Longer Follow-up Data Research Articles

Comparative analysis of first-line therapy with fruquintinib plus chemotherapy versus standard therapy in advanced metastatic colorectal cancer (mCRC): A prospective cohort study compared with propensity score matching (PSM) cohort.

3591 Background: We have previously reported that fruquintinib plus mFOLFOX6/FOLFIRI as the first-line therapy followed by fruquintinib plus capecitabine maintenance (FRU regimens) for advanced mCRC patients (pts) showed durable response and a favorable safety profile in this prospective, open-label, multicenter, single-arm phase 2 study (NCT05004441). We retrospectively collected matching data of standard therapy (STD regimens: bevacizumab/cetuximab plus chemotherapy) as the first-line treatment to compare with longer follow-up data in this study. Methods: Pts diagnosed with unresectable or metastatic CRC pts excluded BRAF mutations (Mut) were enrolled to receive FRU regimens. We collected retrospective data that pts who met our eligibility criteria receiving STD regimens as historical control data. PSM was performed to adjust potential confounders between two regimens. PSM was conducted on the basis of 4 clinically relevant variables (tumor location, RAS/BRAF status, liver metastasis). Efficacy was recorded and compared. Safety from FRU regimens was calculated and reported as well. Results: From Jul 22, 2021 to May 30, 2023, 43 pts were enrolled (median age 57 [range: 37-74], 27 male, 25 harboring RAS Mut, 26 with liver metastases) in FRU regimens. We retrospectively collected 63 pts received STD regimens with 38% (24/63) RAS Mut. There was no significant difference in the baseline between two regimens. Up to Jan 15, 2024, before applying the PSM, pts received FRU regimens were benefit with a higher ORR than STD regimens (83.33% vs 61.90%, p=0.018, OR=3.077, 95%CI: 1.181-8.017), especially RAS Mut pts (87.50% vs 58.33%, p=0.051). The median PFS was 16.76 mo (95%CI 12.25-18.6) in FRU regimens, which was significantly longer than 10.38 mo of STD regimens (p=0.0115). Favorable PFS was observed in RAS Mut pts received FRU regimens compared with STD regimens (14.16 mo vs 10.48 mo, p=0.1635). After 1:1.5 PMS, pts with FRU regimens showed a significantly improvement in median PFS compared with STD regimens (15.9mo vs 11.3mo, p=0.020, HR=0.472, 95%CI: 0.251-0.889). Safety profile exhibited the FRU regimens was tolerable and main TEAEs were grade 1/2. Most common grade 3/4 TEAEs were neutrophil count decreased (18.60%), leukopenia (16.28%) and lymphocytopenia (6.98%). Only one serious AE reported with gastric perforation recovered after non-operative therapy. Conclusions: The fruquintinib combination regimens as a first-line therapy for pts with mCRC significantly improved median PFS compared to standard treatment. Similar to the primary analysis, the safety profile was generally manageable with longer duration of treatment exposure. Fruquintinib combined with mFOLFOX6/FOLFIRI might be a more promising treatment option as first-line therapy for mCRC pts. Clinical trial information: NCT05004441 .

Tumour necrosis is a valuable histopathological prognostic parameter in melanomas of the vulva and vagina

Vulvar and vaginal melanomas (VVMs) are rare and aggressive malignancies with limited prognostic models available and there is no standard reporting protocol. VVMs were selected from six tertiary Canadian hospitals from 2000-2021, resected from patients aged ≥18 years, with 6 months or longer follow-up data, and confirmation of melanocytic differentiation by at least two immunohistochemical markers. Cases were reviewed by pathologists to identify histological biomarkers. Survival outcomes were tested with Kaplan-Meier log-rank, univariate Cox, and multivariate Cox regression. There were 79 VVMs with median follow-up at 26 months. Univariate analysis revealed that tumour necrosis, tumour ulceration, positive lymph nodes, and metastasis at diagnosis were significantly associated with disease-specific mortality, progression, and metastasis. Multivariate analysis identified tumour necrosis as an independent prognostic factor for disease-specific mortality (HR 4.803, 95% CI 1.954-11.803, p<0.001), progression (HR 2.676, 95% CI 1.403-5.102, p=0.003), and time-to-metastasis for non-metastatic patients at diagnosis (HR 3.761, 95%CI 1.678-8.431, p=0.001). Kaplan-Meier survival analyses demonstrated that tumour necrosis was a poor prognostic factor for disease-specific, progression-free, and metastasis-free survival (p<0.001 for all comparisons). Vaginal melanomas displayed decreased survival compared to vulvar or clitoral melanomas. This study identifies tumour necrosis as an independent prognostic factor for VVMs. Vaginal melanomas specifically showed worse survival outcomes compared to vulvar or clitoral melanomas, consistent with previously reported findings in the literature, emphasising the importance of differentiating between these primary tumour epicentres for prognostication and treatment planning in the care of genital melanoma patients.

