5.9 y), 6 male patients, all had fusion-negative RMS (10 group 3 disease; 1 recurrent bladder/vaginal wall). Primary site included bladder (1), prostate (6), uterus (2), and vagina (1). During simulation/daily treatments under GA, Foley catheter with bladder filling to 75% expected capacity was used for 10. Rectal balloon was used for 2; aggressive management of constipation to promote empty rectum was used for all. All pts had IGRT (daily kV +/- CT [6]). RT dose was 41.4 Gy after delayed primary excision (DPE) (3) and 50.4 Gy without (8). Of 10 pts with FU data, all were without evidence of disease at median FU 1.3 y (range 0.3 – 5.6 y). Acute G3 toxicities included anorexia (3), diarrhea (1), and dermatitis (1), with no G4+ toxicities. One pt developed late RT cystitis. Among pts treated to 50.4 Gy, mean bladder dose (p<0.05) and body V5 (p<0.001) were significantly lower for PBS vs. photons. Max bladder, rectum, and body doses were significantly lower for PBS vs. DS (p<0.05 for each). <h3>Conclusion</h3> PBS proton therapy for very young children with pelvic RMS demonstrates acceptable rates of local control and toxicity when delivered under GA with deliberate management of bladder/rectal filling. Integral dose is reduced with PBS vs. VMAT, and OAR doses are reduced with PBS vs. DS. PBS should be considered in future trials as a standard RT approach for pediatric pelvic RMS.

Predictors of Definitive Treatment Interruptions of Long-Course Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Introduction To identify predictors of definitive treatment interruptions (DTI) of the neoadjuvant long-course radiotherapy (LCRT) in locally advanced rectal cancer (LARC), and to determine their impact on clinical outcomes. Methods Patients with stage II-III LARC treated between 2009-2018 were retrospectively analyzed (n=101, median FU 49.5 months). Logistic regression models evaluated the impact of relevant clinical variables on grade 3 or greater (G3+) acute toxicity, definitive treatment interruption (DTI), pCR, and definitive ostomy (dOST) rates. The secondary outcomes were LRC, MFS, PFS, CSS, and OS. Results The incidences of grade 3 and 4 toxicities were 25.3%, and 1.1%, respectively. The most common G3+ toxicities were peri-anal dermatitis (14.7%) and diarrhea (7.4%), which were more frequent in females (p=0.040) and tumors close to the anal verge (p=0.019). In this study, 11 patients (10.9%) developed DTI, which was associated with these G3+ events (p<0.001). Resection occurred after 7.1 weeks (median, IQR:6.1-8.9). Downstaging occurred in 57.4% (17.8% pCR), 88% achieved negative margins and the dOST rate was 56.4%. The five-year LRC, MFS, PFS, CSS and OS were: 94.4%, 78.9%, 74.7%, 85.2% and 81.6%, respectively. DTI events did not impact any outcome. The factors associated with loco-regional failure were close/positive margins (p<0.001) and stage ypIII (p=0.002). Conclusions: Tumors close to the anal verge and female sex were associated with increased G3+ toxicity, which was predictive of DTI. The resultant partial/complete omission of the planned boost, however, dose did not increase the chance of LR. Further studies to clarify the benefit and optimal timing to deliver the boost are warranted, especially for positive margins.

The hemodynamic and prognostic impact of systolic pressure change during right ventricular ejection in patients with HFREF

