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Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

We present the case of a 64-year-old man diagnosed with large B-cell lymphoma who relapsed twice after standard-of-care therapy. Due to persisting cytopenia, Next generation sequencing analysis was performed, revealing a small TP53-mutated clone. As a third-line therapy, the patient was treated with CAR-T cells, which resulted in complete remission. However, this treatment also led to the expansion of the TP53-mutated clone and therapy-related myelodysplasia with a complex aberrant karyotype. This case may serve as a paradigmatic example of clonal hematopoietic progression in a patient undergoing CAR-T cell therapy, especially in the context of a TP53-mutated clone.

We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor.In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants.We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI = 1.11-1.91, p = 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63-1.63, p = 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (30y HR: 3.02, 95%CI = 1.25-7.28, p = 0.014;29y HR: 1.28, 95%CI = 0.94-1.72, p = 0.113).Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.

A common genetic variant within the T cell receptor alpha (TCRA)-T cell receptor delta (TCRD) locus (rs2204985) has been recently found to associate with thymic function. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient’s outcome after unrelated hematopoietic stem cell transplantation (uHSCT). 2016 adult patients were retrospectively analyzed. rs2204985 genotyping was performed by next generation sequencing, p < 0.05 was considered significant and donor rs2204985 GG/AG genotypes were set as reference vs. the AA genotype. Multivariate analysis of the combined cohort regarding the impact of donor’s rs2204985 genotype indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations. A subanalysis on account of HLA incompatibility revealed that donor AA genotype in single HLA mismatched cases (n = 624) associated with significantly inferior overall- (HR: 1.48, p = 0.003) and disease-free survival (HR: 1.50, p = 0.001). This effect was driven by a combined higher risk of relapse incidence (HR: 1.40, p = 0.026) and non-relapse mortality (HR: 1.38, p = 0.042). This is the first study to explore the role of rs2204985 in a clinical uHSCT setting. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely impact post-HSCT outcome and should thus be avoided., publishedVersion

CAR T-cell levels in patients ≥65 years

Overall survival (interim) and progression-free survival in patients ≥70 years

Sensitivity analysis of interim overall survival in patients ≥65 years

Natural killer/T-cell lymphomas (NKTCL) represent rare and aggressive lymphoid malignancies. Patients (pts) with relapsed/refractory disease after Asparaginase (ASPA)-based chemotherapy have a dismal prognosis. To better define the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), we conducted a retrospective analysis of data shared with the European Society for Blood and Marrow Transplantation (EBMT) and cooperating Asian centers. We identified 135 pts who received allo-HSCT between 2010 and 2020. Median age was 43.4 years at allo-HSCT, 68.1% were male. Ninety-seven pts (71.9 %) were European, 38 pts (28.1%) Asian. High Prognostic Index for NKTCL (PINK) scores were reported for 44.4%; 76.3% had >1 treatment, 20.7% previous auto-HSCT, and 74.1% ASPA-containing regimens prior to allo-HSCT. Most (79.3%) pts were transplanted in CR/PR. With a median follow-up of 4.8 years, 3-year progression-free(PFS) and overall survival were 48.6% (95%-CI:39.5–57%) and 55.6% (95%-CI:46.5–63.8%). Non-relapse mortality at 1 year was 14.8% (95%-CI:9.3–21.5%) and 1-year relapse incidence 29.6% (95%-CI:21.9–37.6%). In multivariate analyses, shorter time interval (0–12 months) between diagnosis and allo-HSCT [HR = 2.12 (95%-CI:1.03–4.34); P = 0.04] and transplantation not in CR/PR [HR = 2.20 (95%-CI:0.98–4.95); P = 0.056] reduced PFS. Programmed cell death protein 1(PD-1/PD-L1) treatment before HSCT neither increased GVHD nor impacted survival. We demonstrate that allo-HSCT can achieve long-term survival in approximately half of pts allografted for NKTCL.