Magnetic resonance-guided focused ultrasound unilateral thalamotomy for medically refractory essential tremor: 3-year follow-up data.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy of the ventralis intermediate (Vim) nucleus is an "incisionless" treatment for medically refractory essential tremor (ET). We present data on 49 consecutive cases of MRgFUS Vim thalamotomy followed-up for 3 years and review the literature on studies with longer follow-up data. A retrospective chart review of patients who underwent MRgFUS thalamotomy (January 2018-December 2020) at our institution was performed. Clinical Rating Scale for Tremor (CRST) and Quality of Life in Essential Tremor (QUEST) scores were obtained pre-operatively and at each follow-up with an assessment of side effects. Patients had post-operative magnetic resonance imaging within 24 h and at 1 month to figure out lesion location, size, and extent. The results of studies with follow-up ≥3 years were summarized through a literature review. The CRST total (baseline: 58.6 ± 17.1, 3-year: 40.8 ± 18.0) and subscale scores (A + B, baseline: 23.5 ± 6.3, 3-year: 12.8 ± 7.9; C, baseline: 12.7 ± 4.3, 3-year: 5.8 ± 3.9) and the QUEST score (baseline: 38.0 ± 14.8, 3-year: 18.7 ± 13.3) showed significant improvement that was stable during the 3-year follow-up. Three patients reported tremor recurrence and two were satisfactorily retreated. Side effects were reported by 44% of patients (severe: 4%, mild and transient: 40%). The improvement in tremor and quality of life in our cohort was consistent with the literature. We confirmed the effectiveness and safety of MRgFUS Vim thalamotomy in medically refractory ET up to 3 years.

Primary Pancreatic GIST - A-Single Centre Case Series and Systematic Review of Literature.

GISTs arising from organs outside GI tract are defined as extragastrointestinal GISTs (EGIST). The majority of EGISTs arise from small intestinal mesentry, mesocolon, omentum, retroperitoneum, abdominal wall, liver and pancreas with pancreas comprising less than 5% of it. Due to limited data, it is unknown if the results of GIST can be generalised for EGISTs. We thereby present the largest single-centre case series of primary pancreatic GIST so far with review of existing literature. A total of 9 patients of primary pancreatic GIST were treated at our institute from September 2016 to February 2023. After literature search for all studies published before February 2023, 51 articles including 57 patients were identified. Their clinicopathological data and survival analysis were assessed. The median age of patients treated at our centre was 53years with a female predominance. The most common epicentre was pancreatic head with abdominal pain as the most common presenting symptom. All 57 patients documented in literature belonged to a similar age group with similar gender predilection. The factors impacting DFS were histologic type, mitotic index, NIH risk category and adjuvant therapy. The median DFS was 74months with a 5-year DFS being 71.9%, while the 5-year OS was 90.4%. Pancreatic GIST is a rare entity. Due to limited evidence and evolving literature, results cannot be generalised to a larger population. Larger case series with longer follow-up data are required to further understand the disease biology and long-term outcomes of pancreatic GIST.

Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial.

363 Background: First-line NIVO+IPI has provided substantial long-term survival benefits over SUN in patients (pts) with aRCC in CheckMate 214. We report survival, response per independent radiology review committee (IRRC) and safety after 6 y minimum (80 mo median) follow-up in all randomized pts, by IMDC risk and in pts with overall survival (OS) ≥ 6 y (long-term survivors; LTS). Longer follow-up data (minimum, 7.5 y) will be presented. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO 3 mg/kg Q2W vs SUN 50 mg QD for 4 wk on, 2 wk off. Endpoints: OS, progression-free survival (PFS) and objective response rate (ORR; both per IRRC using RECIST v1.1) in IMDC intermediate/poor risk (IP; primary), intent-to-treat (ITT; secondary) and favorable risk (FAV; exploratory) pts. Exploratory outcomes in LTS pts were assessed post hoc. Results: OS with NIVO+IPI vs SUN remained superior in ITT (HR 0.72) and IP (HR 0.68) pts; OS benefits were similar between arms in FAV pts (HR 0.87; Table). Median PFS was consistent with previous reports. ORR per IRRC was higher with NIVO+IPI vs SUN, with more ongoing responses in ITT (60% vs 50%) and IP (60% vs 50%) pts. In FAV pts, ORR was lower with NIVO+IPI vs SUN, yet more responses were ongoing (59% vs 52%, respectively). Median duration of response (DOR) was longer and complete response (CR) rate was higher with NIVO+IPI vs SUN regardless of IMDC risk. Incidence of any and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. In the LTS subgroup (NIVO+IPI, n = 208; SUN, n = 151), ORR was higher (66% vs 53%), more pts had a CR (27% vs 9%) and fewer progressed (4% vs 11%) with NIVO+IPI vs SUN. Median DOR was longer with NIVO+IPI (n = 137) vs SUN (n = 80) among LTS with confirmed response (76 vs 40 mo). Updated survival, response and safety data with 7.5 y minimum follow-up, along with additional subgroup analyses, will be presented. Conclusions: NIVO+IPI demonstrated long-term survival and more durable response benefits vs SUN in ITT and IP pts. CR rates were higher and median DOR was longer with NIVO+IPI vs SUN regardless of IMDC risk group, and in LTS pts. No new safety signals emerged. Clinical trial information: NCT02231749 . [Table: see text]