Abstract Background and purpose The gold-standard method to evaluate right ventricular (RV) function in pulmonary hypertension (PH) relies on invasive pressure-volume loop (PV-loop) measurement of RV-pulmonary artery (PA) coupling defined as the ratio of end-systolic RV elastance to pulmonary arterial elastance (Ees/Ea). The normal RV PV-loop has a triangular shape with a peaking early systolic pressure (early-SP). With progression of PH the PV-loop changes from trapezoid to a rectangular and ultimately to a trapezoid shape. Along with these geometric changes, the ratio between early-SP and end-systolic pressure (ESP) decreases from &amp;gt;1 to &amp;lt;1 with a late systolic peaking of RV pressure. How all these changes relate to RV afterload, RV-PA coupling, non-invasive RV function, and prognosis in PH due to left heart disease is incomplete understood. Methods We analyzed and categorized the conductance catheter-derived single-beat RV PV-loops in 133 patients with HFREF (110 patients: a post-hoc analysis of the Magdeburg CRT Responder Trial, 23 from a local PV-L-derived CRT-optimization trial) according their shape (triangular, rectangular, trapezoid), and determined the early-SP/ESP ratio. Results Using multivariate linear regression analysis (adjusted for afterload parameter PVR, PA-compliance, PCWP, PAmean), only PCWP (beta=−0.17) and PA-compliance (beta=0.61) remained significant determinants of the early-SP/ESP ratio and PV-loop shape. In turn, early-SP/ESP ratio seems to be an important determinant of RV-PA coupling efficiency (Ees/Ea) of the RV to afterload (r=0.8, p&amp;lt;0.001). The association between early-SP/ESP ratio and Ees/Ea ratio was closer than Ees/Ea ratio to the other afterload parameters Ea (r=−0.7), PVR (r=−0.41), and PA-compliance (r=0.62). Furthermore, the early-SP/ESP ratio was significantly associated with parameters of non-invasive RV function such as TAPSE (r=0.67), FAC (r=0.76), RVEF (r=0.7), and the non-invasive RV-PA coupling parameter TAPSE/PASP (r=0.8) (all p&amp;lt;0.001). In cox regression analysis, the early-SP/ESP ratio was a strong indicator for long-term survival (median FU 4.2 years) (OR 0.025, CI 95% 0.007–0.09). Simple categorization of the RV PV-loop shapes into “triangular” (early-SP/ESP ratio &amp;gt;1.1, mean survival 7.7 years), “rectangular” (0.9–1.1, 6.4 years) and “trapezoid” (&amp;lt;0.9, 3.2 years) clearly differentiated long-term survival of HFREF patients (log rank, Chi square 50.1, p&amp;lt;0.001). Conclusion The early-SP/ESP ratio determines the shape of RV-PV-loops and is closely associated with predominately pulsatile PA load, RV-PA coupling capacity, RV function, and long-term prognosis of patients with HFREF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boston Scientific

Single ventricle dysfunction is the main trigger for late Fontan failure in adult patients

A substantial number of patients experiences late Fontan circulation failure. Previous concepts of Fontan failure implicate increasing pulmonary vascular resistance (PVR) as a key contributor to late circulatory failure. However, data to support this assumption are sparse. We sought to characterize hemodynamic findings in adult failing Fontan patients. We performed a bicentric retrospective cohort study in adult Fontan patients, identifying patients with Fontan failure. Patients were divided into systolic dysfunction (rEF) when ejection fraction (EF) < 40%, diastolic dysfunction (pEF) when EF ≥ 40% with systemic ventricular end-diastolic pressure ≥ 12 mmHg or elevated BNP level (> 200 pg/mL) and pulmonary hypertension (PH) when indexed pulmonary vascular resistance were elevated (≥ 2 WU*m 2 ). Hemodynamic, echocardiographic, and clinical data were recorded. Between 2000 and 2021, 55 adult patients were diagnosed with failing Fontan. Median age at diagnosis was 27 years (interquartile range (IQR), 22–30.7) i.e., 18.0 years [12.0–23.0] after Fontan surgery. The main hemodynamic cause of failing Fontan was the dysfunction of the systemic ventricle in 25 patients (45%), including 15 rEF and 10 pEF without additional hemodynamic lesions. PH was diagnosed in 6 (11%) patients and was isolated in 4 of them. Nine patients (16%) exhibited significant valvular dysfunction and 6 (11%) conduit stenosis. During a median FU of 5 years [1.25–12], Fontan failure-associated morbidity (33/55; 60%) and mortality (6/55, 11%) were substantial regardless of underlying hemodynamic lesions. Dysfunction of the systemic ventricle, systolic and/or diastolic, is frequent feature in late Fontan failure in adults, while increases in PVR were rarely observed. The intricate interplay between hemodynamic compromises in Fontan failure deserves further research to optimize treatment strategies and outcome.

