Prospective Multicenter Phase Research Articles

Treatment of newly diagnosed moderate or severe chronic graft-versus-host disease with prednisone and everolimus (PredEver first): a prospective multicenter phase IIA study

Although most patients with chronic graft-versus-host disease (cGVHD) show initial response to first-line therapy, long-term clinically meaningful success of first-line treatment remains rare. In a prospective multicentre phase II trial in 6 German centers, patients with newly diagnosed moderate or severe cGVHD received prednisone and everolimus for 12 months followed by a 1-year follow-up period. Primary endpoint was treatment success (TS) at 6 months defined as patient being alive, achieving PR or CR of cGVHD, having no relapse of underlying disease and requiring no secondary treatment for cGVHD. Of the 34 patients evaluable for efficacy, 19 (56%) had TS at 6 months with 22 and 52% of the patients in a CR and PR respectively. Overall 30 patients (88%) had a CR or PR as best response, nearly all responses (29/30) occurring within the first 6 weeks of treatment. The cumulative incidence of treatment failure at 1 year was 63%, corresponding to 37% TS. Predefined safety endpoint (thrombotic microangiopathy, pneumonitis, and avascular necrosis) were not observed in any patient. Addition of everolimus to prednisolone is well tolerated and may improve long-term treatment success. Larger studies are necessary to ascertain the possible role of everolimus in first-line treatment of cGVHD.

Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial

BackgroundMirtazapine blocks 5-hydroxytryptamine type (5-HT)2A, 5-HT2C, 5-HT3 and histamine H1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers. MethodsWe conducted a prospective, open‐label, single‐arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24–120 h). ResultsBetween July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24–120 h), overall (0–120 h), and acute periods (0–24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0. ConclusionsProphylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three‐drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA‐based regimen at AUC ≥ 4 mg/mL per minute.

End-of-treatment 18[F]-FDG PET can predict early progression in patients receiving bendamustine-rituximab for follicular lymphoma in first relapse: a prospective West Japan hematology Study Group (W-JHS) NHL01 trial.

Response determined by 18[F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)-CT after induction therapy can predict progression-free survival (PFS) in follicular lymphoma (FL). However, little prospective research has examined the significance of PET after second-line therapy. We conducted a prospective multicenter phase II trial (W-JHS NHL01) of bendamustine plus rituximab (BR) without rituximab maintenance for FL in first relapse. This study aimed to evaluate the usefulness of end-of-treatment (EOT)-PET for predicting PFS in FL patients in first relapse. EOT-PET examinations were performed between 6 and 8weeks from the start of the last BR cycle. The primary endpoint was 1-year PFS. Key secondary endpoints were overall response rate (ORR), complete response rate (CRR), and 1-year overall survival (OS). Seventy-five patients were enrolled, and 8 were excluded from analysis. ORR was 86.6% and CRR was 59.7%. One-year PFS was 88.9% (95% confidence interval [CI] 80.7-94.3%) and 1-year OS in 75 patients was 97.3% (95% CI 89.6-99.3%). One-year PFS was significantly inferior in EOT-PET-positive patients (n = 9) compared with PET-negative patients (n = 58) (77.8% vs. 93.1%; p = 0.02). We confirmed that EOT-PET after second-line BR therapy could predict early progression in FL patients in first relapse.

Artificial intelligence of imaging and clinical neurological data for predictive, preventive and personalized (P3) medicine for Parkinson Disease: The NeuroArtP3 protocol for a multi-center research study.

The burden of Parkinson Disease (PD) represents a key public health issue and it is essential to develop innovative and cost-effective approaches to promote sustainable diagnostic and therapeutic interventions. In this perspective the adoption of a P3 (predictive, preventive and personalized) medicine approach seems to be pivotal. The NeuroArtP3 (NET-2018-12366666) is a four-year multi-site project co-funded by the Italian Ministry of Health, bringing together clinical and computational centers operating in the field of neurology, including PD. The core objectives of the project are: i) to harmonize the collection of data across the participating centers, ii) to structure standardized disease-specific datasets and iii) to advance knowledge on disease's trajectories through machine learning analysis. The 4-years study combines two consecutive research components: i) a multi-center retrospective observational phase; ii) a multi-center prospective observational phase. The retrospective phase aims at collecting data of the patients admitted at the participating clinical centers. Whereas the prospective phase aims at collecting the same variables of the retrospective study in newly diagnosed patients who will be enrolled at the same centers. The participating clinical centers are the Provincial Health Services (APSS) of Trento (Italy) as the center responsible for the PD study and the IRCCS San Martino Hospital of Genoa (Italy) as the promoter center of the NeuroartP3 project. The computational centers responsible for data analysis are the Bruno Kessler Foundation of Trento (Italy) with TrentinoSalute4.0 -Competence Center for Digital Health of the Province of Trento (Italy) and the LISCOMPlab University of Genoa (Italy). The work behind this observational study protocol shows how it is possible and viable to systematize data collection procedures in order to feed research and to advance the implementation of a P3 approach into the clinical practice through the use of AI models.

