Prior Lines Research Articles

Gamma irradiation green synthesis of (polyacrylamide/chitosan/silver nanoparticles) hydrogel nanocomposites and their using as antifungal against Candida albicans and anti-cancer modulator

Silver nanoparticles-loaded hydrogel nanocomposites are exploited for medicinal and pharmaceutical applications. Hydrogel nanocomposites were prepared from acrylamide (Am), chitosan (CS) and AgNO3 utilizing gamma rays. Diverse variables were applied in preparation of silver nanoparticles-laoded hydrogel nanocomposites of (PAm/CS)-AgNPs such as influence of radiation dose and influnece of CS concentration. Diverse techniques were utilized to characterize hydrogel nanocomposites; Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), Transmission electron microscopy (TEM), energy dispersive X-ray (EDX) and scanning electron microscopy (SEM). Results confirmed formation of silver nanoparticles-loaded hydrogel nanocomposites of (PAm/CS)-AgNPs. Antifungal activity of (PAm/CS)-AgNPs hydrogel nanocomposites on viability of C. albicans was esitmated. Results displayed the efficient microbial inhibition activity of treatment against C. albicans compared to control. Furthermore, (PAm/CS)-AgNPs hydrogel nanocomposite against cervical cancer HeLa cell line was investigated. Cytotoxicity of (PAm/CS)-AgNPs hydrogel nanocomposites on prior cancer cell line empolyed to prohibition of cell growth assesssed by MTT test. HeLa cancer cell is treated by (PAm/CS)-AgNPs for 48 h exposed a potential apoptotic activity by noticeable up-regulation of p53 gene expression. Moreover, anticancer activity was investigated by down-regulation of platelet-based growth variable receptor beta (PDGFR-β), Bcl2, Cathepsine, and MMP-2 gene expression. antioxidant activity was investigated and results showed antioxidant activity of (PAm/CS) hydrogel and (PAm/CS)-AgNPs hydrogel nanocomposite are 87.8% and 62.9%, respectively.

Matching-adjusted indirect comparison of Acalabrutinib versus Ibrutinib in relapsed/refractory mantle cell lymphoma

ABSTRACT Objective In the absence of head-to-head clinical trials, matching-adjusted indirect comparison (MAIC) was used to compare 2 Bruton tyrosine kinase inhibitors (BTKis) approved for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL). This analysis compares the efficacy and safety of acalabrutinib versus ibrutinib using a more mature dataset than a previously published MAIC. Methods Individual patient data from 122 patients treated with acalabrutinib in a phase 2 study were weighted to match aggregate baseline characteristics of patients pooled from 3 separate trials of ibrutinib. Patients were matched on Eastern Cooperative Oncology Group performance status, simplified Mantle Cell Lymphoma International Prognostic Index, lactate dehydrogenase, prior lines of therapy, tumor burden, and blastoid histology. Outcomes assessed included progression-free survival (PFS), overall survival (OS), and adverse events. Results After matching, differences in PFS between acalabrutinib (median 17.8 months) and ibrutinib (median 12.8 months) were not statistically significant (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.74–1.15; P = 0.48). Similarly, after matching, OS differences between acalabrutinib (median 36.5 months) and ibrutinib (median 27.9 months) did not reach statistical significance (HR, 0.87; 95% CI, 0.64–1.17; P = 0.35). Acalabrutinib was associated with an improved safety profile compared with ibrutinib, with statistically significantly lower rates of grade ≥3 atrial fibrillation and thrombocytopenia. Conclusions This comparison of 2 BTKis used in the treatment of R/R MCL showed that PFS and OS risk was not statistically different between the treatments; however, acalabrutinib had an improved safety profile compared with ibrutinib.

Long-term three-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies (119/120)

Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407).

Matching-adjusted indirect comparisons of zanubrutinib (MAGNOLIA, BGB-3111-AU-003) versus ibrutinib (PCYC-1121) and rituximab (CHRONOS-3) in relapsed/refractory marginal zone lymphoma.

In the absence of head-to-head randomized trials, unanchored matching-adjusted indirect comparisons were conducted to estimate the relative efficacy of zanubrutinib versus ibrutinib and zanubrutinib versus rituximab in relapsed or refractory marginal zone lymphoma (MZL). Logistic propensity score models were used to estimate weights for the patient-level data from two phase II single-arm trials, MAGNOLIA and BGB-3111-AU-003, such that their characteristics matched the ibrutinib and rituximab aggregate-level data from PCYC-1121 and CHRONOS-3, respectively. The base case model for each comparison incorporated four key prognostic factors: prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis incorporating additional prognostic factors was also conducted for the ibrutinib comparison. The impact of each covariate was explored via a leave-one-out analysis. Compared with ibrutinib and rituximab, zanubrutinib demonstrated significant benefits in terms of both overall response and progression-free survival in patients with previously treated MZL.

