Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population.

Evaluation of Posaconazole Serum Concentrations Achieved With Delayed-release Tablets and Oral Suspension in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Data on posaconazole serum levels of patients on prophylaxis with delayed-release tablets or oral suspension during intensive chemotherapy for acute myeloid leukemia and myelodysplastic syndrome are scarce. In this analysis, the proportion of patients with acute myeloid leukemia/myelodysplastic syndrome achieving posaconazole target concentrations with delayed-release tablets was higher than with oral suspension.

Prevalence of right-left shunt in stroke patients with cancer.

BACKGROUND AND OBJECTIVES: Cancer is associated with an increased risk of acute ischemic stroke (AIS) and venous thromboembolism. The role of a cardiac right-left shunt (RLS) as a surrogate parameter for paradoxical embolism in cancer-related strokes is uncertain. We sought to investigate the relationship between the presence of a RLS and cancer in AIS patients. METHODS: We included consecutive AIS patients hospitalized at our tertiary stroke center between January 2015 and December 2020 with available RLS status as detected on transesophageal echocardiography (TEE). Active cancers were retrospectively identified and the association with RLS was assessed with multivariable logistic regression and inverse probability of treatment weighting to minimize the ascertainment bias of having a TEE obtained. RESULTS: Of the 2236 AIS patients included, 103 (4.6%) had active cancer, of whom 24 (23%) were diagnosed with RLS. A RLS was present in 774 out of the 2133 AIS patients without active cancer (36%). After adjustment and weighting, the absence of RLS was associated with active cancer (adjusted odds ratio [aOR], 2.29; 95% confidence interval [CI], 1.14-4.58). When analysis was restricted to patients younger than 60 years or those with a high-risk RLS (Risk of Paradoxical Embolism Score ≥6), there was no association between RLS and cancer (aOR, 3.07; 95% CI, 0.79-11.88 and aOR, 0.56; 95% CI 0.10-3.10, respectively). CONCLUSIONS: RLS was diagnosed less frequently in AIS patients with cancer than in cancer-free patients, suggesting that arterial sources may play a larger role in cancer-related strokes than paradoxical venous embolization. Future studies are needed to validate these findings and evaluate potential therapeutic implications such as the general indication, or lack thereof, for PFO closure in this patient population.

Daratumumab during Myeloma Induction Therapy Is Associated with Impaired Stem Cell Mobilization and Prolonged Post-Transplant Hematologic Recovery.

Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, n = 110; D-RVd, n = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, p = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, p = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 106/L, p = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 106/kg BW, p = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, p = 0.0164; and 16 vs. 14 days, p = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, p = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; p = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT.

Safety and Efficacy of High-Dose Chemotherapy with TreoMel 200 vs. TreoMel 140 in Acute Myeloid Leukemia Patients Undergoing Autologous Stem Cell Transplantation.

(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m2 combined with either melphalan 140 mg/m2 (TreoMel 140) or melphalan 200 mg/m2 (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m2 and 200 mg/m2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia.

Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells. Emavusertib in combination with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in MOLM-13 cells. In primary AML cells, the response to emavusertib was associated with the presence of the FLT3 gene mutation with an allelic ratio >0.5 and the presence of NPM1 gene mutations. S63845 was effective in all tested AML cell lines and primary AML samples. Blast cell percentage was positively associated with the response to CA4948, S63845, and venetoclax, with elevated susceptibility of primary AML with blast cell fraction >80%. Biomarkers of the response to venetoclax included the blast cell percentage and bone marrow infiltration rate, as well as the expression levels of CD11b, CD64, and CD117. Elevated susceptibility to CA4948 combination treatments with S63845 or PU-H71 was associated with FLT3-mutated AML and CD34 < 30%. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

True Donor Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Diagnostic and Therapeutic Considerations-Brief Report.

