Murthy, Hemant S.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease listed as a separate entity in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. It is a clinically aggressive hematologic malignancy derived from precursors of plasmacytoid dendritic cells. Traditionally, therapeutic options for BPDCN consisted of conventional antineoplastic chemotherapy, adopted from regimens used to treat acute leukemia (myeloid or lymphoblastic, or lymphomas. Tagraxofusp, a CD123 directed antibody conjugate composed of human interleukin-3 (IL-3) and truncated diphtheria toxin, is also approved for treatment of BPDCN. Unfortunately, none of these are curative options of this disease. Allogeneic (Allo) hematopoietic cell transplantation (HCT) is an established treatment modality for patients with BPDCN with reported encouraging survival, whereas reported data on autologous (auto) HCT are limited. Methods: We conducted a systematic review and meta-analysis (SR/MA) to assess the totality of evidence on the role of allo- and auto-HCT in patients with BPDCN. We performed a comprehensive search of EMBASE and PUBMED/MEDLINE, on April 25, 2024. To be eligible for inclusion in this SR/MA, studies must have included ≥10 patients; be published in full manuscript or letter to editor and have evaluated the use of an allo-HCT and/or auto-HCT for treating BPDCN. Pertaining to benefits, we extracted data based on complete remission (CR), progression-free survival (PFS) (substituted with disease-free survival (DFS) if PFS missing), and overall survival (OS). For harms, we extracted data on non-relapse mortality (NRM) and relapse. Data were pooled under a random effects model. Results: Initial search identified 692 references, of which, 10 met our inclusion criteria. For allo-HCT, 10 studies were included; and for auto-HCT, there were 3 studies. For allo-HCT, pooled rates for CR, PFS/DFS and OS were 69% (2 studies, 91 patients (pts)), 49% (10 studies, 561 pts), and 55% (9 studies, 531 pts), respectively. Pooled rates for NRM and relapse were 24% (8 studies, 470 pts) and 24% (10 studies, 561 pts). Tests of heterogeneity were as follows: for CR analysis (I2=97.04%), PFS/DFS (I2=79.57%), OS (I2=33.18%), NRM (I2=0) and relapse (I2=55.55%). For auto-HCT, only one study reported CR=100%. Pooled rates of PFS/DFS and OS were 68% (3 studies, 43 pts), and 66% (3 studies, 43 pts), respectively. Pooled rates for NRM and relapse were 3% (2 studies, 27 pts) and 25% (3 studies, 43 pts). Tests of heterogeneity were as follows: for CR analysis (I2=not applicable), PFS/DFS (I2=0), OS (I2=27.90%), NRM (I2=0) and relapse (I2=0). A subgroup analysis for allo-HCT recipients in CR1 showed pooled rates of PFS and OS of 60% (5 studies, 76 pts) and 69% (5 studies, 76 pts), respectively. Tests of heterogeneity for PFS and OS for the allo-HCT in CR1 were I2=51.99% and I2=0, respectively. Conclusion: Results of this SR/MA demonstrate that both allo-HCT and auto-HCT are effective treatments for patients with BPDCN, although data supporting the latter are scarce. Allo-HCT in CR1 is associated with a higher pooled rate of OS (69%). Efforts should focus on prompt referral of BPDCN patients for an allo-HCT in CR1, whenever possible, to optimize survival outcomes.

AbstractNational performance metrics ultimately enhance patient decision‐making and promote meaningful improvements in health care delivery, which makes having valid and reliable measures essential. This study examined US News and World Report metrics from 2019 to 2012 and used electronic health record data, combined with detailed chart review across 3 in‐system hospitals, to assess the provision of care compared to the attribution of patients assigned to the ear, nose, and throat (ENT) mortality group. Of the initial 47 ENT‐attributed deaths, 23 of those were verified, dimensioning the mortality rate from 1.7% to just 0.8%. These results underscore the necessity of rethinking measures and mortality attribution methodologies to be more accurate. Current methods use Medicare Severity Diagnosis Related Group billing coding to map the attribution. We suggest transitioning away from specialty ranking approaches and towards a procedure and condition “rating” approach to ensure that these ranking types capture data about the provision of care within a given encounter.

Abstract Background Hypomagnesemia has been correlated with inferior outcomes in patients with large B cell lymphoma (LBCL) undergoing stem cell transplants. As T-cell and myeloid cell dysfunction have been associated with low magnesium conditions, we investigated whether serum magnesium (Mg) levels could predict clinical outcomes in LBCL patients who received chimeric antigen receptor T-cell therapy. Methods Patients with LBCL who received axi-cel under the ZUMA-1 trial or as FDA approved therapy at Mayo Clinic were examined. Serum samples were obtained at specified time points and cytokine analysis was performed. Single cell RNA sequencing was performed on peripheral blood mononuclear cells. The Student T-test, Kruskal Wallis, or Fisher's Exact Tests were used to compare differences in demographics across Mg levels. Survival curves were plotted using the Kaplan-Meier methodology and compared using the Wilcoxon test. Results We found that hypomagnesemia before lymphodepletion chemotherapy predicted for inferior progression-free and overall survival in the pivotal study ZUMA-1 (NCT02348216). These results were validated in an independent cohort of LBCL patients receiving axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Hypomagnesemia correlated with increased inflammatory serum markers and cytokine levels including ferritin, IL-6, IL1Ra, IL-8, and MIP1a. scRNAseq analysis unveiled altered immune interactions between monocytes and T cells with a concordant immune suppressive transcriptome. Conclusions Hypomagnesemia at the time of CAR-T infusion associates with an unfavorable inflammatory profile and decreased response and survival in LBCL patients receiving axi-cel. These findings suggest a potentially actionable prognostic factor for patients with large cell lymphoma undergoing CAR-T.

AbstractThe challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients.

Abstract Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.

TPS2682 Background: Myeloid cells are actively recruited to the solid tumor microenvironment (TME) and have the potential to mediate tumor control via phagocytosis, TME remodeling, and T cell activation. We previously developed human chimeric antigen receptor macrophages (CAR-M) and have shown potent anti-tumor activity in pre-clinical solid tumor models. The anti-HER2 CAR-M cell therapy product, CT-0508, is currently being evaluated in a Phase I trial as a monotherapy and in combination with pembrolizumab. Early clinical data have shown feasibility, safety, and validated the mechanism of action. We have developed a next-generation CAR monocyte (CAR-Mono) platform to increase the dose, improve tumor trafficking and engraftment, and shorten the manufacturing and vein-to-vein time as compared to CAR-M therapy. CT-0525 is an autologous anti-HER2 CAR-Mono cell therapy based on CD14+ monocytes engineered with an Ad5f35 adenoviral vector to express an anti-HER2 CAR. Pre-clinical studies have demonstrated the feasibility, phenotype, pharmacokinetics, durable CAR expression, cellular fate, antigen specificity, and anti-tumor activity of CT-0525. Pre-clinical studies have shown that CT-0525 differentiated into pro-inflammatory CAR-M in vivo and controlled tumor growth. The CT-0525 manufacturing process takes one day and enables the production of up to 10 billion cells from a single apheresis. CT-0525 is being investigated in a first-in-human, open-label, multi-center, Phase I study in patients with HER2 overexpressing solid tumors. Methods: This Phase 1, first-in-human study evaluates the feasibility, safety, tolerability, trafficking, TME activation, and preliminary evidence of efficacy of the investigational CAR-Mono product CT-0525 in 6 participants (pts) with locally advanced unresectable/metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. The 1st cohort of pts (n=3) will receive 3 x 109 CT-0525 CAR positive monocytes administered IV in one infusion. If tolerated as per the modified toxicity probability interval algorithm (mTPI), the 2nd cohort of pts (n=3) will receive up to 10 x 109 CT-0525 CAR positive monocytes in one infusion. CT-0525 will be administered without conditioning chemotherapy. Primary endpoints include assessment of safety and tolerability, as well as manufacture feasibility. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety, immunogenicity, pharmacokinetics, tumor trafficking, TME modulation, epitope spreading, and other translational biomarkers. Clinical trial information: NCT06254807 .