IntroductionMulti-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements.MethodsIn this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures.ResultsBy changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p=DiscussionThere are several ways to reduce the workload of all ITB team members while maintaining high quality recommendations and adherence to national and international guidelines.

Mixed model with repeated measures for change from baseline for prespecified patient-reported outcomes endpoints in patients ≥65 years

Tabulated data supporting ZUMA-7 elderly analysis Supplementary Table S1. Patient-reported outcomes instruments Supplementary Table S2. Axi-cel delivery and administration time Supplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7 Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 years Supplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 years Supplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set) Supplementary Table S7. Summary of serum analytes in patients

Purpose:Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7.Patients and Methods:Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs).Results:Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions:Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018–2021) and were one decade older (55–75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1–2], [2.5–3.5], [4–6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a highly significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent strong association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy highly satisfactorily and across other established prognostic factors. TCI has all the features to be used as a well-defined, easy calculated and reproducible tool to define and measure intensity of the preparative regimen.

Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.

PURPOSE In contrast to 5-azacytidine (5-aza), allogeneic stem-cell transplantation (HSCT) represents a curative treatment strategy for patients with myelodysplastic syndromes (MDS), but therapy-related mortality (TRM) limits its broader use in elderly patients with MDS. The present prospective multicenter study compared HSCT following 5-aza pretreatment with continuous 5-aza treatment in patients with higher-risk MDS age 55-70 years. METHODS One hundred ninety patients with a median age of 63 years were enrolled. Patients received 4-6 cycles of 5-aza followed by HLA-compatible HSCT after reduced-intensity conditioning or by continuous 5-aza if no donor was identified. RESULTS Twenty-eight patients did not fulfill inclusion criteria (n = 20), died (n = 2) withdrew informed consent (n = 5), or were excluded for an unknown reason (n = 1). 5-aza induction started in 162 patients, but only 108 (67%) were eligible for subsequent allocation to HSCT (n = 81) or continuation of 5-aza (n = 27) because of disease progression (n = 26), death (n = 12), or other reasons (n = 16). Seven percent died during 5-aza before treatment allocation. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival and overall survival after 5-aza pretreatment and treatment allocation at 3 years were 34% (95% CI, 22 to 47) and 50% (95% CI, 39 to 61) after allograft and 0% and 32% (95% CI, 14 to 52) after continuous 5-aza treatment ( P < .0001 and P = .12), respectively. Fourteen patients progressing after continuous 5-aza received a salvage allograft from an alternative donor, and 43% were alive at last follow-up. CONCLUSION In older patients with MDS, reduced-intensity conditioning HSCT resulted in a significantly improved event-free survival in comparison with continuous 5-aza therapy. Bridging with 5-aza to HSCT before is associated with a considerable rate of dropouts because of progression, mortality, and adverse events.

Lymphoma-associated Hemophagocytic lymphohistiocytosis (HLH) represents a severe complication of disease progression, mediated through cytokine release from the lymphoma cells. Cytokine adsorption may contribute as a supportive treatment to stabilize organ function by reduction of cytokine levels. So far, no experiences of cytokine adsorption and simultaneous stem cell transplantation were published. We report the case of a patient with aggressive lymphoma secondary to chronic lymphocytic leukemia with rapidly progressive HLH (Richter’s transformation) upon conditioning chemotherapy prior to allogeneic stem cell transplantation (ASCT). Continuous hemodiafiltration was initiated in the treatment of shock with acute renal failure, lactacidosis and need for high-dose catecholamine therapy, integrating an additional cytokine-adsorbing filter (CytoSorb®) to reduce cytokine levels. This was followed by scheduled allogenic stem cell transplantation. We observed a marked decrease in interleukin-6 plasma levels, associated with a reduced need for vasopressor therapy and organ function stabilization. Hematopoietic engraftment was present at day 14 post-ASCT, leading to disease-free discharge at day 100 post-transplantation. Cytokine adsorption may serve as a safe adjunct to HLH/sepsis treatment during allogeneic stem cell transplantation. Clinical studies are required to make future treatment recommendations.