Thoracic Endovascular Aortic Repair (TEVAR) First in Patients with Lower Limb Ischemia in Complicated Type B Aortic Dissection: Clinical Outcome and Morphology.

Acute Type B aortic dissection (TBAD) can cause organ malperfusion, e.g., lower limb ischemia (LLI). Thoracic endovascular aortic repair (TEVAR) represents the standard treatment for complicated TBAD; however, with respect to LLI, data is scant. The aim of this study was to investigate clinical and morphological outcomes in patients with complicated TBAD and LLI managed with a “TEVAR-first” policy. Between March 1997 and December 2021, 731 TEVAR-procedures were performed, including 106 TBAD-cases. Cases with TBAD + LLI were included in this retrospective analysis. Study endpoints were morphological/clinical success of TEVAR, regarding aortic and extremity-related outcome, including extremity-related adjunct procedures (erAP) during a median FU of 28.68 months. A total of 20/106 TBAD-cases (18.8%, 32–82 years, 7 women) presented with acute LLI (12/20 Rutherford class IIb/III). In 15/20 cases, true lumen-collapse (TLC) was present below the aortic bifurcation. In 16/20 cases, TEVAR alone resolved LLI. In the remaining four cases, erAP was necessary. A morphological analysis showed a relation between lower starting point and lesser extent of TLC and TEVAR success. No extremity-related reinterventions and only one major amputation was needed. The data strongly suggest that aTEVAR-first-strategy for treating TBAD with LLI is reasonable. Morphological parameters might be of importance to anticipate the failure of TEVAR alone.

S260: A MATCHED COMPARISON OF TISAGENLECLEUCEL AND AXICABTAGENE CILOLEUCEL CAR T CELLS IN RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: A REAL-LIFE LYSA STUDY FROM THE FRENCH DESCAR-T REGISTRY

Background: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In a previous propensity score matching (PSM) analysis (Bachy et al., ASH 2021) allowing for balanced comparison between axi-cel and tisa-cel outcomes, we reported on a prolonged progression-free survival (PFS) but a higher toxicity associated with axi-cel compared with tisa-cel. No OS difference was observed but the follow-up was short (6 months). Aims: We aim at reporting on PSM analysis with longer follow-up and with additionnal patients treated with axi-cel or tisa-cel. Methods: All patients treated in France with axi-cel or tisa-cel from the 1st July 2018 to the 1st October 2021 and included in the DESCAR-T registry were considered. Propensity score matching (PSM) was used to create a balanced covariate distribution between a cohort of patients treated with tisa-cel and a cohort of patients treated with axi-cel. An exhaustive list of covariates was used for PSM: age, sex, LDH level, C reactive protein (CRP), time between last treatment and infusion, Eastern Cooperative Oncology Group (ECOG) performance status (PS), Ann Arbor stage, number of prior lines of treatment before CAR-T, bridging and response to bridging, prior stem cell transplant (SCT) either autologous or allogeneic, bulk assessed at lymphodepletion, centre, histological diagnosis. PSM was performed considering a 1:1 matching without replacement and with optimal matching applying a calliper width of the propensity score set at 0.1. Inverse probability of treatment weighting (IPTW) was used as another approach to further validate PSM analysis. Results: 809 patients from 25 French centres with R/R DLBCL after at least 2 lines of previous therapy had a commercial CAR-T order with axi-cel or tisa-cel and were registered in DESCAR-T. Out of 809 patients with a CAR-T order, 60 were not infused due to progression or death between leukapheresis and lymphodepletion and 20 did not proceed to lymphodepletion for other reasons. Finally, 729 proceeded to lymphodepletion and CAR-T infusion. In the 1:1 matched population (N=418, 209 patients treated with tisa-cel and 209 patients treated with axi-cel), the best ORR/CRR was 66/42% versus 80/60% for patients treated with tisa-cel compared with axi-cel, respectively (P<0.001 for both ORR and CRR comparisons). After a median FU of 11.7 months (95% CI, 10.5-12.0 months) the 1-yr PFS was 33% for tisa-cel and 47% for axi-cel (HR=1.65, 95% CI 1.26-2.18, P=0.0003). OS was also significantly longer following axi-cel infusion than following tisa-cel infusion (1-yr OS 63% versus 49%; HR=1.58, 95% CI, 1.13-2.21; P=0.0072). Similar findings were found using IPTW statistical approach. Grade 1-2 CRS were significantly more frequent with axi-cel than tisa-cel (P=0.004) but no significant difference was observed for grade 3 or more CRS (9% versus 5% for tisa-cel and axi-cel respectively, P=0.130). Regarding ICANS, both all grades and severe (i.e. grade ≥3) ICANS were significantly more frequent with axi-cel than tisa-cel. 48% of patients experienced ICANS after axi-cel infusion compared to 22% after tisa-cel infusion. 29 patients (14%) presented a grade ≥3 ICANS with axi-cel compared with 6 (3%) only with tisa-cel. Image:Summary/Conclusion: In conclusion, our matched-comparison study supports a higher efficacy but also a higher toxicity of axi-cel compared with tisa-cel in third or more treatment line for R/R DLBCL.

