SAFETY AND EFFICACY OF LONCASTUXIMAB TESIRINE WITH RITUXIMAB IN FOLLICULAR LYMPHOMA

There is no standard-of-care for treatment of relapsed/ refractory (rel/ref) follicular lymphoma (FL). Loncastuximab tesirine (loncastuximab) is an antibody-drug conjugate directed against CD19. Here we report initial results of a single-institution study evaluating this combination in rel/ref FL (NCT04998669). Adult patients with rel/ref FL previously treated with ≥1 line of systemic therapy presenting GELF criteria or progression of disease within 24 months (POD24) at enrollment were eligible. Primary study endpoint was complete response (GR) by week 12 PET/GT. The initial 21 weeks of therapy consisted of 4 weekly doses of rituximab i.v. 375mg/m2 followed by 1 dose every 8 weeks for a total of 5 doses in association with loncastuximab i.v. 0.15mg/kg every 3 weeks for 2 doses followed by 0.075mg/kg every 3 weeks for a total of 7 doses. Premedication with dexamethasone 4 mg twice daily for 3 days was required. Patients achieving GR at week 21 discontinued loncastuximab and received two doses of rituximab every 8 weeks. Twenty-six patients have been enrolled from January 2022 to July 2023,25 evaluable for toxicity and 21 for response. Median age was 68 years (range 47 to 89). Most were women (n=14; 54%), with advanced-stage (11=20; 77%), high-risk FLIPI score (n=i3; 50%), and 12 (46%) demonstrating POD24 after immunochemotherapy. Median lines of prior therapy were 1 (range 1 to 6). Most common adverse events included alkaline-phosphatase, ALT, AST elevation; maculo-papular rash, fatigue, thrombocytopenia, photosensitivity, leg edema, anasarca and neutropenia. All toxicities resolved with supportive management and dose delays (n= 4). GR was observed in 7 of the initial 10 patients meeting pre-specified criteria to proceed to stage II. Among 21 patients evaluable for response, the overall response rate at week 12 was 95.2% [GR rate of 66.7% (n=i4), partial response (PR) rate of 28.6% (n=6)]. All GR were maintained and 4 of the 6 PR (2 patient have not yet re-evaluated) improved to GR at week 21 for a best GR rate of 86% (n= 18). All seven patients who completed the study remained in G R after end of treatment for a median follow up of 4.8 months (range 3.2 to 6.7). Loncastuximab with rituximab in patients with rel/ref FL is well tolerated and highly effective with a metabolic G R rate

Redox state of iron during high-pressure serpentinite dehydration

International audienceThe Cerro del Almirez massif (Spain) represents a unique fragment of serpentinized oceanic lithosphere that has been first equilibrated in the antigorite stability field (Atg-serpentinites) and then dehydrated into chlorite–olivine–orthopyroxene (Chl-harzburgites) at eclogite facies conditions during subduction. The massif preserves a dehydration front between Atg-serpentinites and Chl-harzburgites. It constitutes a suitable place to study redox changes in serpentinites and the nature of the released fluids during their dehydration. Relative to abyssal serpentinites, Atg-serpentinites display a low Fe3+/FeTotal(BR) (=0.55) and magnetite modal content (=2.8–4.3 wt%). Micro-X-ray absorption near-edge structure (μ-XANES) spectroscopy measurements of serpentines at the Fe–K edge show that antigorite has a lower Fe3+/FeTotal ratio (=0.48) than oceanic lizardite/chrysotile assemblages. The onset of Atg-serpentinites dehydration is marked by the crystallization of a Fe3+-rich antigorite (Fe3+/FeTotal = 0.6–0.75) in equilibrium with secondary olivine and by a decrease in magnetite amount (=1.6–2.2 wt%). This suggests a preferential partitioning of Fe3+ into serpentine rather than into olivine. The Atg-breakdown is marked by a decrease in Fe3+/FeTotal(BR) (=0.34–0.41), the crystallization of Fe2+-rich phases and the quasi-disappearance of magnetite (=0.6–1.4 wt.%). The observation of Fe3+-rich hematite and ilmenite intergrowths suggests that the O2 released by the crystallization of Fe2+-rich phases could promote hematite crystallization and a subsequent increase in fo2 inside the portion of the subducted mantle. Serpentinite dehydration could thus produce highly oxidized fluids in subduction zones and contribute to the oxidization of the sub-arc mantle wedge