Background: The advance directive holds patients’ health care choices and fosters the patients’ autonomy. Nevertheless, understanding the patients’ wishes based on the information provided in advance directives, remains a challenge for health care providers. Based on the ethical premises of positive obligation to autonomy, an advanced directive that is disease-centred and features problems and complications of the disease the patient has, should help the health care providers to understand the patients’ wishes correctly. To test this hypothesis, a pilot-study was conducted to compare if physicians could make the correct end-of-life decision for their patients when patients used a disease-centred advance directive versus a common advance directive.Material and Methods: A randomised, controlled, prospective pilot study was designed, that included patients with NSCLC stage VI from the Department of Haematology and Medical Oncology, University Medical Centre, Goettingen. Patients were randomised into intervention and control groups. The control group received a common advance directive and the intervention group a disease-centred advance directive. Both groups filled out their advance directives and returned it. Subsequent, patients were asked to complete nine medical scenarios with different treatment decisions. For each scenario the patients had to decide whether they wanted to receive treatment on a 5-point-Likert scale. Four physicians were given the same scenarios and asked to decide on the treatment, according to the patients’ wishes as stated in the advance directive. The answers by patients and physicians were compared whether the physicians had made the correct assumptions.Results: Recruitment was stopped prematurely. 15 patients completed the study, 9 patients were randomised into the control group and 6 patients in the intervention group. A total of 135 decisions were evaluated. Concordance of physicians’ and patient’s answers, was 0.83 (95%-CI 0.71-0.91) in the intervention group, compared to 0.60 (95%-CI 0.48-0.70) in the control group and the difference between the two groups was statistically significant (p=0.005).Conclusions: This pilot study showed that disease-centred advance directives help physicians to understand their patients’ wishes more precisely and make treatment choices according to their wishes. Trial registration: The study is registered at the German Clinical Trial Register (no. DRKS00017580, registration date 27/08/2019)

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61–65 years, 66–70 years, 71–75 years, and 76–80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76–80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-020-04345-3.

PURPOSE High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all- trans-retinoic acid with or without GO. The early ( P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( P = .005), with no difference in the cumulative incidence of death ( P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication–negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.

BackgroundThe advance directive represents patients’ health care choices and fosters patients’ autonomy. Nevertheless, understanding patients’ wishes based on the information provided in advance directives remains a challenge for health care providers. Based on the ethical premises of positive obligation to autonomy, an advanced directive that is disease-centred and details potential problems and complications of the disease should help health care providers correctly understand patients’ wishes. To test this hypothesis, a pilot-study was conducted to investigate whether physicians could make the correct end-of-life decision for their patients when patients used a disease-centred advance directive compared to a common advance directive. Material and methodsA randomised, controlled, prospective pilot study was designed that included patients with non-small cell lung cancer (NSCLC) stage VI from the Department of Haematology and Medical Oncology, University Medical Centre, Goettingen. Patients were randomised into intervention and control groups. The control group received a common advance directive, and the intervention group received a disease-centred advance directive. Both groups filled out their advance directives and returned them. Subsequently, patients were asked to complete nine medical scenarios with different treatment decisions. For each scenario the patients had to decide whether they wanted to receive treatment on a 5-point Likert scale. Four physicians were given the same scenarios and asked to decide on the treatment according to the patients’ wishes as stated in their advance directives. The answers by patients and physicians were then compared to establish whether physicians had made the correct assumptions.ResultsRecruitment was stopped prior to reaching anticipated sample target. 15 patients with stage IV NSCLC completed the study, 9 patients were randomised into the control group and 6 patients in the intervention group. A total of 135 decisions were evaluated. The concordance between physicians’ and patients’ answers, was 0.83 (95%-CI 0.71–0.91) in the intervention group, compared to 0.60 (95%-CI 0.48–0.70) in the control group, and the difference between the two groups was statistically significant (p = 0.005).ConclusionThis pilot study shows that disease-centred advance directives help physicians understand their NSCLC patients’ wishes more precisely and make treatment choices according to these wishes.Trial registrationThe study is registered at the German Clinical Trial Register (no. DRKS00017580, registration date 27/08/2019).