Safety and performance of a synthetic sealant patch aimed to prevent postoperative pancreatic fistula after distal pancreatectomy (SHIELDS) – Prospective international multicenter phase II study

ObjectiveThe incidence for clinically relevant postoperative pancreatic fistulas (CR-POPF) in distal pancreatectomy (DP) ranges up to 25%. None of the available sealants significantly reduce CR-POPF. A new biodegradable sealant patch was able to reduce POPF and to achieve bleeding control in a preclinical porcine DP model. The aim of this first-in-human study was to assess the safety and performance of the sealant patch. MethodsIn this multicenter, single-arm study, 40 patients undergoing distal pancreatectomy were prospectively enrolled from 8 centers. Following surgical resection, the transection plane was closed according to the standard of care and manually covered with the sealant patch. As primary endpoint the incidence of CR-POPF up to 30-days postoperatively was evaluated. The secondary endpoints included the assessment of complications and device usability. ResultsAmong 40 patients after distal pancreatectomy, CR-POPF occurred in 7 (17.5%) up to postoperative day 30. No type C POPF was observed. There was no intraoperative bleeding observed after patch application. ConclusionThe results of this international phase II study demonstrate promising results of a new sealant patch regarding the rate of CR-POPF. Randomized studies are now needed to confirm the superiority of the current patch as compared to the best current practice.

Pre-surgical 68Ga-PSMA-11 PET for biochemical recurrence risk assessment: A surrogate of pelvic lymph node dissection? Follow-up analysis of a multicenter prospective phase 3 imaging trial.

285 Background: To compare the prognostic value of presurgical PSMA-PET and pelvic lymph nodes invasion (pN1) for biochemical recurrence (BCR) free-survival (FS) in patients with intermediate-risk to high-risk prostate cancer (PCa) treated with radical prostatectomy (RP) and pelvic lymph node dissection. Methods: This is a follow-up study of the surgery cohort included in the multicenter prospective phase 3 imaging trial (n=277; NCT03368547, NCT02611882, NCT02919111). Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. Local histopathology risk score (CAPRA-S (Cancer of the Prostate Risk Assessment) score without pN data), PSMA-PET extra-prostatic disease (N1/M1), and pN were used to assess risk of BCR. Patients were followed up after RP by the local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level ≥0.2 ng/ml after RP or an initiation of PCa specific secondary treatment (>6 months after surgery). Univariate, multivariate Cox model, and c-statistic index were performed to assess the prognostic value of PSMA-PET, LNI and its added value to Local histopathology risk score. Results: From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. Median follow-up from surgery was 32.4 (IQR 23.3-42.9) months. Ninety-one/240 BCR events (38%) were observed. PSMA-PET N1/M1 and pN1 were found in 41/240 (17%) and 67/240 (28%) patients respectively. Local histopathology risk score, PSMA-PET and pN were significant univariate predictors of BCR. Only Local histopathology risk score and PSMA PET were significant in multivariate analysis (HR [95% CI] 1.4 (1.2-1.5) p<0.0001) and (1.7 (1-2.9) p=0.03). Prognostic value of model combining local histopathology and PSMA-PET was not significantly different than model combining local histopathology and pN (c-statistic 0.74 (0.69-0.79) vs 0.73 (0.68-0.78); p= 0.69). In patient group with low-risk Local histopathology score and PSMA-PET N0-M0 only 4/109 (5%) were pN1. In patients with high-risk local histopathology score, a PSMA-PET N1/M1 was associated with a significant lower BCR-FS than a PSMA-PET N0-M0 (median survival (95% CI) 32.7 (14.9-NR) vs 8 (3.2-15.5) p= 0.001). pN1 was found in respectively 25/34 (74%) and 34/90 (38%). Conclusions: Combination of pre-surgical PSMA-PET and Local histopathology was not statistically different than the reference standard, i.e local histopathology and pN to predict BCR-FS. Interestingly rate of discrepancy with pN was low among patient with low histopathology risk and PSMA-PET (N0-M0) and patient with high histopathology risk and PSMA-PET (N1/M1). Clinical trial information: NCT03368547 , NCT02611882 , NCT02919111 .

A prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in JAPAN: ENSEMBLE-1 study.