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Metachromatic Leukodystrophy (MLD): A Case Series

Introduction Adult Metachromatic Leukodystrophy (MLD) is a rare neurological disorder leading to devastating and progressive cognitive impairment and motor impairment with ataxia, spasticity and neuropathy as well as incontinence resulting in complete disability and reduced life expectancy. MLD is caused by autosomal recessive mutations of the ARSA gene, resulting in reduced arylsulfatase A enzyme (ARSA) activity and consecutive accumulation of galactosylceramide-3-0-sulfate in the central nervous system (CNS). Potential therapies in infantile and juvenile MLD include allogeneic hematopoietic stem cell transplantation (allo-HCT), ex-vivo gene therapy (Atidarsagen autotemcel), and (intrathecal) enzyme replacement as tested in ongoing trials. Allo-HCT may slow down or stop MLD progression. However, the outcome in adult patients treated with allo-HCT has been only reported in a few case reports. In this case series, we report our experience of allogeneic transplantation in four patients with adult MLD. Methods Four patients (2 male and 2 female) with a genetically confirmed diagnosis of adult MLD, with enzyme deficiency detectable in peripheral blood (ARSA activity range 0.00-0.06 E514nm/10 -6), evidence of white matter lesions on MRI and demyelinating polyneuropathy in EMG were treated with allo-HCT. One patient was still clinically asymptomatic at the treatment timepoint. Allo-HCT was performed at an age between 18 and 37 years (mean 25.75 years) and within one year after diagnosis. Bone marrow (n=2) or mobilized peripheral blood stem cells (n=2) from 10/10 matched related (n=1) or unrelated (n=3) donors were infused at a dose of 2.2-7.82x10 6 CD34+/kg after a reduced intensity conditioning regime with Fludarabine (150 mg/m²) and Treosulfane (10 or 14 g/m²). Three patients received further infusions with allogeneic mesenchymal stem cells (MSCs) manufactured in the hospital´s own GMP laboratory around day 30 after transplantation. One patient received a second MSC infusion at day 182. MSCs are able to secrete ARSA and were used to consolidate enzyme levels. In case of transplant failure donor lymphocytes (DLI) were given. For posttransplant immunosuppression Tacrolimus, Methotrexate, Mycophenolate mofetil or Anti-thymocyte globulin (ATG, Grafalon®, Neovii 10 mg/kg) were used. Results All patients engrafted 16-21 days after HCT. Platelets regenerated within 14 to 21 days (mean 16 days), neutrophils recovered within 16 to 21 days (mean 18.5 days). In two patients hepatitis and exanthema associated with ATG administration were observed as transient adverse events. Other therapy-associated adverse events were innappetence, hyperkalemia and diarrhea. A mild Graft-versus-host disease of the skin occurred only in one patient with full resolution on a course of steroids and Tacrolimus. After allo-HCT, an increase in ARSA levels reaching normal range values within the first 12 months after treatment was already documented in 3 out of 4 patients; measurements are pending in the 4 th more recently transplanted patient. Three out of four patients developed consistent full donor chimerism within 11 (1-11 ) months after HCT. In the fourth 18-year-old patient autologous chimerism increased to 60-80%, while ARSA activity decreased from 1.05 to 0.61 E514nm/10 -6. Consequently, the patient received DLIs. However, an improvement in chimerism has not be achieved so far. Longer follow-up data will be reported at the meeting. Discussion and Conclusion Allo-HCT in patients with MLD can be used to restore normal range ARSA activity. Donor-derived macrophages with an adequate secretion of ARSA migrate to the central nervous system and release ARSA. To our knowledge, there have been only a few individual case reports on allo-HCT in adult MLD so far. Our case series indicates that allo-HCT can be performed with tolerable risks and evident efficacy in adult patients with MLD. Based on this experience and previously reported cohorts in juvenile and infantile MLD allo-HCT should be thus also considered as a therapeutic option for adult patients with MLD. Longer clinical follow-up, higher patient numbers and ultimately a prospective randomised trial containing an untreated group would be needed to evaluate allo-HCT as a treatment option for adult MLD.