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P

TheHLA-DRB3/4/5loci are closely linked to theHLA-DRB1gene. Mismatches in these loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors forHLA-DRB3/4/5compatibility and to correlate theHLA-DRB3/4/5matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors wereHLA-DRB3/4/5andHLA-DPB1typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) ofHLA-DRB3/4/5genes were correlated with clinical outcome.HLA-DRB3/4/5incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively.HLA-DRB3/4/5mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD ofHLA-DRB3/4/5genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged80 years and 29 patients aged 61-80 years with elevated Cumulative Illness Rating Scalescore6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64-80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age80 years with 40 patients aged 76-80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option.

PurposeExtrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases.MethodsWe retrospectively analyzed clinical characteristics and HLA haplotypes from allogeneic (allo) or autologous (auto) HSCT patients from January 2001 through May 2021 at the University Medicine Goettingen (UMG), and data from previously published cases.ResultsA total number of 19 patients was identified. These included 4 patients from our center (3 allo HSCT and 1 auto HSCT) and 15 patients from the literature review. Thirteen patients had received an allo HSCT, and six patients had received an auto HSCT. Sarcoidosis occurred after a median interval of 20 (after allo HSCT) and 7 (after auto HSCT) months, respectively. The predominant HLA allele associated with sarcoidosis was HLA DRB1*03:01. Sarcoidosis involved the respiratory tract in 15 patients (three unknown, one without pulmonary involvement), and it was associated with graft-versus-host disease in 7 of 13 patients receiving allo HSCT. None of the donors or patients had a history of sarcoidosis before transplantation. Disease manifestations resolved with standard glucocorticoid treatment without long-term sequelae.ConclusionSarcoidosis may occur at low frequency during reconstitution of the immune system after HSCT. HLA allele associations reflect the associations observed in the general population, particularly with DRB1*03:01. Further insights into the interplay between Tcell reconstitution and the development of sarcoidosis could also provide novel approaches to an improved understanding of the pathogenesis in sarcoidosis.