123 Background: The short- and long-term prognosis of total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) is elucidated in the world. We evaluated the feasibility and safety of TNT for patients with LARC in Japan. Methods: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (6 courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. With a pCR rate threshold of 5%, an expected value of 28%, a one-sided significance level of 5%, and a power of at least 80%, the sample size required by the exact binomial distribution method would be ≥19 patients. Considering a few dropouts, ineligible cases, and patients in which resection was not performed, the target sample size was set to 27 patients. Results: Thirty patients (male, n=26; female, n=4; median age, 62.5 [44-74] years; cT [T2, n=1; T3, n=25; T4, n=4]; cN [N0, n=13; N1, n=13; N2, n=4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients at TME or restaging. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 21.8 (10.9-29.6) months. Recurrences in three patients (10.0%) were observed. In NOM, regrowth (28.6%) in two patients occurred, of which one patient was performed TME and one patient is on chemotherapy. Conclusions: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in JAPAN. Further long-term prognosis observation is required. A phase III trial, ENSEMBLE (NCT05646511/jRCTs031220342) is currently ongoing in JAPAN. Clinical trial information: jRCT s051200113 .

Treatment planning for patients with low rectal cancer in a multicenter prospective organ preservation study

BackgroundNon-surgical management of rectal cancer relies on (chemo)radiotherapy as the definitive treatment modality. This study reports and evaluates the clinical high dose radiotherapy treatment plans delivered to patients with low resectable rectal cancer in a Danish multicenter trial. MethodsThe Danish prospective multicenter phase II Watchful Waiting 2 trial (NCT02438839) investigated definitive chemoradiation for non-surgical management of low rectal cancer. Three Danish centers participated in the trial and committed to protocol-specified treatment planning and delivery requirements. The protocol specified a dose of 50.4 Gy in 28 fractions to the elective volume (CTV-/PTV-E) and a concomitant boost of 62 Gy in 28 fractions to the primary target volume (CTV-/PTV-T). ResultsThe trial included 108 patients, of which 106 treatment plans were available for retrospective analysis. Dose coverage planning goals for the main target structures were fulfilled for 94% of the treatment plans. However, large intercenter differences in doses to organs-at-risk (OARs) were seen, especially for the intestines. Five patients had a V60Gy>10 cm3 for the intestines and two patients for the bladder. ConclusionPrescribed planning goals for target coverage were fulfilled for 94% of the treatment plans, however analysis of OAR doses and volumes indicated intercenter variations. Dose escalation to 62 Gy (as a concomitant boost to the primary tumor) introduced no substantial high dose volumes (>60 Gy) to the bladder and intestines. The treatment planning goals may be used for future prospective evaluation of highdose radiotherapy for organ preservation for low rectal cancer.

Intravenous lidocaine for refractory pain in patients with pancreatic ductal adenocarcinoma and chronic pancreatitis (LIDOPAN): a multicenter prospective non-randomized phase II trial

Intravenous lidocaine for refractory pain in patients with pancreatic ductal adenocarcinoma and chronic pancreatitis (LIDOPAN): a multicenter prospective non-randomized phase II trial

Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial.

DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency. This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline]. A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for BRCA2 (n = 5), CDK12 (n = 3), ATM (n = 3) CHEK2 (n = 2), CHEK1 (n = 1), and BRCA1 (n = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event. The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations. NCT03652493, EudraCT ID number 2017-004764-35.

Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial.

Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Endoscopic full-thickness resection for gastric submucosal tumors: Japanese multicenter prospective study.

Early gastric cancer endoscopic resection (ER) is prominent in Japan. However, evidence regarding ER of gastric submucosal tumors (SMT) is limited. This prospective multicenter phase II study investigated the efficacy and safety of endoscopic full-thickness resection (EFTR) for gastric SMT. Endoscopic full-thickness resection indication for gastric SMT was 11-30 mm, histologically proven or clinically suspicious (irregular margin, increasing size, or internal heterogeneity) gastrointestinal stromal tumors (GIST), with no ulceration and intraluminal growth type. The primary end-point was the complete ER (ER0) rate, with a sample size of 42. We enrolled 46 patients with 46 lesions between September 2020 and May 2023 at seven Japanese institutions. The mean ± SD (range) endoscopic tumor size was 18.8 ± 4.5 (11-28) mm. The tumor resection and defect closure times were 54 ± 26 (22-125) min and 33 ± 28 (12-186) min, respectively. A 100% ER0 was achieved in all 46 patients. The EFTR procedure was accomplished in all patients without surgical intervention. One patient had delayed perforation and was managed endoscopically. GIST accounted for 76% (n = 35) of the cases. R0, R1, and RX rates were 33 (77%), 3 (6.5%), and 7 (15%), respectively. Endoscopic full-thickness resection for gastric SMT of 11-30 mm is efficacious. It warrants further validation in a large-scale cohort study to determine the long-term outcome of this treatment for patients with gastric GIST.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