Effects of Float Nursing on Patient Care and Safety

https://scholarlycommons.baptisthealth.net/cohort-5-ebp-showcase/1011/thumbnail.jp

Limited Duration Loncastuximab Tesirine with Rituximab Induces High Complete Metabolic Response Rate in High-Risk Relapsed/Refractory Follicular Lymphoma - a Phase 2 Study

Introduction: There is no standard-of-care for treatment of relapsed/refractory (rel/ref) follicular lymphoma (FL) with worse prognosis in those demonstrating progression of disease within 24 months (POD24) from frontline immunochemotherapy. Loncastuximab tesirine (loncastuximab) is an antibody-drug conjugate comprising a monoclonal antibody directed against CD19 and a DNA cross-linking pyrrolobenzodiazepine. Preclinical data demonstrated synergistic activity between rituximab-induced cytotoxicity and loncastuximab. Here we report pre-specified initial results of a single-institution investigator-initiated study evaluating this combination for the first time in FL (NCT04998669). Methods: Adult patients with rel/ref FL previously treated with ≥1 line of systemic therapy presenting GELF criteria or POD24 at enrollment were eligible.Primary study endpoint was complete response (CR) by week 12 PET/CT based on Lugano 2014 criteria. Bone marrow biopsy was required at screening and repeated at week 12 if initial involvement. The initial 21 weeks of therapy consisted of 4 weekly doses of rituximab i.v. 375mg/m 2 followed by 1 dose every 8 weeks for a total of 5 doses in association with loncastuximab i.v. 0.15mg/kg every 3 weeks for 2 doses followed by 0.075mg/kg every 3 weeks for a total of 7 doses. Patients achieving CR by week 21 PET/CT discontinued loncastuximab and received two more doses of rituximab every 8 weeks. Premedication with dexamethasone 4 mg twice daily for 3 days was required with loncastuximab. No antibiotic or growth factor prophylaxis was mandated by study protocol. Enrollment occurred according to a Simon's minimax two-stage design with a total sample size of 39 patients based upon a projected CR rate ≥50% vs ≤30% (H0), type I error alpha 5%, power 80%. In stage 1, 19 patients enrolled and 7 or more CRs were required to proceed with stage II. In stage II, an additional 20 patients will be enrolled. Based on n=39, a total of ≥17 CRs are required for rejecting the H0. Results: Twenty-six patients have been enrolled from January 2022 to July 2023, 25 evaluable for toxicity (1 patient has not yet initiated treatment) and 21 for response. Median age was 68 years (range 47 to 89). Most were women (n=14; 54%), with advanced-stage (n=20; 77%), high-risk FLIPI score (n=13; 50%), and 12 (46%) demonstrating POD24 after immunochemotherapy. Median lines of prior therapy were 1 (range 1 to 6). R-CHOP was most common first-line therapy (n=14; 54%) followed by bendamustine with rituximab and single-agent rituximab (n=6; 23%; each). Most common grade 1 adverse events (AEs) included alkaline-phosphatase (48%), ALT (44%), AST (36%) elevation; maculo-papular rash (44%), fatigue (28%), thrombocytopenia (28%), photosensitivity (28%), leg edema (24%), and anasarca (20%). Grade 2 AEs were alkaline phosphatase elevation (12%), anasarca (8%) and leg edema (4%) Grade 3 AEs included neutropenia (n=2; 8%), and one case each (4%) of cellulitis and pleural effusion. Neutropenia was the only grade 4 AE in a patient post-CAR T-cell. All toxicities resolved with supportive management and dose delays (n= 4); no treatment-related deaths occurred during study period. CR was observed in 7 of the initial 10 patients meeting pre-specified criteria to proceed to stage II. Among 21 patients evaluable for response, the overall response rate at week 12 was 95.2% [CR rate of 66.7% (n=14), partial response (PR) rate of 28.6% (n=6)]. All CR were maintained and 4 of the 6 PR (2 patient have not yet re-evaluated) improved to CR at week 21 for a best CR rate of 86% (n= 18). Baseline bone marrow involvement by FL resolved in all patients (n=5) at week 12 reassessment. Two patients were removed from the study. One patient due to disease progression on week 12 PET/CT with biopsy-proven diffuse large B-cell lymphoma in a kidney mass and another with cholangiocarcinoma, who achieved CR with respect to known lymphoma involvement. Both lesions were present before study enrollment but radiologically considered FL. All seven patients who completed the study remained in CR after end of treatment for a median follow up of 4.8 months (range 3.2 to 6.7) ( Figure 1). Updated analysis will be presented at the meeting. Conclusion: A limited duration program combining loncastuximab with rituximab in patients with rel/ref FL is well tolerated and highly effective with a metabolic CR rate of 86% including high-risk patients with POD24 and/or high disease burden