EO2401, a novel microbiome-derived therapeutic vaccine for patients with adrenocortical carcinoma (ACC): Preliminary results of the SPENCER study.

4596 Background: In advanced ACC, no significant progress has been made since introduction of mitotane and cisplatin-based therapy. EO2401 (EO) was designed to activate existing commensal memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in ACC, IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This Phase 1/2 trial (NCT04187404) investigated EO + nivolumab (N) (EO + N = EN) in pts with ACC. Cohort 1 lead-in established safety of EN. Cohort 2 includes pts with metastatic ACC, with (C2a), or without (C2b) prior systemic therapy. EN was given 4 times q2 w, followed by boosters q4 w until PD (iRECIST). Results: 33 pts with ACC started study treatment: C2a 26 pts (58% 1; 42% 2 prior lines), C2b 7 pts. Median age 47; 24% men; ECOG 0/52%, 1/42%, 2/6%; 61% ≥2 organs involved by metastases (61% liver, 76% lung). EN was well tolerated. The combination safety profile was consistent with the profile of N monotherapy except for higher local administration site reactions (any erythema/pain/induration in 35% of pts). Overall (n = 33), best RECIST response was PR 12%, SD 24%, PD 45%, NE 18%; median PFS was 1.9 mo (range 0.4-7.6+); median survival not reached, and survival rate at 6-mo 63% (median FU 4.9 mo, range 0.9-12.0). Strong CD8 T cell ELISPOT responses against the vaccine peptides (9/9 pts) and cross-reactivity against targeted TAAs (8/8 evaluable pts) was observed. Tetramer staining of specific CD8 cells for all 3 peptides was detected in 7/8 tested. When investigated, positive staining against BIRC5 was detected as early as 4 w after the first vaccination. In C2a, a group of pts (n = 10) with SD at the first CT (incl. 4 pts with PR) seemed to fare well; all investigated tumor samples in this group showed a low level of TMB, low MSI, and low PDL1 expression. In contrast, 10 pts had PD &lt; 2mo and died &lt; 6mo. There was no correlation between clinical benefit and a large panel of cytokines/chemokines. However, post-hoc analysis identified several clinical factors (prior mitotane, ECOG ≤ 1, ACC 1st diagnosis &gt; 9 mo, max lesion ≤125 mm, ≤3 organs involved, lymphocytes ≤ grade 1) that excluded 90% of pts without benefit to EN. In the post-hoc selected group (n = 14) with median FU 6.9 mo (12 pts censored) the DCR was 64% (4 PR, 5 SD), 6-mo PFS was 42% and 6-mo survival rate 93%. Conclusions: EO2401 in combination with nivolumab was well tolerated and induced a specific immune response in all tested pts. In addition, efficacy was seen in a subpopulation of pts with ACC defined by clinical parameters in a post-hoc analysis. A randomized phase 2 study based on the findings of Cohort 2a is being planned. Clinical trial information: NCT04187404.

