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Background: Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated symptom benefit measured by TSS (v2.0, excluding tiredness) vs best available therapy (BAT) in PERSIST-2, which enrolled cytopenic myelofibrosis patients with platelets ≤100×10 9/L. Recent datashowed that in patients with cytopenic MF, a ≥10% reduction in spleen volume at 12 weeks is associated with improved survival in patients treated with pacritinib ( Ajufo H, et al., J Clin Oncol;2023:14(16):Suppl). Surprisingly, this association was not confirmed in patients treated with BAT (82% of whom were on ruxolitinib). The association between other important measures of clinical benefit such as symptom burden reduction and anemia improvement on survival in patients treated with pacritinib has not previously been described. Methods: Patients randomized to pacritinib 200 mg BID and to BAT on PERSIST-2 were included if they were alive and on study at the start of the week 12 efficacy assessment period. Survival was assessed by Total Symptom Score (TSS; v2.0 excluding tiredness) reduction at various thresholds (≥50%, ≥20%, ≥10%, >0%) and transfusion independence (TI) response. TI was assessed among patients who required red blood cell (RBC) transfusion at baseline (within 90 days) and was defined, for the purposes of a landmark survival analysis, as the absence of RBC transfusions over any 12-week period from first dose through week 14 (allowing for a ±2-week window around week 12). Overall survival (OS) was estimated via the K-M method following the landmark approach; survival in responders vs non-responders was compared using the log-rank test. Results: Of the 59 patients treated with pacritinib who had a reduction of TSS≥10%, the median age was 67 years, 25% had a baseline high-risk DIPSS, median platelet count was 61 x10 9/L, median hemoglobin was 9.7 g/dL, and baseline TSS was 19.1. Reduction of TSS≥10% was associated with improved OS, with 1 death among 59 responders vs 4 deaths among 30 non-responders (hazard ratio [HR]=0.12, 95% confidence interval [CI]: 0.01, 0.79] P=0.021, Fig 1a). Similar to spleen volume reduction, the association between TSS response and OS weakened at more stringent TSS response thresholds (Fig 1c, e), with the BAT arm not showing an association between TSS response and OS at any threshold. (Fig 1b, d, f). In order to assess the relationship of specific TSS domains and survival , a landmark OS analysis was performed based on ≥20% reduction in physical function scores (sum of ‘tiredness’ and 'inactivity'), spleen-related symptom scores (sum of 'abdominal discomfort', ‘early satiety’, and 'left rib pain'), and cytokine-related symptom scores (sum of 'itching', ‘night sweats’, and ‘bone pain‘). For cytokine-related symptoms, the number of deaths in PAC responders was significantly different compared to non-responders, with 0 deaths among 35 responders vs 2 among 15 non-responders ( P=0.0325). Conversely the deaths among responders (2/22) vs non-responders (2/20) were not significantly different in the BAT arm. For the physical function and spleen-related symptom subscales, no significant differences between PAC responders and non-responders was observed (HR=0.60; 95% CI [0.05, 6.74] P=0.679) and (HR=0.26; 95% CI 0.02, 2.93, P=0.2435) respectively. Among 36 patients on PAC who received RBC transfusions at baseline, 7 achieved TI over at least a 12-week period up to the time of the landmark analysis. There were no deaths among TI responders compared to 2 (6.9%) among TI non-responders. There were too few TI responders on BAT (only 2 out of 38) to assess the impact on survival. Conclusion: In cytopenic myelofibrosis patients enrolled in PERSIST-2, having a reduction of TSS≥10% on full-dose PAC was associated with OS benefit - a finding that has not been noted with other JAK inhibitors to date. By contrast, this association was not found with BAT, (82% of these patients received ruxolitinib). Thus, reductions in TSS in patients treated with PAC were associated with an OS benefit. It is possible that pacritinib, with its distinctive mechanism of action, may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia, and further studies are required to understand the potential mechanisms of these distinct clinical observations. Study funded by CTI BioPharma Corp., a Sobi company.

Our group has reported that transient CD19 antigen masking of leukemic cells with the CD19 monoclonal antibody (mAb), tafasitamab, resulted in reduction of CD19 chimeric antigen receptor T cell (CART19) apoptosis, enhanced CAR T proliferation, improved anti-tumor activity, diminished tumor pyroptosis, and reduced severity of cytokine release syndrome (CRS) in preclinical models. In this report, we aimed to study the mAb characteristics responsible for these observations. Specifically, we hypothesized that binding affinity of CD19 mAbs might affect the subsequent activation and apoptosis of CART19 as well as tumor cell pyroptosis in preclinical models. To test our hypothesis, we first determined the affinities of the CD19-targeting antibodies tafasitamab, HD37 and FMC63 to recombinant human CD19 protein. Tafasitamab demonstrated the strongest binding affinity among the three tested antibodies [tafasitamab ( K D: 1.0±0.2 nM), HD37 ( K D: 4.1±0.3 nM), FMC63 ( K D: 3.4±1.2 nM)]. Next, we studied CART19 apoptosis in the presence of these CD19 mAbs with different binding affinities. Here, we co-cultured CART19, CD19 + mantle cell lymphoma JeKo, and 400 μg/mL of CD19 mAb for 1 hour and measured CD3 + 7-AAD - Annexin V + T cells with flow cytometry. The number of apoptotic CART19 cells was significantly reduced by tafasitamab co-treatment compared to HD37, FMC63, or control IgG [control IgG (mean = 19.1, standard deviation (SD) = 0.8), tafasitamab (mean = 13.1, SD = 2.9), HD37 (mean = 17.8, SD = 0.8), FMC63 (mean = 18.4, SD = 1.0)]. We also performed an in vitro high mobility group box 1 (HMGB1) assay to assess if different affinities of the CD19 mAbs affect tumor cell pyroptosis triggered by CART19. Here, we co-cultured CART19, CD19 + JeKo, and 400 μg/mL of CD19 mAb for 24 hours and assessed HMGB1 on JeKo. In analogy to the apoptosis data, tafasitamab was the only mAb that prevented tumor cell pyroptosis, indicated by reduced HMGB1 expression (Fig 1A). Given these results, we aimed to study the impact of CD19 occupancy with different CD19 mAbs prior to CART19 infusion on tumor pyroptosis in vivo. We utilized a mouse model that mimics CAR T toxicities. Immunocompromised NSG mice were inoculated via tail vein with 5x10 6 leukemic cells derived from patients with relapsed/refractory acute lymphoblastic leukemia. Two weeks later (day -7), tumor burden was assessed by peripheral blood sampling. Leukemic cells were defined as murine CD45 -, human CD45 + CD19 + CD20 + via flow cytometry, and volumetric absolute number was calculated. Mice were then randomized according to tumor burden to receive IgG control [Group 1 (G1)], tafasitamab (G2), HD37 (G3), or FMC63 (G4) (5 mg/kg, ip) at day -7. CRS was determined by weight loss, development of motor weakness, poor body posture, and elevated serum cytokine levels. At day 0, all mice received 3x10 6 luciferase + CART19 via tail vein. Mice were monitored with daily bioluminescent imaging (BLI) to track and quantify CART19 expansion and physical assessment to detect toxicity. BLI on day 4 revealed that CART19 expansion in the tafasitamab-treated group (G2, mean = 1x10 7, SD = 2.3x10 7) was significantly lower than in the control group (mean = 3.5x10 7, SD = 9.3x10 7), the HD37-treated group (G3, mean = 4x10 7, SD = 6.6x10 7), and the FMC63-treated group (G4, mean = 2x10 7, SD = 3.59x10 7), [G1 vs G2: 95% confidence interval (CI) 3.5x10 7 to 1.1x10 8, p <0.0001, G1 vs G3: 95% CI -7.5x10 7 to -1.1x10 8, p=0.005, G1 vs G4: 95% CI -4.5x10 7 to 1.9x10 7, p=0.71] indicating that tafasitamab pretreatment significantly reduced early activation of CART19 compared to IgG control and HD37 in this model. Mice were bled on day 4 to analyze plasma cytokine. Tafasitamab-treated mice (G2) secreted significantly less IFNγ (Fig 1B), IL10 (Mean G1: 78, G2: 2.52, G3: 12.2, G4: 13.9 pg/mL), MDC (Mean G1: 4072, G2: 445, G3: 921, G4: 1364 pg/mL), and MIP1β (Mean G1: 283, G2: 59.1, G3: 148, G4: 123 pg/mL) compared to G1, G3, and G4. Satellite mice were euthanized on day 1 and spleens were harvested. Western blot analysis of splenocytes revealed that G1, 3, and 4 showed significantly lower expression of apoptosis-inducing protein gasdermin E on leukemic cells compared to G2, indicating reduced tumor pyroptosis in G2. In summary, application of the high affinity mAb tafasitamab prior to CART19 resulted in reduced CAR T apoptosis, diminished tumor cell pyroptosis, and reduction of CRS compared to lower affinity CD19 mAbs in preclinical models.

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leucocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, paralleldesign, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to Day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥0.3 mg/dL (or 26.5 µmol/L) from presurgery baseline within 48±4 hours of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen reduced RBCs through 75 days after the last study transfusion. With ≥292 evaluable, transfused patients (>146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBC.

OBJECTIVE The goal of this study was to characterize local tumor control (LC), overall survival (OS), and safety of stereotactic radiosurgery for colorectal brain metastasis (CRBM). METHODS Ten international institutions participating in the International Radiosurgery Research Foundation provided data for this retrospective case series. This study included 187 patients with CRBM (281 tumors), with a median age of 62 years and 56.7% being male. Most patients (53.5%) had solitary tumors, although 10.7% had > 5 tumors. The median tumor volume was 2.7 cm3 (IQR 0.22–8.1 cm3), and the median margin dose was 20 Gy (IQR 18–22 Gy). RESULTS The 3-year LC and OS rates were 72% and 20%, respectively. Symptomatic adverse radiation effects occurred in 1.6% of patients. In the multivariate analysis, age > 65 years and tumor volume > 4.0 cm3 were significant predictors of tumor progression (hazard ratio [HR] 2.6, 95% CI 1.4–4.9; p = 0.003 and HR 3.4, 95% CI 1.7–6.9; p < 0.001, respectively). Better performance status (Karnofsky Performance Scale score > 80) was associated with a reduced risk of tumor progression (HR 0.38, 95% CI 0.19–0.73; p = 0.004). Patient age > 62 years (HR 1.6, 95% CI 1.1–2.3; p = 0.03) and the presence of active extracranial disease (HR 1.7, 95% CI 1.1–2.4; p = 0.009) were significantly associated with worse OS. CONCLUSIONS Stereotactic radiosurgery offers a high LC rate and a low rate of symptomatic adverse radiation effects for the majority of CRBMs. The OS and LC favored younger patients with high functional performance scores and inactive extracranial disease.

A growing body of research has begun to link exposure to environmental contaminants, such as heavy metals, with a variety of negative health outcomes. In this paper, we sought to review the current research describing the impact of certain common contaminant metals on cardiovascular (CV) health. We reviewed ten metals: lead, barium, nickel, chromium, cadmium, arsenic, mercury, selenium, zinc, and copper. After a literature review, we briefly summarized the routes of environmental exposure, pathophysiological mechanisms, CV health impacts, and exposure prevention and/or mitigation strategies for each metal. The resulting article discloses a broad spectrum of pathological significance, from relatively benign substances with little to no described effects on CV health, such as chromium and selenium, to substances with a wide-ranging and relatively severe spectrum of CV pathologies, such as arsenic, cadmium, and lead. It is our hope that this article will provide clinicians with a practical overview of the impact of these common environmental contaminants on CV health as well as highlight areas that require further investigation to better understand how these metals impact the incidence and progression of CV diseases.

Abstract In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.

OBJECTIVE Spine metastases are commonly treated with radiotherapy for local tumor control; pathologic fracture is a potential complication of spinal radiotherapy. Both Hounsfield units (HUs) on CT and vertebral bone quality (VBQ) on MRI have been argued to predict stability as measured by odds of pathologic fracture, although it is unclear if there is a difference in the predictive power between the two methodologies. The objective of the present study was to examine whether one methodology is a better predictor of pathologic fracture following radiotherapy for mobile spine metastases. METHODS Patients who underwent radiotherapy (conventional external-beam radiation therapy, stereotactic body radiation therapy, or intensity-modulated radiation therapy) for mobile spine (C1–L5) metastases at a tertiary care center were retrospectively identified. Details regarding underlying pathology, patient demographics, and tumor morphology were collected. Vertebral involvement was assessed using the Weinstein-Boriani-Biagini (WBB) system. Bone quality of the non–tumor-involved bone was assessed on both pretreatment CT and MRI. Univariable analyses were conducted to identify independent predictors of fracture, and Kaplan-Meier analyses were used to identify significant predictors of time to pathologic fracture. Stepwise Cox regression analysis was used to determine independent predictors of time to fracture. RESULTS One hundred patients were included (mean age 62.7 ± 11.9 years; 61% male), of whom 35 experienced postradiotherapy pathologic fractures. The most common histologies were lung (22%), prostate (21%), breast (14%), and renal cell (13%). On univariable analysis, the mean HUs of the vertebrae adjacent to the fractured vertebra were significantly lower among those experiencing fracture; VBQ was not significantly associated with fracture odds. Survival analysis showed that average HUs ≤ 132, nonprostate pathology, involvement of ≥ 3 vertebral body segments on the WBB system, Spine Instability Neoplastic Score (SINS) ≥ 7, and the presence of axial pain all predicted increased odds of fracture (all p < 0.001). Cox regression found that HUs ≤ 132 (OR 2.533, 95% CI 1.257–5.103; p = 0.009), ≥ 3 WBB vertebral body segments involved (OR 2.376, 95% CI 1.132–4.987; p = 0.022), and axial pain (OR 2.036, 95% CI 0.916–4.526; p = 0.081) predicted increased fracture odds, while prostate pathology predicted decreased odds (OR 0.076, 95% CI 0.009–0.613; p = 0.016). Sensitivity analysis suggested that an HU threshold of ≤ 132 and a SINS of ≥ 7 identified patients at increased risk of fracture. CONCLUSIONS The present results suggest that bone density surrogates as measured on CT, but not MRI, can be used to predict the risk of pathologic fracture following radiotherapy for mobile spine metastases. More extensive vertebral body involvement and the presence of mechanical axial pain additionally predict increased fracture odds.

PURPOSE To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2–positive (HER2+) metastatic biliary tract cancer (mBTC). METHODS SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380 ) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks). RESULTS Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs. CONCLUSION Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.