Predictors of response to CDK4/6i retrial after prior CDK4/6i failure in ER+ metastatic breast cancer

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8–16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2–5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7–6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM).

Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18-70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution's records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan-Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy.

Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma

The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines. To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma. The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock). The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review. The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics. A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm. Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design. ClinicalTrials.gov Identifier: NCT04154189.

Engaging a New Treatment Paradigm: Elranatamab in Relapsed/Refractory Multiple Myeloma.

To review the therapeutic profile of elranatamab, a novel bispecific T-cell-redirecting therapy, in treating relapsed or refractory (R/R) multiple myeloma (MM). A PubMed search was conducted for English-language articles published from January 2000 through June 2024, using the search terms: PF-06863135, elranatamab, Elrexfio, and "Multiple Myeloma." Additional data were obtained from ClinicalTrials.gov and other pertinent publications and meeting abstracts. Clinical trials, guidelines, and prescribing information pertaining to elranatamab were included. The phase II MagentisMM-3 trial demonstrated an overall response rate of 61.0% (95% confidence interval, 51.8-69.6) in patients naïve to B-cell maturation antigen targeting therapy (cohort A, n = 123), establishing elranatamab monotherapy as a viable treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. The duration of response and progression-free survival at 12 months were 75.3% and 56.6%, respectively. Despite the promising activity of elranatamab in R/R MM, the significant treatment-related adverse effects (AEs) associated with this therapy necessitate careful monitoring and expert management. Common AEs include cytokine release syndrome, neurotoxicity, hematologic toxicity, and infectious complications. The cost-effectiveness of elranatamab has yet to be evaluated. Elranatamab is approved by the Food and Drug Administration as a treatment option for patients with heavily pretreated R/R MM. Further studies are warranted to identify the optimal treatment strategy for elranatamab and other bispecific antibodies in the management of R/R MM.

FDA Approval Summary: Teclistamab - A Bispecific CD3 T-cell Engager for Patients with Relapsed or Refractory Multiple Myeloma.

On October 25, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to teclistamab-cqyv (TECVAYLI; Janssen Biotech) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Substantial evidence of effectiveness was obtained from the MajesTEC-1 trial, a phase 1/2, single-arm, open-label, multi-center study. Patients received step-up doses of teclistamab at 0.06 mg/kg and 0.3 mg/kg followed by 1.5 mg/kg subcutaneously once weekly until disease progression or unacceptable toxicity. An overall response rate of 61.8% was observed, with a complete response or better rate of 28.2%. Cytokine release syndrome (CRS) occurred in 72% of patients and neurologic toxicity (NT) occurred in 57%, including immune effector cell-associated neurotoxicity syndrome (ICANS) in 6%. Due to the risk of CRS and NT, including ICANS, the U.S. prescribing information for teclistamab includes a boxed warning and teclistamab is available only through a restricted program under a risk evaluation and mitigation strategy. Here, we summarize the data and FDA review supporting the accelerated approval of teclistamab, a BCMA-directed bispecific antibody that was the first bispecific CD3 T-cell engager approved for treatment of multiple myeloma.