Introduction The antibody-drug conjugate polatuzumab vedotin (Pola) has recently been approved in combination with bendamustine and rituximab (Pola-BR) for patients with r/r diffuse LBCL (DLBCL). Methods To characterize the efficacy of Pola-BR in a real-world setting, we retrospectively analyzed data from 97 patients with r/r LBCL who were treated with Pola in 24 German centers within the national CUP. Clinical baseline and follow-up (FU) data were collected by chart review and summarized descriptively. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods. Fisher's exact test was used to compare categorical factors between groups of patients. Results 97 patients with LBCL (DLBCL n=90, High-grade B-cell lymphoma n=6, Primary mediastinal B-cell lymphoma n=1) were included as of July 22nd, 2020. 49 patients were treated with Pola as bridging concept to immunotherapies (bridging cohort: chimeric antigen receptor T-cells (CART) n=39, allogeneic stem cell transplantation (alloSCT) n=9, bispecific antibodies n=1), and 48 patients were treated with Pola in palliative intention (palliative cohort). Within the bridging cohort the median age was 61 years (range: 22-82). Patients were heavily pretreated with a median of 3 treatment lines (range: 2-6). 84% (41/49 patients) had been refractory to their last treatment line, and 31% had failed an autologous stem cell transplantation. Notably, 14% and 10% of patients had failed prior CART and alloSCT, respectively, and were planned for the alternate cellular immunotherapy. Based on an individual decision, patients were treated with Pola-Rituximab (Pola-R, n=20), Pola-chemotherapy (Pola-chemo, BR n=25; R-CHP n=1) or Pola-monotherapy (Pola-mono, n=3). With a median of 2 Pola cycles (range 1-6), overall response rate (ORR) of all evaluable patients was 33% (15/46 patients) including patients with complete response (CR n=1), partial response (PR n=9) and clinical response (n=5). Although not significant, ORR tended to be better in patients treated with Pola-chemo versus Pola-R/Pola-mono (ORR: 42% versus 20%, Fishers test p=0.1). 11 of these 15 responders (24% of the entire bridging cohort) proceeded to CART or alloSCT, while 4 responders (8% of entire bridging cohort) experienced fast progression after their initial response and were referred to best supportive care. 15 of 31 non-responders (33% of entire bridging cohort) underwent immunotherapy with either stable disease (n=6), mixed response (n=2), or progression on Pola (n=7). The remaining 16 patients (35% of entire bridging cohort) were all refractory to Pola and either received alternative salvage treatments which enabled 8 further patients to proceed to the intended immunotherapy, or best supportive care. Taking the effects of CART or alloSCT into account, median OS from initiation of Pola treatment was 8.2 months (median FU 7.2 months, Fig. 1A). The palliative cohort tended to be older than the bridging cohort with a median age of 73.5 years (range: 37-86, p Conclusion Pola permits effective bridging to CART and alloSCT in r/r LBCL. In the palliative setting, Pola represents an effective salvage option for patients with transplantation-ineligible r/r LBCL. Compared to the approval study, the inferior outcome of the patients of this real-world analysis might be explained by their more advanced disease course. Disclosures Duell: Morphosys: Research Funding. Kerkhoff:BMS: Honoraria. Leng:Roche: Other: lecture fee; Celgene: Other: traveling expenses and congress attendance fee. Holtick:Miltenyi Biotec B.V. & Co. KG: Honoraria. Mayer:Amgen: Honoraria, Other: travel grants; Abbvie: Other: travel grants; Novartis: Honoraria; Roche: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy. Brunnberg:Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Other: Travel grants. Bullinger:Menarini: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Hess:Roche: Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mueller-Tidow:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deutsche Krebshilfe: Research Funding; BMBF: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; Deutsche Forschungsgemeinschaft: Research Funding. Lenz:Verastem: Research Funding; AQUINOX: Research Funding; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy; Morphosys: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Dreger:Roche: Consultancy, Speakers Bureau; Neovii: Research Funding; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

Als periphere T‑Zell-Lymphome (PTCL) wird eine heterogene Gruppe klinisch aggressiver Erkrankungen mit dem Phanotyp reifer T‑Zellen und schlechter Prognose zusammengefasst. Neue Therapien werden intensiv untersucht und konnen die Behandlung fur einige Subtypen schon in naher Zukunft verbessern. Der aktuelle Wissenstand zu PTCL mit Fokus auf moderne Therapiestandards und neue therapeutische Optionen wird dargestellt. Basierend auf einer selektiven Literaturreche werden Grundlagenarbeiten und Leitlinien diskutiert. Aktueller Konsens fur die Erstlinientherapie von PTCL sind anthrazyklinhaltige Kombinationschemotherapien, abhangig vom Subtyp und Erkrankungsstadium gefolgt von autologer Stammzelltransplantation. Darunter ist fur etwa 50 % der Patienten eine langfristige Erkrankungsfreiheit zu erwarten; bei 30 % der PTCL-Patienten sind die Lymphome primar refraktar. Im Rezidiv ist die Prognose bei alleinigem Einsatz von Zytostatika sehr ungunstig. Fur geeignete Patienten stellt die allogene Stammzelltransplantation ein Verfahren mit der Chance auf eine langfristige Erkrankungskontrolle dar. Fur Patienten mit anaplastischen groszelligen T‑Zell-Lymphomen steht mit dem gegen CD30 gerichteten Antikorper-Chemotherapie-Konjugat Brentuximab Vedotin im Rezidiv eine effektive Therapie zur Verfugung. Auch in der Erstlinientherapie wurde fur Brentuximab Vedotin in Kombination mit Chemotherapie ein erhohter Nutzen bei CD30-positiven PTCL nachgewiesen. Das zunehmend vertiefte Verstandnis der Biologie und Pathogenese von PTCL fuhrt zur Testung weiterer zielgerichteter Therapien als Monotherapie und in Kombinationen. So wurde in den letzten Jahren die Inhibition von Histondeacetylase (HDAC) auf Ebene der epigenetischen Regulation gepruft. Unter den innovativen Therapieprinzipien wurden vor allem mit der Inhibition der Phosphoinositid-3-Kinasen (PI3K) auf Ebene der Signaltransduktion ermutigende Ansprechraten fur Patienten mit rezidivierter oder refraktarer Erkrankung erreicht. Die aktuelle Behandlung der PTCL basiert auf Chemotherapie- und Transplantationskonzepten. Aktuell werden fur viele PTCL-Subtypen potenziell effektivere Therapien entwickelt.