FLT3 Ligand Kinetic Profile Predicts Response to Treatment and Event-Free Survival (EFS) in Adults with High-Risk MDS/CMML Receiving CPX-351: A GFM Study

Background: Our group recently reported, in a prospective multicentre phase 2 study of 31 patients with higher-risk (HR)-MDS or CMML receiving CPX-351 as first-line induction treatment 87% of overall responses (including 64.5% of CR/ CR according to ELN2017 criteria), and 93.5% of the patients could be bridged to transplant (GFM-CPX MDS trial, Peterlin et al. Lancet Haematol 2023). We had also previously reported, in AML, that the soluble forms of FLT3 ligand (FL) and IL6 could be prognostic factors of refractoriness to chemotherapy and overall survival (OS) (Peterlin et al. Cancer Medicine, 2021). A secondary objective of the GFM-CPX MDS trial was to assess the prognostic value of these two cytokines in HR-MDS/CMML receiving CPX-351. Methods: All patients included in the GFM-CPX MDS trial (clinicaltrials.gov#NCT04273802), induction chemotherapy with CPX-351 (44 mg Daunorubicin/100 mg Aracytine/m 2 on days 1, 3, and 5) also consented for the present biological FLAM-MDS sub-study. Using a new cytokine multiplex assay from Milliplex (MILLIPLEX®), FL levels (expressed in pg/mL) were evaluated on Day (D) 1, D8, D15 and D22 of the first cycle of induction; IL-6 (expressed in pg/mL) and CRP (known to be correlated with IL6, expressed in mg/L, normal value 0-5) levels were evaluated on D1 and D22 only. Patients who failed to achieve response (CR or CRi or MLFS, ELN2017 criteria) after the first induction cycle could receive a second one. The impact on CR/CRi rate after one cycle of CPX-351, OS and EFS of FL, IL-6 and CRP dosages and their kinetic profile during this first cycle were studied. Results: Dosages could be performed in 28 of the 31 patients included ( Table 1). Overall response (CR+CRi+MLFS) after cycle 1 was achieved in 24 (87%, MLFS n=7, CR+CRi n=17) patients; 3/4 non-responders received a second induction (1 achieved CR). Allograft was performed in 26/28 (93%). With a median follow-up of 18 months for surviving patients, 1y and 18-month OS were 79% and 75%, respectively. 1y and 18-month EFS were both 76%, respectively. Achieving CR/CRi versus MLFS/non-response was associated with better 1-y EFS (71% (52-96) vs 27% (10-72), p=0.009) but not 1-y OS (82% (66-100) vs 73% (51-100), p=0.8). Median (range) FL levels were 4.5 [0- 33.5] on D1, 74.1 [4.1-296.6] at D8, 326.6 [47.4-678] at D15 and 381.3 [4.4-800.1] at D22. As in AML (Peterlin et al, 2021), patients could be categorized according to three FLc kinetic profiles: i) sustained increase from D 1 to 22 (FLI group n=17, 61% of the cohort), ii) increase from D 1 to 15, then decrease on D 22 (FLD group, n=9, 32% of the cohort) and iii) persistent low levels (<100 pg/mL from D 1 to 22, FLL group, n=2, 7% of the cohort). Median (range) IL6 levels were 11 (0-587.8) on D1 and 179.8 (0-531) on D22. Increase of IL6 levels between D1 and D22 was observed in 19 patients (68%) and decrease in 7, while 2 patients had no IL6 detectable at either times. Finally, median (range) CRP levels were 2.3 (0-108) on D1 and 40.5 (7.2-323) on D22. Increase of CRP level was observed in most patients between D1 and D22 (n=25, 96%). There was no correlation between IL6 and CRP levels on D1 (p=0.64) or D22 (p=0.48). CR/CR rates, 1-y OS and EFS were not correlated with FL levels (< vs > median) at the 4 time points considered. However, a FLD kinetic profile was significantly associated with higher CR/CRi rates (100% vs FLI 47% vs FLL 50%, p=0.002) and 1-y EFS (78% (55-100) vs FLI 47% (28-78) vs FLL: 0%, p=0.003), Figure 1). 1-y OS was similar between the 3 FL kinetic profile groups (FLD: 89% (71-100) vs FLI 76% (59-100) vs FLL 50% (13-100), p=0.7)). In multivariate analysis, taking into account age, gender, R-IPSS and the FL kinetic profile during cycle 1 of CPX-351, a FLD kinetic profile was the only factor associated with higher CR/CRi rate (OR: 24.2, 95%CI: 2.4-3278, p=0.004) and better EFS (OR: 21.91; 95%CI: 2.47-194.77, p=0.006). Levels and kinetic profiles of IL6 and CRP had no impact on CR/CRi rates, OS and EFS. Conclusion: As in AML, FL kinetic profile predicts response and survival in HR-MDS/CMML. A FLD kinetic profile was the only factor independently associated with higher CR/CRi rates and better EFS. These results have to be confirmed on larger cohorts. Other treatment approaches may be of interest in patient with a non FLD profile.