PD-1 inhibitor sintilimab treated patients with metastatic triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly challenging subtype due to a unique tumor microenvironment. Several evidence (IMpassion130 trial and KEYNOTE-355 trial) supported the therapeutic effect of the immune checkpoint inhibitor in TNBC. However, the efficacy and safety of the PD-1 inhibitor sintilimab in breast cancer (BC) has not been well-investigated. So the real-world data on sintilimab-treated patients with metastatic BC were collected and analyzed in this study. The patients were eligible according to the requirements included: ages between 18years and 75years; recurrent or metastatic TNBC; measurable disease based on RECIST v1.1; no limitation on the prior systemic treatments; and ECOG performance status of 0-1. Patients received sintilimab 200mg intravenously every 3 weeks until unacceptable toxicity or disease progression. From 1 June 2019 to 1 October 2022, 40 female patients (median age, 55.5years) with metastatic TNBC (mTNBC) were enrolled into the study. The median prior lines of systemic therapy for mTNBC was three (range, 1-8), with 60% of cases receiving at least three lines of therapy for metastatic disease. The visceral or brain metastasis was detected in 40.4% or 9.6% of patients, respectively. The median duration of response was 2.8months (range, 0.7-21.0), and the median number of sintilimab doses administered was 4 (range, 1-30). The ORR and DCR were 22.5% and 72.5%, separately. The median PFS was 3.5 months (range, 1.4-21.0), with a 6-month PFS rate of 15.0% (6/40). The median OS was 52.5months (range, 9.0-247.0) as of data cut-off. Common adverse effects were acceptable, and fatigue, skin rash, and pruritus were the frequent toxicity observed. Two cases of grade 3 curable adverse events were considered to be treatment-related. PD-L1-positive tumor was found in 40% cases (4/10) of mTNBC. Although statistical difference was not reached, the trend was obvious. Patients with PD-L1-positive tumor gained better treatment response, while the TMB-high carrier received more benefits of PFS and OS. In our study, preliminary evidence provided the anticancer activity and acceptable adverse effects of sintilimab administered every 3 weeks to pretreated patients with mTNBC. Sintilimab showed its efficacy and safety of immunotherapy for patients with advanced TNBC.

Daratumumab-Based Therapeutic Approaches and Clinical Outcomes in Multiple Myeloma and other Plasma Cell Dyscrasias: Insights from a Nationwide Real-World Chart Review Study.

Singapore leads Southeast Asia in the routine use of daratumumab for multiple myeloma and other plasma cell dyscrasias. This retrospective review analyzed 112 patients who received daratumumab between 2012 and 2020. Tolerability, and efficacy based on prior lines (PL) of therapy, cytogenetic risk group, and the presence of renal impairment were presented. Infusion-related reactions occurred in 26.8% of patients. Grades 1 and 2 hematological and non-hematological adverse events were observed in 14.3% and 33.9% of patients, respectively. After a median follow-up of 16.9 months, there was no significant difference in overall response rates (ORR) (86% versus 76.3%, p = 0.082) or depth of response (≥ complete response (CR), 35.1% versus 28.9%, p = 0.469) between myeloma patients with and without renal dysfunction. Newly diagnosed and relapsed/refractory patients had an ORR of 92% and 76.3%, and a ≥ VGPR (very good partial response) rate of 80% and 55.3%, respectively. Median progression-free survival (PFS) was better for patients with 0/1 PL compared to ≥ 2 PLs (19.8 versus 6.2 months, p < 0.001), with a deeper response (≥ CR, 38.5% versus 16.7%, p = 0.033). Forty-six and a half percentage of patients had high-risk FISH abnormalities, and those with 0/1 PL had a significantly better ORR than those with ≥ 2 PLs (83.3% vsersus 47.1%, p = 0.022), achieving an ORR similar to that of the general cohort (80.2%, p = 0.905). In conclusion, positioning daratumumab in earlier lines of therapy leads to better outcomes and may mitigate the impact of high-risk FISH abnormalities.

Reduced Intensity Conditioning Prior Autologous Stem Cell Transplantation in Elderly DLBCL Patients.

High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is widely used in patients with diffuse large B-cell lymphoma. HDCT/ASCT is associated with increased morbidity in elderly/unfit patients. We retrospectively evaluated the use of reduced intensity conditioning in DLBCL patients. Our study included 146 patients aged 60 years and older treated at our institution between 2005 and 2019; 86 patients received standard intensity conditioning (SI group) with BEAM or TEAM (BCNU or thiotepa, etoposide, cytarabine, melphalan). Sixty patients received reduced intensity high-dose conditioning (RI group) with BM (BCNU, melphalan, 43.3%), TM (thiotepa, melphalan, 16.7%), BCNU or busulfan thiotepa (38.4%), or bendamustine melphalan (1.7%). Median follow-up was 62.4 months. We observed comparable toxicities in the SI and RI groups. The cumulative incidence of relapse at 3 years was higher in the RI group (30.8% vs. 23.4%, p = 0.034). There was no difference in nonrelapse mortality (NRM). In univariate analyses, SI vs. RI conditioning resulted in superior progression-free survival (PFS) (HR 1.80 CI 1.11-2.92, p = 0.017) but not in superior overall survival (OS) (HR 1.48 CI 0.86-2.56, p = 0.152). On multivariate analysis, we observed no difference in PFS (HR 0.74 CI 0.40-1.38, p = 0.345) and a trend toward better OS with RI conditioning (HR 0.45 CI 0.22-0.94, p = 0.032). Age 60-69 versus ≥ 70 years and remission prior to ASCT were the only factors predicting better PFS. Factors associated with better OS were RI conditioning, age 60-69 versus ≥ 70 years, ECOG 0 versus ≥ 1 performance status, bulky disease, and prior lines 1 versus ≥ 2. In conclusion, RI conditioning prior to ASCT may be feasible in elderly patients and led to a comparable outcome when corrected for several significant confounders.

Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma

AbstractCiltacabtagene autoleucel (cilta-cel) chimeric antigen receptor (CAR) T-cell therapy was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. In terms of results, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel. Of patients who underwent leukapheresis, 56% would not have met the CARTITUDE-1 trial eligibility criteria. Manufacturing failure rates at first attempt and overall were 6% and 1%, respectively. The median of prior lines of therapy was 6. In treated patients (n = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Best overall and complete response or better rates were as follows: for patients who received infusion (n = 236), 89% and 70%; patients receiving conforming CAR T-cell product (n = 191), 94% and 74%; and conforming CAR T-cell product with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from CAR T-cell therapy, the median progression-free survival (PFS) was not reached, with the 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a novel anti-CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa-Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real-world efficacy and safety are poorly reported. In this Italian multicenter real-life observational retrospective study, efficacy and safety of the Isa-Kd regimen were evaluated in a cohort of 103 RRMM patients. Overall response rate (ORR) was 85%, with stringent (sCR) or complete response (CR) in 18% of cases and very good partial response (VGPR) in 39%. Median PFS and OS were not reached within the study period, while 1-year PFS and OS were 72% and 77%, respectively. Hematological toxicities were observed in 42% of subjects, and cardiac toxicities occurred in 24% of cases. Moreover, we conducted a subanalysis on patients (N = 69) treated with Isa-Kd after one prior line of therapy, showing an ORR of 88%, with sCR + CR in 20% of subjects, VGPR in 46%, and PR in 22% of patients. In this group, median PFS and OS were not reached, while 1-year PFS and OS were 92% and 95%, respectively. In conclusions, our study confirmed Isa-Kd as an effective treatment option for RRMM with a manageable safety profile even in real-life settings.

Elacestrant in ER+, HER2- Metastatic Breast Cancer with ESR1-Mutated Tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy plus CDK4/6 Inhibitor and in Clinical Subgroups.

Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months. EMERALD, an open-label phase III trial, randomly assigned patients with ER+, HER2- metastatic breast cancer who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post hoc exploratory analyses without adjustment for multiple testing. In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, the median PFS for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% confidence interval, 0.26-0.63). In this population, the median PFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3 catalytic subunit α mutation), 8.6 versus 1.9 (tumor protein p53 gene mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1D538G-mutated tumors), and 9.0 versus 1.9 (ESR1Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population. The duration of prior ET+CDK4/6i ≥12 months in metastatic breast cancer was associated with a clinically meaningful improvement in PFS for elacestrant compared with SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.

Preferences of patients and physicians in the United States for relapsed/refractory follicular lymphoma treatments.

Patients with follicular lymphoma (FL) often relapse or become refractory to treatment (R/R). While the R/R FL treatment landscape evolves, little is known about the priorities of patients and physicians. This discrete-choice experiment (DCE) study assessed patients' and physicians' treatment preferences, and the trade-offs they would be willing to make between efficacy, tolerability, and administration. An online survey was conducted in US-based patients (≥18 years) with R/R FL and FL-treating physicians. The DCE was informed by a targeted literature review, clinical data, expert oncologist input, and pilot interviews. Participants completed eight experimental choice tasks where they chose between two hypothetical treatment profiles defined by six attributes: progression-free survival (PFS), administration/monitoring, risks of laboratory abnormalities requiring intervention, severe infections, diarrhea, and cytokine release syndrome (CRS). Relative attribute importance (RAI) and willingness to trade-off between PFS and other attributes were estimated. Two-hundred patients (mean age 63.5 years; median three prior lines of therapy) and 151 FL-treating physicians participated. Increasing PFS was most important for both groups, although it was relatively less important to patients than physicians (RAI 35.2% vs. 45.7%). Administration/monitoring was three times more important to patients than physicians (RAI 28.8% vs. 9.5%); patients preferred oral treatment and would be willing to tolerate a significant reduction in PFS for oral administration over weekly intravenous infusions. Avoiding CRS was less important to patients than to physicians (RAI 7.7% vs. 15.8%). Both groups would accept shorter PFS for reduced risks of side effects (especially of laboratory abnormalities for patients and of CRS for physicians). Although PFS was the most important attribute to patients and physicians, both would tolerate lower PFS for reduced side effects. Patients would also accept a substantial reduction in PFS for oral administration. Differences between the preferences/priorities of patients and physicians highlight the importance of shared decision-making.

OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL

AbstractLisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidence of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.

A Scan Strategy Based Compensation of Cumulative Heating Effects in Electron Beam Powder Bed Fusion

AbstractThe fabrication of complex geometries with uniform material properties in electron beam powder bed fusion (PBF-EB) remains a major challenge. Local material properties in PBF-EB are determined by the local thermal conditions and the spatio-temporal melt pool evolution. The local thermal conditions are governed by the cumulative heating effect on the hatch scale, which results from the superposition of temperature fields from adjacent hatch lines. The build-up of the cumulative heating effect at the beginning of a new hatch segment, without prior hatch lines, which results in regions with underdeveloped thermal conditions, is so far only rarely considered in the design of process strategies. This study introduces a numerical optimization scheme with the objective to minimize the extent of regions with underdeveloped thermal conditions at the beginning of line-based hatches, by means of scan strategy modifications. For this purpose, a simplified thermal solution is combined with an optimization approach to determine an optimal process strategy for line-based PBF-EB of a cuboid model geometry through the adaptation of individual hatch line spacing. Based on the approach determined for the model geometry, a generalized process strategy is derived for complex geometries and is numerically validated for different process parameter and geometry combinations.

Lenvatinib and pembrolizumab versus platinum doublet chemotherapy as second-line therapy for advanced or recurrent endometrial cancer.

There is no consensus on whether platinum doublet chemotherapy or lenvatinib and pembrolizumab (LEN/PEM) is superior for advanced or recurrent endometrial cancer. Thus, this study aimed to compare the prognosis and adverse events in patients with advanced or recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM. We retrospectively reviewed the medical records of patients who received platinum doublet chemotherapy or LEN/PEM at our institution for advanced or recurrent endometrial cancer and had a history of platinum-based chemotherapy between January 2013 and August 2023. During the study period, 11 regimens were identified in the platinum doublet chemotherapy group, and 11 regimens were identified in the LEN/PEM group. The objective response rates of the platinum doublet chemotherapy and LEN/PEM groups were 36.4% and 54.5% (P=0.67), respectively. The 6-month progression-free survival (PFS) rates of the platinum doublet chemotherapy and LEN/PEM groups were 27.3% (95% confidence interval [CI], 13.8-40.7%) and 70.0% (95% CI, 55.5-84.5%), respectively. The differences were significant between the two groups. Multivariate analyses of histology, prior lines of chemotherapy, platinum-free intervals, and regimens revealed that the LEN/PEM group had significantly better PFS rates. Treatment with LEN/PEM resulted in significantly longer PFS than that of treatment with platinum doublet chemotherapy in patients with advanced and recurrent endometrial cancer. However, further large-scale studies are required to validate these findings.

Epstein-Barr virus-positive, primary cutaneous marginal zone lymphoma, with transformation: Case report and review of the literature.

We report a patient with EBV positive PCMZL with subsequent transformation to plasmablastic lymphoma and review the literature for transformed PCMZL to assess clinical and pathologic characteristics. In the case we describe, the patient presented with multifocal PCMZL, developed large B cell transformation with plasmacytic differentiation, followed by plasmablastic transformation (PBL), and ultimately died of disease progression despite multiple lines of therapy. Past history was significant for psoriatic arthritis (multiple prior lines of immunomodulatory therapy). The lymphomas and non-involved bone marrow share the same somatic DNMT3A and TET2 mutations, suggesting clonal relatedness and an association with clonal hematopoiesis (CH). Eighteen cases complied the cohort (seventeen cases from the literature and the case reported herein). Nearly half of the eighteen cases of PCMZL with transformation died of progressive disease (44%). Transformed cases were more commonly seen in patients with >2 sites at initial diagnosis. EBV was assessed in 5 patients, 3 were positive (all died of disease). Two patients with NGS studies demonstrated TET2 and DNMT3A mutations. Transformation of EBV positive PCMZL appears to be a poor prognostic indicator, with our reported case being the first well defined case transformed to PBL, suspected to arise from myeloid-CH.