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

7548 Background: Elderly pts with R/R LBCL are at risk of inferior outcomes, increased toxicity, and inability to tolerate second-line (2L) SOC treatment (Tx) (Di M, et al. Oncologist. 2021). Further 2L SOC Tx is often associated with poor health-related quality of life (QoL) (Lin V, et al. J Clin Oncol . 2020;38:e20070). In the pivotal Phase 3 ZUMA-7 study, we assessed outcomes, including PROs, of 2L axi-cel (an autologous anti-CD19 CAR T-cell therapy) versus SOC in elderly pts with R/R LBCL. Methods: Pts aged ≥65 y were assessed in a planned subgroup analysis. Pts with ECOG PS 0-1 and R/R LBCL ≤12 mo after 1L chemoimmunotherapy (CIT) were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based CIT; pts with partial or complete response [CR] proceeded to HDT-ASCT). PRO instruments, including the EORTC QLQ-C30 (Global Health [GH] and Physical Functioning [PF]) and the EQ-5D-5L VAS, were administered at timepoints including baseline (BL; prior to Tx), Day (D) 50, D100, D150, and Month (M) 9, then every 3 mo up to 24 mo or time of event-free survival event (EFS), whichever occurred first. The QoL analysis set included all pts who had a BL PRO and ≥1 completed measure at D50, D100, or D150. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score, 7 points for EQ-5D-5L VAS score. Results: As of 03/18/2021, 51 and 58 elderly pts were randomized to the axi-cel and SOC arms, respectively, with median ages (range) of 70 y (65-80) and 69 y (65-81). At BL, more axi-cel versus SOC pts had high-risk features, including 2L age-adjusted IPI 2-3 (53% vs 31%) and elevated LDH (61% vs 41%). EFS was superior with axi-cel versus SOC (HR, 0.276, P< 0.0001), with higher CR rates (75% vs 33%). Grade ≥3 Tx-emergent adverse events (AEs) occurred in 94% and 82% of axi-cel and SOC pts, respectively, and Grade 5 Tx-related AEs occurred in 0 and 1 pt. In the QoL analysis set comprising 46 axi-cel and 42 SOC pts, there were statistically significant and clinically meaningful differences in mean change of scores from BL at D100 favoring axi-cel for EORTC QLQ-C30 GH ( P

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD–mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of INa density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The Ito in BrS-CMs was significantly augmented, and the ICaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of Ito in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell-derived cardiomyocytes from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to cardiomyocytes derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of INa density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 at the cell surface. BrS-CMs exhibited reduced action potential upstroke velocity and conduction slowing. The Ito in BrS-CMs was significantly augmented, and the ICaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of Ito in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.

For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5'-untranslated regions (5'-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5'-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+ -specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe2+ ) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.