Use of inclisiran in a real-world setting: results from the italian Cholinet registry

Abstract Background Real world data indicate that PCSK9 inhibitors (PCSK9i) are started in very high-risk patients at higher LDL cholesterol (LDL-C) values than those recommended by guidelines. Different reimbursement rules may have an impact on access to injectable therapy among different countries. In Italy, reimbursement of injectable lipid lowering therapies (LLT) (i.e., PCSK9i and inclisiran) has been recently allowed for very high risk patients with LDL-C levels >70 mg/dl while on statin/ezetimibe LLT or statin intolerant, and, thereafter, inclisiran has been introduced in clinical practice. No data are available on inclisiran real world use in Italy and on the impact of new reimbursement rules on patient access to inclisiran. Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence, as well characteristics of very high risk patients with atherosclerotic CV disease (ASCVD) and/or familial hypercholesterolemia (FH) receiving inclisiran. Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran due to elevated LDL-C levels in Italian centers as part of their medical therapy. Baseline characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at follow-up. Results We enrolled 105 patients (14% FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. 37 of them reached 3 months follow up (i.e., time of first reinjection dose) and none of them missed the reinjection dose. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% reduction). In patients with ASCVD median LDL-C at baseline was 90.4 mg/dL and 44.4 mg/dl at follow-up (51% reduction). In patients with FH median LDL-C at baseline was 177.4 mg/dL and 109.5 mg/dL at follow-up (38% reduction). Of 105 patients enrolled, 92 patients (88%) were on LLT. Heterogeneity was found on the LDL-C reduction across our cohort (Figure 1) (Shapiro-Wilk test p<0.05) that appeared to be influenced by background LLT (Kruskal-Wallis rank for previous PCSK9i exposure p=0.0028, for background LLT p=0.0435) (Figure 2), but not by baseline LDL-C levels (ANOVA p=0.06). LDL-C target was achieved in 21 (66%) of 32 patients receiving background LLT and in 2 (40%) of 5 patients who did not. No patient reported side effects. Conclusion These preliminary results from the Cholinet registry show that, in a context of facilitated reimbursement access, inclisiran is introduced at substantially lower baseline LDL-C values than previously reported for PCSK9i, reflecting a favorable change in clinical practice. Inclisiran effectively and safely reduces LDL-C in patients with ASCVD or FH, with some etherogeneity that was associated with background LLT.Kernel density plot, LDL-C % reductionStratified Kernel density plot

Efficacy and safety of inclisiran in real world practice: insights from the Cholinet registry

Abstract Background Inclisiran has been recently introduced in clinical practice. Thus, efficacy and safety data from real world settings are scarce. In Italy, reimbursement of inclisiran has been recently introduced for very high cardiovascular (CV) risk patients with LDL cholesterol (LDL-C) >70 mg/dl on statin/ezetimibe background lipid lowering therapy (LLT). Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence of inclisiran, and clinician’s behavior on LLT in very high CV risk patients with atherosclerotic CV disease and/or familial hypercholesterolemia (FH). Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran in Italian centers as part of their optimal medical therapy. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and in subsequent follow-up. Background therapy was assessed to evaluate treatment withdrawal, reduction of doses or any change from baseline during follow up. Results We enrolled 105 patients (14% with FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. Data on follow-up at 3 months (i.e., time of first reinjection dose) were available for 37 of them. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% mean reduction, 47,8 mg/dl absolute median reduction). None of the 37 patients reaching 3 months follow up missed the reinjection dose administration. Of 105 patients enrolled, 92 patients (88%) were on LLT, of them 16 (17%) were on ezetimibe alone, 11 (12%) on statin alone and 65 (71%) on a statin and ezetimibe combination. Of the enrolled patients, 6 (6%) were previously treated with evolocumab and 4 (4%) with alirocumab. At the end of the observation period, of the 37 patients with a follow-up, 18 (49%) did not change background LLT. Of 19 patients changing background LLT, 3 withdrew therapy (16%) and 16 (84%) reduced dose or changed type of LLT. Among patients evaluated at 3 months follow up, 23 patients (62%) achieved their target LDL-C (Figure 1), of them 21 (91%) were on LLT (Figure 2). No adverse drug reactions were reported. Conclusion These preliminary findings from the Cholinet Italian registry show that inclisiran effectively reduces (49%) LDL-C in real world settings, with no patients missing the first reinjection dose. Yet, concomitant LLT was reduced or discontinued in 51% of patients. Target LDL-C was achieved in 23 out of 37 patients, 21 of them receiving LLT background therapy. Thus, combination of oral therapy and inclisiran is needed in the majority of very high CV risk patients to achieve LDL target, and use of inclisiran should not prompt discontinuation or reduction of concomitant LLT.LLT in patient achieving LDL-C targetLDL-C target % by LLT