Real-World Venetoclax-Obinutuzumab in 232 Treatment Naive CLL Patients: Feasibility and Tolerability

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi. Consecutive pts receiving first-line therapy after VO approval/reimbursement in Italy (May 2022) were considered. Reasons for choosing the fixed duration treatment were recorded. The impact of clinical, biological, and demographic characteristics on VO feasibility (definitive treatment discontinuation and/or schedule modifications due to toxicity) and tolerability were analyzed. Debulking (Deb) phase (D1-D56) was separately evaluated to better understand its influence on treatment management. From May 2022 to June 2023, 790 treatment naïve continuous pts were treated with targeted agents in 49 centers. Treatment choice consisted of: continuous BTKi in 558 pts and fixed-duration VO in 232 (the latter representing the population of our analysis). The main reasons given by physicians for choosing VO instead of BTKi were: disease biology 46% (mutated IgHV status), fixed duration 33%, comorbidities 15%, patient choice 6%. Pts' characteristics are shown in Table 1. When considering Deb-phase (232 pts), VO was regularly administered according to the investigator brochure in 150 (64.7%). In 22 cases (9.5%) the schedule was a priori modified by clinicians: 12 pts started with V led-in and postponed O infusion at C2D1; in 10 planned O D8 and D15 infusions were omitted. Overall, 12 pts (5.2%) permanently discontinued VO due to toxicity. 3 of them dying due to: COVID pneumonia, invasive aspergillosis, VO-unrelated cachexia. In the remaining 48 (20.7%) schedule was adjusted due to AEs. Treatment modifications, overlapping in some cases were: 42 extended the Deb-phase (median days to completion 63, range 59-130); 14, never reached the full V dose; 31 did not perform the planned 5 O infusions (median 3 infusions, range 1-4). No age, neither coexisting conditions influenced treatment feasibility. The only parameters having an impact on Deb-phase discontinuation or schedule modifications due to toxicity were: baseline ANC&amp;lt;1500/mmc (OR 3.1, p=.035), hypogammaglobulinemia (OR 2.2, p=.018), concomitant use of anticoagulants (3.13, p=.029). Overall 23 pts (9.9%), including 7 categorized as high risk TLS, were hospitalized for treatment initiation. During Deb-phase grade 3-4 AEs occurred in 69 pts (30%): neutropenia (18%); thrombocytopenia (14%); infections (5%); IRR (5%). Development of any severe AE was influenced by: upper GI disorder, baseline neutropenia or thrombocytopenia. TLS was recorded in 13 pts (6%): 11 O-related and 4 V-related. All 4 clinical TLS were considered as secondary to O. Only high CLL-CI risk was associated with TLS. None of the baseline factors nor type of steroids premedication predicted IRR. At the present follow-up of the 232 pts considered: 142 completed the 6 cycles of combinations treatment, 75 are still ongoing, 15 definitively discontinued treatment for AEs. Overall, 42 pts received VO with an adjusted schedule for toxicities: 22 are receiving V at reduced dose, 39 pts did not complete the planned O infusions (treatment modifications overlapping in some cases). G 3-4 toxicity developed in 78 pts being neutropenia and infections the most common reported. At univariate analysis factors affecting treatment feasibility were: presence of endocrine comorbidity; intermediate/high CLL-CI and hypogammaglobulinemia. To our knowledge this is the first real-world study on clinical factors that may influence VO feasibility. Despite this setting of unselected population, most clinicians were adherent to VO schedule. A low rate of pts permanently discontinued therapy during Deb-phase with no impact of age or comorbidities on feasibility. Furthermore, TLS and IRR were in line with clinical trials. Longer follow-up data will be reported at the meeting allowing by multivariate analysis to better clarify the role of comorbidities on treatment management and the reproducibility of VO tolerability in common clinical practice.

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Comparison of bilateral axillo-breast approach robotic thyroidectomy and open thyroidectomy for papillary thyroid carcinoma.

For papillary thyroid carcinoma (PTC) surgery requiring total thyroidectomy and central lymph node dissection, it is controversial whether the bilateral axillo-breast approach robotic thyroidectomy (BABA RT) can replace the open thyroidectomy (OT). To evaluate the efficacy of two surgical approaches. Relevant literatures were searched from PubMed, EMBASE and Cochrane Library. Studies comparing two surgical approaches and meeting the inclusion criteria were selected. Compared with OT, BABA RT showed a similar incidence of postoperative complications, including recurrent laryngeal nerve palsy, hypocalcemia, hypoparathyroidism, bleeding, chyle leakage and incision infection, as well as number of retrieved central lymph nodes and postoperative total dose of radioactive iodine. However, BABA RT involved longer operative time (weighted mean difference [WMD] 72.62, 95% confidence interval [CI] 48.15-97.10, P < .00001) and higher postoperative stimulated thyroglobulin level ([WMD] 0.12, 95% [CI] 0.05-0.19, P = .0006). The efficacy of BABA RT is basically similar to OT in this meta-analysis, but the higher postoperative stimulated thyroglobulin level attracts our attention. Longer operative time requires us to shorten. Randomized clinical trials with large samples and longer follow-up data are still essential to further demonstrate the value of the BABA RT.