Donor cell leukemia (DCL) is a rare complication after allogeneic hematopoietic stem cell transplantation (HSCT) accounting for 0.1% of relapses and presenting as secondary leukemia of donor origin. Distinct in phenotype and cytogenetics from the original leukemia, DCL's clinical challenge lies in its late onset. Its origin is affected by donor cell anomalies, transplant environment, and additional mutations. A 43-year-old woman, treated for early stage triple-negative breast cancer, developed mixed-phenotype acute leukemia (MPAL), 12 years later. Following induction chemotherapy, myeloablative conditioning, and allo-HSCT from her fully HLA-matched brother, she exhibited multiple cutaneous relapses of the original leukemia, subsequently evolving into DCL of the bone marrow. Cytogenetic analysis revealed a complex male karyotype in 20 out of 21 metaphases, however, still showing the MPAL phenotype. DCL diagnosis was confirmed by 90.5% XY in FISH analysis and the male karyotype. Declining further intensive chemotherapy including a second allo-HSCT, she was subsequently treated with repeated radiotherapy, palliative systemic therapies, and finally venetoclax and navitoclax but died seven months post-DCL diagnosis. This case underlines DCL's complexity, characterized by unique genetics, further complicating diagnosis. It highlights the need for advanced diagnostic techniques for DCL identification and underscores the urgency for early detection and better prevention and treatment strategies.

Chimeric antigen receptor-T cell therapy shows similar efficacy and toxicity in patients with diffuse large B-cell lymphoma aged 70 and older compared to younger patients: A multicenter cohort study.

CD19-directed chimeric antigen receptor (CAR)-T cell therapy has become a standard treatment for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). While the benefits of CAR-T cell treatment are clear in the general patient population, there remains a relative scarcity of real-world evidence regarding its efficacy and toxicity in patients (pts) aged ≥70 years with DLBCL. We conducted a multicenter retrospective analysis including 172 r/r DLBCL pts with CAR-T cell treatment, axicabtagene ciloleucel or tisagenlecleucel, between 2019 and 2023 at three tertiary centers. Pts were grouped by age at CAR-T infusion (<70 vs. ≥70 years). Subsequently, descriptive and survival analyses, including propensity score matching, were performed to compare outcomes between both age groups. We identified 109 pts aged <70 and 63 pts aged ≥70 years. Overall response rates for both age groups were comparable (77.7% vs. 78.3%; p = 0.63). With a median follow-up of 8.3 months, median progression-free survival was 10.2 months (95% confidence interval [CI]: 6.5-21.8) and 11.1 months (95% CI: 4.9-NR) (p = 0.93) for both cohorts. Median overall survival reached 21.8 months (95% CI: 11.8-NR) and 34.4 months (95% CI: 10.1-NR) (p = 0.97), respectively. No significant differences in the incidence of cytokine release syndrome (p = 0.53) or grade ≥3 neurotoxicity (p = 0.56) were observed. Relapse and nonrelapse mortality were not significantly different between both groups. Our findings provide additional support that CAR-T cell therapy is feasible and effective in patients with r/r DLBCL aged 70 years or older, demonstrating outcomes comparable to those observed in younger patients. CAR-T cell therapy should be not withheld for elderly patients with r/r DLBCL.

Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial.

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a "7 + 3" induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81-1.69), 1.05 (95% CI 0.86-1.30), 1.00 (95% CI 0.84-1.19), and 1.02 (95% CI 0.87-1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

Peeling Back the Layers: Recurrent Talquetamab Skin Toxicity After Supportive Stem Cell Boost in Multiple Myeloma.

Bispecific antibodies have meaningfully expanded the therapeutic armentarium in multiple myeloma. Talquetamab is a CD3+ T cell redirecting antibody targeting GPRC5D, which is expressed on multiple myeloma plasma cells as well as in keratinized tissues. Due to the expression pattern, toxicity of talquetamab involves skin toxicity. Here we report the case of a patient who was treated with talquetamab after relapse after CAR-T therapy. The patient developed a severe recurrence of talquetamab-mediated skin toxicity after the administration of a supportive hematopoietic stem cell boost to treat persistent late cytopenias after CAR-T therapy. This case underscores the complex dynamics between novel immunotherapies like talquetamab and stem cell-based interventions in the context of MM treatment, shedding light on the need for personalized approaches to maximize the benefits of these therapies while minimizing their associated adverse effects.

In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT.

Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

Hematopoietic cell transplantation and cellular therapies in Switzerland. Evolution over 25 years. A report from the stem cell transplantation and cellular therapies working groups of the SBST 1997-2021.

The Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25 years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care.

Identification of novel targets for immunotherapies in subsets of patients with diffuse large B-cell lymphoma (DLBCL).