Abstract 14234: Fast Track Use of PCSK9i in Acute Coronary Syndromes in Real World Practice. Insights From the AT-TARGET-IT Registry

Introduction: In patients with recent acute coronary syndrome (ACS), PCSK9 inhibitors (PCSK9i), alirocumab and evolocumab, intensively decrease LDL-C and determine reduction of ischemic events. Yet, scant data are available on the initiation of PCSK9i in ACS patients in real-world setting. Aim: AT-TARGET-IT is an Italian multicenter prospective phase 4 registry involving 23 centers, designed to assess efficacy, safety and adherence of PCSK9i, as well as clinician’s behavior on lipid lowering therapies (LLT) in patients at very high CV risk. Aim of the current analysis is to report efficacy and safety in patients suffering ACS who received early prescription of PCSK9i during hospital stay, according to national reimbursement rules. Methods: From March 2020 through May 2023, we enrolled patients receiving PCSK9i as part of their optimal medical therapy. Clinical, laboratory and demographic characteristics and concomitant therapies were recorded at the time of first prescription and in subsequent follow-up. Results: We report 405 patients (22% female, age 61 years, 60% chronic coronary syndromes). Median LDL-C was 142 mg/dL at hospital admission, reached 45 mg/dL at first control (time 37 days, 67% reduction, 97 mg/dl absolute reduction) and remained unchanged at latest lipid control (time 11 months, 66% reduction, 94 mg/dl absolute reduction). Of 405 patients enrolled, 252 patients (62%) were receiving LLT at time of hospital admission, of them 91 (36%) were on ezetimibe, 48 (19%) on statin and 113 (45%) were on a statin and ezetimibe combination. LDL-C target according to the ESC guidelines was reached in 272 patients (67%), with differences based on LLT (Figure 1-A). Also LDL-C percentage reduction was influenced by background LLT (Figure 1-B). No serious adverse reactions were reported. Conclusions: Early PCSK9i administration effectively reduces LDL-C in ACS patients in the real-world setting. However, concomitant LLT is needed to optimize early LDL.values.

Mega-Dose Decitabine Intensified Regimen Is More Effective at Eliminating Pre-HSCT Measurable Residual Disease Compared to the Bu/Cy Regimen: A Multicenter Prospective Phase II Study

Background: Acute myeloid leukemia (AML) patients with high-risk pre-HSCT measurable residual disease (MRD, KMT2A-r, etc.) have a high relapse rate (>50%) even after allogeneic hematopoietic stem cell transplantation(allo-HSCT). In 2018, we developed two multi-institutional, single-arm, prospective phase II trials, to investigate the efficacy and safety of a novel intensified conditioning with “Mega-Dose 400mg/m 2” decitabine following allo-HSCT for high-risk MRD AML (NCT03793517). Method： Inclusion: 1) Detectable pre-HSCT MRD detected by recurrent genetic abnormalities (KMT2A-r, DEK, etc.) in ELN adverse-risk AML; or high-level pre-HSCT MRD in all risk groups, defined as the reduction of recurrent genetic abnormalities ≤1 log compared to initial diagnosis (RUNX1:RUNX1T1, etc.); 2) Age≥18; no HSCT history, available donor; ECOG 0-2, HCT-CI 0-3. Uniform conditioning regimen: intravenous decitabine (200mg/m 2/day) on days-12, -11, intravenous cytarabine+ busulfan+ cyclophosphamide (Bu/Cy) on days -10 to -2 (Blood. 2015;125(25):3956-62). The primary endpoint was cumulative incidence of relapse (CIR). Competing risk analysis and time-dependent Cox model were constructed in R software 4.21. Contemporary MRD+ AML patients with the same recurrent genetic abnormalities following Bu/Cy regimen or relapsed/refractory AML patients following 400mg/m 2 decitabine regimen (NCT03799224) were enrolled as nest-control to compare the post-HSCT kinetics of recurrent genetic abnormalities. Results: Between Dec 2018-Feb 2023, twenty-one patients received allo-HSCT from HLA-matched siblings (n=2), and haploidentical donors (n=19), including 13 patients with KMT2A-r genes. Median follow-up was 19 (4.6-58) months after HSCT. The cumulative 30-day neutrophil (median 13 days) was 100.0% and 100-day platelet engraftment and 95.2% (median 21 days); all patients reached negative MRD by flow cytometry after HSCT. This conditioning regimen was well tolerated without irreversible grade III-IV toxicity peri-engraftment. Primary endpoint: 2-year CIR was 5.6% (95%CI: 0.3-23.3). Secondary endpoint: 2-year NRM was 4.8% (0.3-20.2); 2-year LFS was 89.6% (77-100); 2-year OS was 89.3% (76.2-100). The median fold reductions (log10) of leukemia burden with recurrent genetic abnormalities were 3.6 (range 1.3-5.1) one month after HSCT (Figure). Conclusion: Compared to Bu/Cy regimen, “Mega-Dose” decitabine (400mg/m2) is a novel conditioning regimen with improved efficacy to eradicate pre-HSCT MRD and reduce post-HSCT relapse.