Cost-effectiveness of transcatheter aortic valve implantation in patients at low surgical risk in France: a model-based analysis of the Evolut LR trial

BackgroundIn the recent Evolut Low Risk randomized trial, transcatheter aortic valve implantation (TAVI) was shown to be non-inferior to surgery (SAVR) regarding the composite end point of all-cause mortality or disabling stroke at 24 months.AimsTo evaluate the cost-effectiveness of self-expandable TAVI in low-risk patients, using the French healthcare system as the basis for analysis.MethodsMortality, health-related quality of life, and clinical event rates through two-year follow-up were derived from trial data (N = 725 TAVI and N = 678 SAVR; mean age: 73.9 years; mean STS-PROM: 1.9%). Cost inputs were based on real-world data for TAVI and SAVR procedures in the French healthcare system. Costs and effectiveness as quality-adjusted life years (QALYs) were projected to lifetime via a decision-analytic model under assumption of no mortality difference beyond two years. The discounted incremental cost-effectiveness ratio (ICER) was evaluated against a willingness-to-pay threshold of €50,000 per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted, including assumptions about differential long-term survival.ResultsFor the base case, mean survival was 13.69 vs 13.56 (+ 0.13) years for TAVI and SAVR, respectively. Discounted QALYs were 9.34 vs. 9.21 (+ 0.13) and discounted lifetime costs €52,267 vs. €51,433 (+ €833), resulting in a lifetime ICER of €6368 per QALY gained. In probabilistic sensitivity analysis, TAVI was found dominant or cost-effective in 74.4% of samples.ConclusionTAVI in patients at low surgical risk is a cost-effective alternative to SAVR in the French healthcare system. Longer follow-up data will help increase the accuracy of lifetime survival projections.Graphical

Cost-Effectiveness of brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma

Brexucabtagene autoleucel is a chimeric anti CD19 antigen receptor T-cell therapy that allows durable responses in relapsed/refractory (R/R) mantle cell lymphoma (MCL). The present study compared the clinical and economic outcomes of R/R MCL patients (pre-exposed to ibrutinib and chemoimmunotherapy) treated with brexucabtagene autoleucel versus Rituximab, bendamustine, cytarabine (R-BAC) in the Italian Healthcare System. A partitioned-survival model extrapolated survival and healthcare costs of R/R MCL patients over a lifetime horizon. Discounted and quality-adjusted life expectancy (QALY) was 6.40 versus 1.20 for brexucabtagene autoleucel versus R-BAC and lifetime costs were €411,403 versus €74,415, respectively, which corresponds to a cost of €64,798 per QALY gained. The results were highly sensitive to brexucabtagene autoleucel acquisition cost and to assumptions on long-term survival, therefore the cost-effectiveness of brexucabtagene autoleucel for patients with R/R MCL requires validation with longer follow-up data and in specific risk subgroups.

Impact of de-escalating systemic therapy guided by 21-gene assay on locoregional recurrence after partial-breast irradiation

PURPOSEPartial-breast irradiation (PBI) has been performed as alternative to whole-breast irradiation (WBI) in breast-conserving therapy (BCT). Recently, the 21-gene recurrence score (RS) was introduced to determine the adjuvant therapy for estrogen receptor (ER)-positive, and human epidermal growth factor receptor 2 (HER2)-negative diseases. However, the impact of RS-based systemic therapy on locoregional recurrence (LRR) following BCT with PBI remains uninvestigated. METHODS AND MATERIALSPatients with ER-positive, HER2-negative, and node-negative breast cancer who underwent BCT with PBI were examined during May 2012–March 2022. In addition to immunohistochemistry (IHC), RS was available to decide on adjuvant therapy. RESULTSIn total, 431 patients were evaluated with a median followup of 48.6 months. The 4-year LRR-free survival rates were 97.3% and 96.4% in the IHC and RS cohorts, respectively (p = 0.50). Ki67 of >20% was significantly associated with LRR in the multivariate analysis (HR 4.39, p < 0.05). For patients with Ki67 > 20%, 29 of 71 (40.8%) and 46 of 59 (78.0%) patients received only endocrine therapy in the IHC and RS cohorts, respectively (p < 0.0001). For patients with Ki67 >20% who received only endocrine therapy, the 4-year LRR-free survival rates were 91.8% in the IHC cohort and 94.6% in the RS cohort (p = 0.29) CONCLUSIONSAlthough the introduction of RS increased the number of patients receiving endocrine therapy alone for Ki67 >20% of disease by two times, the LRR-free survival after BCT with PBI could be maintained. However, further studies from multiple institutions with longer followup data are required.