Tislelizumab, a PD-1 inhibitor for relapsed/refractory mature T/NK-cell neoplasms: Results from a phase 2 study.

7552 Background: Effective treatment choices for patients (pts) with relapsed/refractory (R/R) mature T/NK-cell neoplasms after failure of standard therapies are limited. Tislelizumab (TIS), a humanized anti-PD-1 mAb, demonstrated outstanding efficacy and favorable safety in pts with R/R classical Hodgkin lymphoma or solid tumors. We present safety and efficacy of the phase 2 study of TIS in pts with R/R mature T/NK-cell neoplasms. Methods: Pts were enrolled into 3 cohorts stratified by the type of T/NK-cell neoplasm to receive TIS 200 mg intravenously every 3 weeks until disease progression or intolerable toxicity. Eligible pts had ≥1 prior systemic therapy, disease progression during/after most recent therapy completion or refractory disease, ECOG ≤2, and life expectancy ≥6 mo. Primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DoR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS) in cohorts 1 and 2, and safety. Results: 77 pts were treated. Cohort 1: R/R extranodal NK/T-cell lymphoma (n = 22); cohort 2: R/R mature T-cell neoplasms (n = 44; 21 peripheral T-cell lymphoma not otherwise specified; 11 angioimmunoblastic T-cell lymphoma; 12 anaplastic large cell lymphoma); cohort 3: R/R cutaneous T-cell lymphomas (CTCL; stage ≥1B; n = 11; 8 mycosis fungoides and 3 Sézary syndrome). Of all pts, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% had ≥3 prior systemic regimens. Median treatment cycles for cohorts 1, 2, and 3 were 5 (range, 1-37), 4.5 (range, 1-38), and 17 (range, 3-25), respectively. Cohort 3 had promising efficacy (median follow-up [FU] 16.6 mo): ORR 45.5%; CR 9.1%; median DoR 11.3 mo (95% CI: 2.76-11.30); median PFS 16.8 mo; median OS not reached (NR). Modest efficacy was reported in cohort 1 (median FU 8.4 mo): ORR 31.8%; CR 18.2%; median DoR NR (95% CI: 2.66-not estimable [NE]); median PFS 2.7 mo; median OS 8.8 mo and also in cohort 2 (median FU 9.3 mo): ORR 20.5%; CR 9.1%; median DoR 8.2 mo (95% CI: 2.50-NE); median PFS 2.7 mo; median OS 13.3 mo. Most frequent adverse events (AEs) were pyrexia (32.5%), anemia (18.2%), arthralgia (18.2%), and diarrhea (15.6%); most frequent grade ≥3 AEs were anemia (7.8%), pneumonia (6.5%), and neutropenia (5.2%). Any grade immune-mediated AEs occurred in 22 (28.6%) pts, most frequently hypothyroidism (10.4%), hyperglycemia (5.2%), and rash (5.2%); and grade ≥3 in 4 (5.2%) pts (blood creatine phosphokinase increased, hepatitis, hypothyroidism, rash, and urticaria [1 pt each]). No treatment-related AEs led to death. Conclusions: TIS was well tolerated, achieving modest efficacy in R/R mature T/NK-cell neoplasms, with some long-lasting remissions particularly in CTCL. Further studies are warranted to determine the biologic features associated with response and explore optimal combination therapies. Clinical trial information: NCT03493451.