Personalized treatment options for subsets of patients with DLBCL are beginning to emerge. Caracciolo et al. explore UMG1, an epitope of CD43 as a potential target for certain patients with DLBCL, and demonstrate promising preclinical activity of an Anti-UMG1-antibody. Commentary on: Caracciolo et al. UMG1/CD3ε-bispecific T-cell engager (BTCE) redirects T-cell cytotoxicity against diffuse large B-cell lymphoma (DLBCL). Br J Haematol 2024;204:555-560.

Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.

The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (n = 328) and 86.7% after ABVD alone (n = 300; HR = 2.05 [1.20-3.51]; p = 0.0072). 5-year OS was 98.3% and 98.8%, respectively (p = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (n = 353; 94.0%) than in PET-2-positive patients (n = 340; 90.3%; p = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n = 571; 94.0% vs. DS ≥ 4: n = 122; 83.6%; p < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result.

Increasing insight in the value of repetitive COVID-19 vaccination in patients with haematological malignancies in the Omicron era.

The study by Kevlicius et al. from Lithuania gives further confirmation of the efficacy of booster mRNA COVID-19 vaccination for patients with haemato-oncological malignancies in the Omicron era. The risk of COVID-19 and mortality was considerably reduced when patients received the booster vaccination. The threshold of the humoral response to vaccination that was protective for haemato-oncological patients was defined. In particular, ruxolitinib and anti-CD20 treatments limited the humoral response to the third booster vaccination. These data may influence the clinical management of haemato-oncological patients in future waves of the COVID-19 pandemic, regarding for example the selection of patients for passive immunization against SARS-CoV-2. Commentary on: Kevlicius et al. Immunogenicity and clinical effectiveness of mRNA vaccine booster against SARS-CoV-2 Omicron in patients with haematological malignancies: A national prospective cohort study. Br J Haematol 2024;204:497-506.

CAR-T Cell Therapy Shows Similar Efficacy and Toxicity in Patients With DLBCL Regardless of CNS Involvement.

Efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement remain understudied. Here we analyzed the outcomes of CAR-T cell therapy in r/r DLBCL patients with CNS involvement and compared them with patients without CNS disease. Retrospective and monocentric comparative analysis of patient cohort with r/r DLBCL treated with CAR-T cell therapy: 15 patients with CNS versus 65 patients without CNS involvement. Overall response rates (80% versus 80%; P = 1.0), progression-free survival (P = 0.157), and overall survival (P = 0.393) were comparable for both cohorts. The frequency of cytokine release syndrome was comparable in the CNS and non-CNS cohorts; 93% versus 80%; P = 1.0. Numerically, immune effector-cell-associated neurotoxicity syndrome (all grades) was more frequent in patients with CNS manifestation (53% versus 29%; P = 0.063), although no grade 4 events were documented. Our study suggests that CAR-T cell therapy is effective and feasible in patients with r/r DLBCL and CNS manifestation.

Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma.

Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of PPM1D mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency PPM1D mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of PPM1D gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without PPM1D mutations. Clinical outcomes were globally worse in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months (p = 0.07) and median overall survival (OS) was 5 vs. 37 months (p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

Characterization of particle size segregation and heterogeneity along the slopes of a waste rock pile using image analysis.

Large amounts of waste rock are produced during mining operations and often disposed of in large piles. Particle size segregation usually occurs during waste rock disposal, which can lead to high variations of particle size distribution (PSD) along the pile slope, increasing the risk for hydrogeotechnical instabilities. Determining segregation in situ is, therefore, critical to implement control measures and optimize deposition plans. However, characterizing PSD at field scale remains challenging because of the large dimensions of the pile, the instability of the blocks and the steep slopes. In this study, images, covering a 1400 m wide and 10 m high section of a waste rock pile, were taken and analyzed using image analysis to characterize segregation along the slope of the pile. PSD curves in different sections along the slope were determined and the segregation degree and characteristic diameters (e.g., D10, D50, D80, D95) were quantitatively compared. Results allowed to quantify segregation along the vertical direction of the pile, showing that segregation degree increased from - 0.77 ± 0.39 in the top (finer zone) to + 0.4 ± 0.14 in the bottom (coarser zone). Significant lateral heterogeneity was also observed with maximum diameters varying between 80 and 180 cm in the bottom section. Such segregation and lateral heterogeneity could induce significant variations of waste rock properties, with, for example, hydraulic conductivities varying by more than 2 orders of magnitude within the pile.