Midterm Outcomes of Endoleak Type 2 Embolization after Endovascular Aortic Aneurysm Repair Using a Neurointerventional Approach

Type 2 endoleaks (T2ELs) have been considered a benign condition and intervention is recommended when they are associated to sac expansion. The aim of this study was to report on T2EL embolization midterm outcomes, using neurointerventional material. A single-center retrospective analysis of consecutive patients treated with transarterial embolization, using neurointerventional material, for T2EL after standard endovascular aortic aneurysm repair (EVAR) between January 01, 2017 and July 30, 2022, was undertaken. Primary outcome was technical success and secondary outcome was T2EL recurrence during follow-up. Twenty six patients [92.3% males, mean age 73.9±7.7years] were included. The median time between EVAR and T2EL diagnosis was 12months (range: 1-84months). In 38.5% of patients, T2EL was detected at first month after EVAR. The time to embolization was 18months (range: 1-96months). In 42.3% of cases, a patent inferior mesenteric artery was suspected to relate to T2EL formation while in 42.3% of cases, a lumbar artery. Twelve procedures (38.4%) were performed using coils and Onyx and 13 (50%), using only Onyx. Technical success was 84.6%. The mean follow-up was 24months (range: 1-60months), including 20 patients. In 30% of cases, an T2EL recurrence was detected. Three patients (11.5%) underwent secondary embolization. Transarterial embolization for T2EL, using neurointerventional material, provided acceptable technical success and T2EL recurrence rates at 2years of follow-up. Longer follow-up data would further estimate the durability of the technique.

GPP03 Presentation Time: 8:20 AM: Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial Cancer: Preliminary Results of the SAVE Randomized Clinical Trial

<h3>Purpose</h3> Prospective randomized trials in early stage endometrial cancer demonstrate increased locoregional control with adjuvant radiotherapy for patients with select high risk features. Vaginal cuff brachytherapy (VCB) is widely utilized, yet there is substantial practice variation and limited randomized data examining optimal dose/fractionation. We aimed to study the safety and efficacy of short course VCB compared to commonly used regimens, and herein report on short-term adverse events, patient reported outcomes, and recurrences. <h3>Materials and Methods</h3> We conducted a prospective, multi-center, randomized trial examining short course adjuvant VCB (11 Gy x 2 fractions at the surface delivered in 2 weeks) compared with the commonly used regimens (7 Gy x 3 fractions at 0.5 cm depth, 6 Gy x 5 fractions at the surface, or 5-5.5 Gy x 4 fractions at 0.5 cm depth). Eligible patients underwent hysterectomy and had pathologically confirmed endometrioid adenocarcinoma, serous, clear cell, or carcinosarcoma histology. Patients with stage I and II cancers were included, with additional risk factors required for stage IA (IAG1 with LVSI). The primary outcome was Global Health Status measured by the EORTC QLQ-C30. Secondary outcomes included differences in patient-reported outcomes using the EORTC EN24 for vaginal, bladder, and bowel symptoms, cost effectiveness, toxicities as assessed by CTCAEv4, and patterns of recurrence. Data were collected at each brachytherapy fraction and at 1, 6 and 12 month follow-up with a compliance rate of 94% at 1 month. <h3>Results</h3> 108 patients were enrolled. Of these, 52 patients experienced short-term AEs related to study treatment, 21 in the experimental arm and 31 in the control arm (p=0.05). All study treatment-related AEs were grade 1-2, except for 1 grade 3 urinary symptom in the control arm. In the experimental arm, the most frequent short-term AEs were fatigue (n=6), diarrhea (n=4), vaginal discharge (n=3), and vaginal dryness (n=3). In the control arm, the most frequent short-term AEs were vaginal dryness (n=8), urinary incontinence (n=6), urinary tract infection (n=5), and pelvic pain (n=5). At median follow-up of 12 months, 5 patients experienced recurrence including 2 distant recurrences and 1 distant and pelvic recurrence in the experimental arm and 2 pelvic recurrences in the control arm. There have been no isolated vaginal recurrences in either arm. The QLQ-C30 Global Health Status for the experimental arm was within the predefined boundary and thus 2 fractions was non-inferior to standard of care (p=0.00002) at one month. <h3>Conclusions</h3> Short course VCB is safe and well-tolerated with acceptable acute toxicity and non-inferior patient reported outcomes. Although longer follow-up data is pending, short course VCB shows promise to improve patient convenience and access to care for rural or underserved populations while providing similar local control and toxicity profile.