High-Dose Methotrexate, Ibrutinib and Temozolomide (MIT) for the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma: A Multi-Center Prospective Phase II Study

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with poor survival. Genetic alterations often occur in the chronic active B-cell receptor signaling which mediate the response to BTK inhibition (BTKi) in PCNSL. However, the efficacy of traditional high-dose methotrexate-based regimen as a first-line treatment was suboptimal with a short effective remission time and low response rate. Therefore, we initiated this phase II trial to investigate the efficacy of novel induction combination of high-dose methotrexate (HD-MTX) plus ibrutinib and temozolomide (MIT), in the treatment of newly diagnosed PCNSL for the first time (ClinicalTrials.gov identifier: NCT04514393). Methods: Patients aged 18-75 years, newly diagnosed PCNSL and at least one measurable or evaluable lesion were enrolled. The MIT induction treatment included six cycles of HD-MTX (3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients < 65 years) or daily ibrutinib maintenance (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of MIT treatment. The primary objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment. The safety profile of MIT was also investigated. At the same time, next generation sequencing (NGS) of baseline tissues and dynamic monitoring with CSF/ plasma ctDNA were performed by Nanjing Geneseeq Technology Inc. Results: Between July 2021 and October 2022, thirty-three patients were enrolled in this open-label, multi-center phase II prospective clinical study. The median age was 56 years (range: 27-75) and 17 of them were male. Eye involvement occurred in 5 patients (15%). Twenty-five patients (76%) had multiple cerebral lesions. The best ORR was 94% and complete response rate was 73%. The median follow-up was 17.5 months (range: 5.8-21.3 months) for survivors. Twenty-three patients underwent ibrutinib maintenance after 6 cycles of induction therapy. The swimmer plot of the 33 patients was shown in Figure 1. The 1-year progression-free survival was 66.4% (95%CI: 58.1-74.7%) and overall survival was 90.5% (95%CI: 85.2-95.8%) (Figure 2). Treatment-related toxicities were acceptable, with grade 3-4 neutropenia occurring in 9%, thrombocytopenia in 6%, subdural hematoma (SH) in 6%, and atrial fibrillation in 3%. The 2 patients with SH recovered following discontinuation of ibrutinib. No fungal infections and treatment-related deaths were observed. NGS of Tissue/CSF was tested in 30 patients, 19 (63%) of whom were classified as MCD subtype, 2 (7%) as BN2 subtype. The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 75.9% and 65.5% of the entire cohort followed by BTG2 (55.2%) and CD79B (51.7%). Patients with dynamic CSF ctDNA monitoring during MIT treatment were analyzed (Figure 1). The consistence of ctDNA clearance in CSF/plasma samples and imaging complete remission was observed. Patients with clearance of ctDNA in the CSF after 2 cycles of MIT treatment achieved better PFS. Conclusions: The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival. Disclosures No relevant conflicts of interest to declare.