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

International audienceAbstract Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis

Abstract 1185: H3B-8800, a novel orally available SF3b modulator, shows preclinical efficacy across spliceosome mutant cancers

Abstract Genomic characterization of hematologic and solid cancers has revealed recurrent somatic mutations affecting genes encoding the RNA splicing factors SF3B1, U2AF1, SRSF2 and ZRSR2. Recent data reveal that these mutations confer an alteration of function inducing aberrant splicing and rendering spliceosome mutant cells preferentially sensitive to splicing modulation compared with wildtype (WT) cells. Here we describe a novel orally bioavailable small molecule SF3B1 modulator identified through a medicinal chemistry effort aimed at optimizing compounds for preferential lethality in spliceosome mutant cells. H3B-8800 potently binds to WT or mutant SF3b complexes and modulates splicing in in vitro biochemical splicing assays and cellular pharmacodynamic assays. The selectivity of H3B-8800 was confirmed by observing lack of activity in cells expressing SF3B1R1074H, the SF3B1 mutation previously shown to confer resistance to other splicing modulators. Although H3B-8800 binds both WT and mutant SF3B1, it results in preferential lethality of cancer cells expressing SF3B1K700E, SRSF2P95H, or U2AF1S34F mutations compared to WT cells. In animals xenografted with SF3B1K700E knock-in leukemia K562 cells or mice transplanted with Srsf2P95H/MLL-AF9 mouse AML cells, oral H3B-8800 treatment demonstrated splicing modulation and inhibited tumor growth, while no therapeutic impact was seen in WT controls. These data were also evident in patient-derived xenografts (PDX) from patients with CMML where H3B-8800 resulted in a substantial reduction of leukemic burden only in SRSF2-mutant but not in WT CMML PDX models. Additionally, due to the high frequency of U2AF1 mutations in non-small cell lung cancer, H3B-8800 was tested in U2AF1S34F-mutant H441 lung cancer cells. Similar to the results from leukemia models, H3B-8800 demonstrated preferential lethality of U2AF1-mutant cells in vitro and in in vivo orthotopic xenografts at well tolerated doses. RNA-seq of isogenic K562 cells treated with H3B-8800 revealed dose-dependent inhibition of splicing. Although global inhibition of RNA splicing was not observed; H3B-8800 treatment led to preferential intron retention of transcripts with shorter and more GC-rich regions compared to those unaffected by drug. Interestingly, H3B-8800-retained introns commonly disrupted the expression of spliceosomal genes, suggesting that the preferential effect of H3B-8800 on spliceosome mutant cells is due to the dependency of these cells on expression of WT spliceosomal genes. These data identify a novel therapeutic approach with selective lethality in leukemias and lung cancers bearing a spliceosome mutation. Despite the essential nature of splicing, cancer cells without a spliceosome mutation were less sensitive to H3B-8800 compared with potent eradication of mutant counterparts. H3B-8800 is currently undergoing clinical evaluation in patients with MDS, AML, and CMML. Citation Format: Silvia Buonamici, Akihide Yoshimi, Michael Thomas, Michael Seiler, Betty Chan, Benjamin Caleb, Fred Csibi, Rachel Darman, Peter Fekkes, Craig Karr, Gregg Keaney, Amy Kim, Virginia Klimek, Pavan Kumar, Kaiko Kunii, Stanley Chun-Wei Lee, Xiang Liu, Crystal MacKenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Sudeep Prajapati, Nathalie Rioux, Justin Taylor, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel-Wahab, Peter Smith. H3B-8800, a novel orally available SF3b modulator, shows preclinical efficacy across spliceosome mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1185. doi:10.1158/1538-7445.AM2017-118

Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

International audienceThe cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect