ALBERT

Description: Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34+ cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 × 106 CD34+ cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m2) and either SCF (20 μg/kg/d) combined with filgrastim (5 μg/kg/d) or filgrastim alone (5 μg/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 μg/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 × 106 CD34+ cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P = .008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 × 106 CD34+ cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34+ cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 × 106/kg, P = .003) and all leukaphereses (12.4v 8.2 × 106/kg, P = .007). Total colony-forming unit–granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34+ cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34+cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 × 106CD34+ cells/kg.

Description: To assess whether treatment with enoxaparin and low-dose aspirin, along with intensive pregnancy surveillance, reduces rate of pregnancy loss compared with intensive pregnancy surveillance alone in women with history of 2 or more consecutive previous pregnancy losses, a parallel group, multicenter, randomized controlled trial was performed in the United Kingdom and New Zealand. Participants (n = 294) presenting for initial antenatal care at fewer than 7 weeks' gestation with history of 2 or more consecutive previous pregnancy losses at 24 or fewer weeks' gestation and no evidence of anatomic, endocrine, chromosomal, or immunologic abnormality were randomly assigned to receive either enoxaparin 40 mg subcutaneously and 75 mg of aspirin orally once daily along with intense pregnancy surveillance or intense pregnancy surveillance alone from random assignment until 36 weeks' gestation. The primary outcome measure was pregnancy loss rate. Of the 147 participants receiving pharmacologic intervention, 32 (22%) pregnancy losses occurred, compared with 29 losses (20%) in the 147 subjects receiving intensive surveillance alone, giving an odds ratio of 0.91 (95% confidence interval, 0.52-1.59) of having a successful pregnancy with pharmacologic intervention. Thus, we observed no reduction in pregnancy loss rate with antithrombotic intervention in pregnant women with 2 or more consecutive previous pregnancy losses. The trial was registered at http://www.controlled-trials.com as ISRCTN06774126.

Description: Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34+ cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 × 106 CD34+ cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m2) and either SCF (20 μg/kg/d) combined with filgrastim (5 μg/kg/d) or filgrastim alone (5 μg/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 μg/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 × 106 CD34+ cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P = .008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 × 106 CD34+ cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34+ cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 × 106/kg, P = .003) and all leukaphereses (12.4v 8.2 × 106/kg, P = .007). Total colony-forming unit–granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34+ cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34+cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 × 106CD34+ cells/kg.

Description: Activation of the transcription factor NFκB in peripheral blood T cells from patients with renal cell carcinoma (RCC) is compromised. This impaired signaling function results from a failure of RelA and c-Rel to translocate to the nucleus though normal levels of Rel proteins are present in the cytoplasm. We demonstrate here in a subset of RCC patients that the defect in NFκB activation is attributable to the absence of phosphorylation and degradation of the inhibitor IκB. In patient T cells there was no stimulus dependent decrease in the cytoplasmic level of IκB. Coimmunoprecipitation studies showed that RelA was in complex with IκB and was not released after stimulation. Moreover, the phosphorylated form of IκB detected in normal T cells after activation is absent in patient T cells. Additional experiments showed that soluble products from RCCs (RCC-S) can reproduce the same phenotype in T cells from healthy individuals. Supernatant fluid from cultured explants of RCC, but not normal kidney, inhibited the stimulus dependent nuclear translocation of NFκB without altering the cytoplasmic levels of RelA, c-Rel, and NFκB1. Phosphorylation and degradation of IκB was also blocked by RCC-S. The mechanistic similarities between patient-derived T cells and normal T cells cultured with RCC-S suggest that the tumor-derived products may be the primary mediators of impaired T-cell function in this tumor system. © 1998 by The American Society of Hematology.

Description: Activation of the transcription factor NFκB in peripheral blood T cells from patients with renal cell carcinoma (RCC) is compromised. This impaired signaling function results from a failure of RelA and c-Rel to translocate to the nucleus though normal levels of Rel proteins are present in the cytoplasm. We demonstrate here in a subset of RCC patients that the defect in NFκB activation is attributable to the absence of phosphorylation and degradation of the inhibitor IκB. In patient T cells there was no stimulus dependent decrease in the cytoplasmic level of IκB. Coimmunoprecipitation studies showed that RelA was in complex with IκB and was not released after stimulation. Moreover, the phosphorylated form of IκB detected in normal T cells after activation is absent in patient T cells. Additional experiments showed that soluble products from RCCs (RCC-S) can reproduce the same phenotype in T cells from healthy individuals. Supernatant fluid from cultured explants of RCC, but not normal kidney, inhibited the stimulus dependent nuclear translocation of NFκB without altering the cytoplasmic levels of RelA, c-Rel, and NFκB1. Phosphorylation and degradation of IκB was also blocked by RCC-S. The mechanistic similarities between patient-derived T cells and normal T cells cultured with RCC-S suggest that the tumor-derived products may be the primary mediators of impaired T-cell function in this tumor system. © 1998 by The American Society of Hematology.

Description: Background: Tisagenlecleucel was approved in Europe for relapsed/refractory acute lymphoblastic leukemia (ALL) in young patients in 2018. In England, a national CAR T cell panel (NCCP ALL) ensures equity of access and assesses eligibility using inclusion and exclusion criteria based on the ELIANA study. All UK cases are discussed. Eligible cases are allocated to one of 9 JACIE-FACT IEC-approved centres based on age-appropriate service, capacity, distance and patient preference. We systematically reviewed all cases from panel inception providing an opportunity to analyse complete real-world ALL outcomes from this national access programme for tisagenlecleucel on an intention-to-treat (ITT) basis. Methods: We included all patients discussed in the NCCP ALL from Nov 2018 up to July 16th 2020. Clinical data were retrospectively reported in a standardised dataset to allow central analysis of disease and toxicity-related outcomes. Survival outcomes were assessed as for other CAR studies, using Kaplan-Meier estimates of survival from infusion. These included overall survival (interval to death from any cause) and event-free survival as defined in the ELIANA study (interval to death, disease relapse, or treatment failure defined in turn as failure to respond by day 30, with patients receiving further therapy being censored). In order to report outcomes on an ITT basis, survival outcomes were also assessed from time of treatment allocation for all patients considered eligible for tisagenlecleucel. Further, a more comprehensive event-free survival measure encompassing interval to molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Median follow up was calculated using a reverse Kaplan-Meier method. Results: Figure 1 demonstrates all patients: 66 patients were screened, 60 patients were deemed eligible for therapy (the ITT cohort), 57 patients were harvested and 49 infused. A total of 3 patients were not harvested and 2 not infused because of progressive disease (n=4) and 1 manufacturing failure. Patient and disease characteristics are summarised in Table 1. The cohort comprised patients with advanced ALL, having been treated with a median of 2.5 therapy lines not including HSCT (range 1-6), and with 47.5% of the cohort having had a prior HSCT. The median follow-up from infusion was 9.9 months and from treatment allocation for the ITT cohort was 11.9 months. The median lead time from allocation to infusion was 2 months. The CR/CRi rate was 95% in the first 90 days, 78.9% were MRD-. On an ITT basis, CR/CRi rate was 84.8%. Median OS and EFS as defined in the ELIANA study were not reached. Overall survival at 6 and 12 months for infused patients was 97.6% and 86.1%, and for the ITT cohort was 90.4% and 78.3%. EFS for infused patients at 6 and 12 months were 74.8% and 68.2%, and for the ITT cohort were 78.5% and 60.9%. Of 49 patients infused, 14 (28.5%) received further therapy including 6 (8.2%) who received allogeneic SCT for relapse or B cell recovery. For patients relapsing following CR (n=10 infused) there were 4/10 CD19- relapses. A composite EFS including molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Using this more stringent definition from infusion, the 6, 12 month EFS were 47.6%, and 33.6% and from treatment allocation for the ITT cohort were 63% and 34.3% Toxicity outcomes are summarised in Table 2. Severe (grade ≥3) CRS, neurotoxicity, infection or cytopenia after day 30 post infusion occurred in 20.4%, 10.2% 27.1% and 54.2% respectively. 71.4% of the cohort developed hypogammaglobulinaemia, (Figure 3A). The 6 and 12 month probabilities of B cell depletion were 67.1% and 51.3% respectively. Conclusions: Whilst registry data provide outcomes of large cohorts receiving Tisagenlecleucel, standardised data collection on complete populations are lacking. The framework of a national access scheme provides a unique opportunity to study outcomes on an ITT basis. The CR and MRD negative CR rates, as well as conventional EFS and OS and severe toxicities noted in our cohort compare favourably to published registry reports (Grupp et al., 2019). We found a greater proportion of CD19+ compared to CD19- relapses than noted in the ELIANA study. Consideration of OS and EFS on an ITT basis are informative for clinicians when screening patients for eligibility. If selected for presentation at ASH 2020, updated data will be presented Disclosures Ghorashian: Amgen: Honoraria; Novartis: Honoraria; UCLB: Patents & Royalties. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Roddie:Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Neill:Novartis: Other: Funded attendance at academic conferences; Celgene: Other: Funded attendance at academic conferences. Pagliuca:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Patel:Novartis: Honoraria, Other: travel support. Hough:Novartis: Other: Travel support.