Cost-effectiveness analysis of nivolumab plus ipilimumab plus two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States

Aim This economic analysis evaluated the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of platinum-doublet chemotherapy (PDC) compared with four cycles of PDC as first-line treatment for patients with advanced NSCLC in the United States (US). Methods A partitioned survival model was constructed with three mutually exclusive health states: progression free, progressed disease, and death. The analysis was conducted from a US healthcare payer perspective, using a time horizon of 25 years. Costs and outcomes were discounted at 3% annually. Survival outcomes from CheckMate 9LA were extrapolated with longer follow-up data from CheckMate 227 Part 1 (NIVO + IPI) and validated against data from other relevant clinical trials and real-world registries. Health-related quality of life utility values were derived from EQ-5D-3L data collected in CheckMate 9LA. US-specific costs (2020 dollars) were used for disease management; drug acquisition, administration, and monitoring; end-of-life care; adverse events; and subsequent treatments. Model outcomes included life years (LYs) gained, quality-adjusted LYs (QALYs) gained, and incremental cost-effectiveness ratio (ICER) for NIVO + IPI + PDC versus PDC. Sensitivity and scenario analyses were conducted. Results NIVO + IPI + PDC was associated with higher projected health benefits than PDC, including gains in LYs (3.71 vs 1.89) and QALYs (2.86 vs 1.37), and higher costs ($317,581 vs $119,909). The ICER was $132,960/QALY gained. NIVO + IPI + PDC had a 78–100% probability of being cost-effective at a willingness-to-pay threshold of $150,000–$250,000/QALY. Sensitivity and scenario analyses indicated that the results were robust to changes in key parameters. Limitations The inherent limitation in extrapolating clinical trial data was mitigated using data from the more mature CheckMate 227 Part 1 trial and validating the outcomes against data from other relevant trials and real-world registries. Conclusion NIVO + IPI + PDC (two cycles) provides a new first-line treatment option for patients with advanced NSCLC that is cost-effective within a range considered acceptable in the US.

Brexucabtagene autoleucel: a breakthrough in the treatment of mantle cell lymphoma.

In July 2020, the U.S. Food and Drug Administration (FDA) approved brexucabtagene autoleucel (BA), the first anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The pivotal ZUMA-2 trial led to the approval of BA in patients who experienced relapsed disease on prior therapies (chemotherapy and/or Bruton tyrosine kinase [BTK] inhibitors). The FDA approval of BA was based on excellent responses with this therapy in highly refractory patients with MCL, who conventionally had poor outcomes. Longer follow-up data from the ZUMA-2 study have been presented at recent international meetings. As is common with other CAR T-cell therapies in lymphomas, the main toxicities of BA therapy included cytokine release syndrome (CRS), infections, cytopenias and CAR-associated neurotoxicity. In this review, we provide a summary of the data in the development of BA and its impact on MCL patient survival and future directions.

Gender Disparities in Aortoiliac Revascularization in Patients with Aortoiliac Occlusive Disease

Gender disparities have been previously reported in aortic aneurysm and critical limb ischemia outcomes; however, limited info is known about disparities in aortoiliac occlusive disease. We sought to characterize potential disparities in this specific population. Patients who underwent aortobifemoral bypass and aortic thromboendarterectomy (Current Procedural Terminology codes 35646 and 35331) between 2012 and 2019 were identified in the National Surgical Quality Improvement Program database. A binomial regression model was used to estimate gender differences in 30-day morbidity and mortality. Inverse probability weighting was used to standardize demographic and surgical characteristics. We identified 1,869 patients, of which 39.8% were female and the median age was 61years. Age, body composition, and other baseline characteristics were overall similar between genders; however, racial data were missing for 26.1% of patients. Females had a higher prevalence of preexisting chronic obstructive pulmonary disease (20.9% vs. 14.7%, prevalence difference 6.1%, P<0.01), diabetes mellitus (25.4% vs. 19.4%, prevalence difference 6.0%, P<0.01), and high-risk anatomical features (39.4% vs. 33.7%, prevalence difference 5.8%, P=0.01). Preprocedural medications included a statin in only 68.2% of patients and antiplatelet agent in 76.7% of patients. Females also had a higher incidence of bleeding events when compared to males (25.2% vs. 17.5%, standardized risk difference 7.2%, P<0.01), but were less likely to have a prolonged hospitalization greater than 10days (18.2% vs. 20.9%, standardized risk difference -5.0%, P=0.01). The 30-day mortality rate was not significantly different between genders (4.7% vs. 3.6%, standardized risk difference 1.2%, P=0.25). Female patients treated with aortobifemoral bypass or aortic thromboendarterectomy are more likely to have preexisting chronic obstructive pulmonary disease, diabetes mellitus, and high-risk anatomical features. Regardless of a patient's gender, there is poor adherence to preoperative medical optimization with both statins and antiplatelet agents. Female patients are more likely to have postoperative bleeding complications while males are more likely to have a prolonged hospital stay greater than 10days. Future work could attempt to further delineate disparities using databases with longer follow-up data and seek to create protocols for reducing these observed disparities.