A Prospective Multicenter Phase II Study of Orelabrutinib-Lenalidomide-Rituximab (OLR) in Patients with Untreated Mantle Cell Lymphoma (MCL) in China (POLARIS Study): Preliminary Analysis on Efficacy, Safety, Mutation Spectrum and Impact of Mutation Profiling on Treatment Responses

Background: Recently, the first-line treatment of MCL has been continuously evolving with the introduction of targeted agents and chemo-free regimens. It is well-known that bruton's tyrosine kinase (BTK) inhibitors were effective with MCL patients (pts). Orelabrutinib (O), a novel highly selective BTK inhibitor, has shown high response rates and good tolerability in R/R MCL (Song et al. Blood. 2020). Besides, O combined with rituximab (R) could preserve NK cell mediated ADCC induced by R and enhance the apoptosis of tumor (Yu et al. Mol Ther Oncolytics. 2021). Thus, we hypothesized that OLR would exhibit synergistic antitumor activity in MCL and improve the depth and durability of responses. Here, we reported the preliminary data on efficacy, safety, and mutation spectrum of OLR regimen in untreated MCL from the POLARIS study (NCT05076097). Methods: Pts ≥18 years with untreated MCL were enrolled in this prospective, multicenter, single-arm phase 2 study. All pts received OLR-induction therapy on a 28-day cycle for 6 cycles (O, 150 mg/d; L, 15 mg on days 1-21, then 20 mg of cycles 2-6 if tolerated or 10 mg if not tolerated; R, 375 mg/m 2 on days 1, 8, 15, 22, then day 1 of cycles 3, 5), followed by OLR-maintenance therapy for up to 18 cycles. Primary endpoint was complete response rate (CRR) after 6 cycles of induction treatment. Secondary endpoints included overall response rate (ORR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoint was to explore the prognostic value of detecting peripheral blood (PB) ctDNA by NGS. Results: As of July 10, 2023,a total of 28 pts (male, 89.3%; median age, 60.0 y [range, 53.0-64.5]) were enrolled. Baseline characteristics included 96.4% Eastern Cooperative Oncology Group performance status of 0-1, 82.1% stage III-IV disease, 57.1% Ki67 index (≥30%), 75.0% low-risk MIPI scores, 42.9% bone marrow involvement, and 60.7% maximum lesion diameter of ≥5 cm. Twenty-one pts (75.0%) who have completed 6 cycles of induction therapy were evaluable for response, 16 (76.2%) had a complete response (CR) and 5 (23.8%) had a partial response (PR), with an ORR of 100% ( Figure 1). In addition, 18 of 21 pts were available for minimal residual disease (MRD) analysis, and PB-MRD and bone marrow MRD (BM-MRD) of the 18 pts were negative. The results of CRR were reported across different subgroups stratified by Ki67 index (<30% vs. ≥30%, 66.7% and 83.3%), MIPI scores (low vs. intermediate, 81.3% and 60.0%), maximum lesion diameter (<5 cm vs. ≥5 cm, 87.5% and 69.2%), and bone marrow involvement (yes vs. no, 83.3% and 73.3%). With a median follow-up of 11.0 months, the median TTR was 3.0 months (range, 2.8-3.4). Median DOR and median PFS were not reached, with the estimated 12-month DOR rate and PFS rate of 90.9% and 92.3%, respectively. Mutationalspectrum (475 panels) was determined in 23 pts. The spectrum of gene mutations is depicted by PB samples and tissue samples at baseline in Figure 2. The most common mutated genes in tissues samples were: ATM (48%), KMT2D (43%), CCND1 (17%), SMARCA4(17%), ARID2 (13%), BCOR (13%), BIRC3 (13%), NFKBIE (13%), NOTCH1 (13%), ACTB (9%), CDK12 (9%), FANCC(9%),FAT1(9%),KLF2(9%),MEF2B(9%),MET(9%),SETD2(9%), TP53 (13%),TERT(9%). The most common mutated genes in PB samples were: ATM (48%), KMT2D (39%), DNMT3A (17%), BIRC3 (13%), CCND1 (13%), TP53 (13%), BCOR (9%), CARD11 (9%), CBLB (9%), CRYBG1 (9%), FAT1(9%), NOTCH1 (9%), GRIN2A (9%), KDM5A (9%), KLHL6(9%), KRAS (9%), MAP3K14 (9%). For all gene mutations, 75.4% (43/57) detected in tissue were also found in PB samples. Further, more additional mutated genes can be detected in plasma. Meanwhile, 4 of 23 pts had a PR, 1 of 4 had multiple gene mutations in PB samples, including BTK and TP53. This suggests that ctDNA detection may potentially predict that these gene mutations are associated with depth of remission. Twenty-six (92.9%) pts experienced adverse events (AEs). The most common AEs (any grades, ≥3 grades) were neutropenia (64.3%, 39.3%), leukopenia (60.7%, 14.3%), thrombocytopenia (35.7%, 7.1%), lymphopenia (35.7%, 3.6%), and COVID-19 infection (28.6%, 7.1%). At the time of data cut-off, 26 pts remained on study. No deaths were observed. Conclusions: The preliminary findings show that the OLR exerted synergistic antitumor activity, with manageable toxicity in untreated MCL. Detection of PB ctDNA by NGS method may help to predict prognosis.