Clinical outcomes of open abdominal wall reconstruction with the use of a polypropylene reinforced tissue matrix: a multicenter retrospective study

ObjectiveTo assess mesh behaviour and clinical outcomes of open complex abdominal wall reconstruction (CAWR) with the use of a polypropylene reinforced tissue matrix.MethodsA multicenter retrospective study of adult patients who underwent open CAWR with the use of a permanent polypropylene reinforced tissue matrix (OviTex®) between June 2019 and January 2021.ResultsFifty-five consecutive patients from four hospitals in the Netherlands were analysed; 46 patients with a ventral hernia and 9 patients with an open abdomen. Most patients with a ventral hernia had one or more complicating comorbidities (91.3%) and one or more complicating hernia characteristics (95.7%). Most procedures were performed in a (clean) contaminated surgical field (69.6% CDC 2–4; 41.3% CDC 3–4). All nine patients with an open abdomen underwent semi-emergent surgery. Twelve out of 46 patients with a ventral hernia (26.1%) and 4 of 9 patients with an open abdomen (44.4%) developed a postoperative surgical site infection that made direct contact with the mesh as confirmed on computed tomography (CT), suspicious of mesh infection. No patient needed mesh explantation for persistent infection of the mesh. During a median follow-up of 13 months, 4 of 46 ventral hernia patients (8.7%) developed a CT confirmed hernia recurrence.ConclusionPolypropylene reinforced tissue matrix can withstand infectious complications and provides acceptable mid-term recurrence rates in this retrospective study on open complex abdominal wall reconstructions. Longer follow-up data from prospective studies are required to determine further risk of hernia recurrence.

Cost-Effectiveness of Brexucabtagene Autoleucel versus Best Supportive Care for the Treatment of Relapsed/Refractory Mantle Cell Lymphoma following Treatment with a Bruton's Tyrosine Kinase Inhibitor in Canada.

For patients with Mantle Cell Lymphoma (MCL), there is no recognized standard of care for relapsed/refractory (R/R) disease after treatment with a Bruton’s tyrosine kinase inhibitor (BTKi). Brexucabtagene autoleucel (brexu-cel) represents a promising new treatment modality in MCL. We explored whether brexu-cel was cost-effective for the treatment of R/R MCL. We developed a partitioned survival mixture cure approach to model the costs and outcomes over a lifetime horizon. The clinical data were derived from the ZUMA-2 clinical trial. The costs were estimated from the publicly available Canadian databases, published oncology literature, and pan-Canadian Oncology Drug Review economic guidance reports. The health state utilities were sourced from the ibrutinib submission to the National Institute for Health and Care Excellence for R/R MCL and supplemented with values from the published oncology literature. In the base case over a lifetime horizon, brexu-cel generated an incremental 9.56 life-years and an additional 7.03 quality-adjusted life-years compared to BSC, while associated with CAD 621,933 in additional costs. The resultant incremental cost-utility ratio was CAD 88,503 per QALY gained compared with BSC. Based on this analysis, we found brexu-cel to be a cost-effective use of healthcare resources relative to BSC for treatment of adult patients with R/R MCL previously treated with a BTKi in Canada, though additional research is needed to confirm these results using longer follow-up data.

Gender-affirming hormone therapy: An updated literature review with an eye on the future.

In line with increasing numbers of transgender (trans) and gender nonbinary people requesting hormone treatment, the body of available research is expanding. More clinical research groups are presenting data, and the numbers of participants in these studies are rising. Many previous review papers have focused on all available data, as these were scarce, but a more recent literature review is timely. Hormonal regimens have changed over time, and older data may be less relevant for today's practice. In recent literature, we have found that even though mental health problems are more prevalent in trans people compared to cisgender people, less psychological difficulties occur, and life satisfaction increases with gender-affirming hormone treatment (GAHT) for those who feel this is a necessity. With GAHT, body composition and contours change towards the affirmed sex. Studies in bone health are reassuring, but special attention is needed for adolescent and adult trans women, aiming at adequate dosage of hormonal supplementation and stimulating therapy compliance. Existing epidemiological data suggest that the use of (certain) estrogens in trans women induces an increased risk of myocardial infarction and stroke, the reason that lifestyle management can be an integral part of trans health care. The observed cancer risk in trans people does not exceed the known cancer-risk differences between men and women. Now it is time to integrate the mostly reassuring data, to leave the overly cautious approach behind, to not copy the same research questions repeatedly, and to focus on longer follow-up data with larger cohorts.