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In 2022, the European LeukemiaNet (ELN) risk stratification for patients with AML has been updated. We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) evaluating 1,570 newly diagnosed AML patients (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens. As compared to the 2017 ELN classification (ELN17), allocating 595 (38%), 413 (26%) and 562 (36%) patients to the favorable, intermediate and adverse risk category, ELN22 risk was favorable, intermediate, and adverse in 575 (37%), 410 (26%), and 585 (37%) patients, respectively. Risk group allocation was revised in 340 patients (22%). Most patients were re-classified into ELN22 intermediate or ELN22 adverse risk group. The allocation of patients according to the ELN22 risk categories resulted in a significantly distinct event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). As compared to ELN17, reallocation according to the ELN22 recommendations resulted in a significantly improved prognostic discrimination for OS (3-year area under the curve (AUC) 0.71 vs. 0.67). In patients with ELN22 favorable risk AML, co-occurring MR gene mutations did not significantly impact outcome. Within the ELN22 adverse risk group, we observed marked survival differences across mutational groups (5-year OS rate of 21% and 3% in patients with myelodysplasia-related (MR) gene mutations and TP53-mutated patients, respectively). In patients harboring MR gene mutations, EZH2-, STAG2- and ZRSR2-mutated patients showed an intermediate-like OS. In patients with secondary AML and those who underwent allogeneic HCT, EFS and OS significantly differed between ELN22 risk groups, while prognostic abilities of ELN17 and ELN22 classifications were similar. In conclusion, the ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML patients. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest reevaluation of risk allocation in these patients., (Copyright © 2024 American Society of Hematology.)

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m 2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m 2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients., Methods: We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies., Results: Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P = 0.015) and CR1 rate (78.7% vs. 84.3%, P = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction., Conclusions: In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy., (© 2023. The Author(s).)

Purpose: Higher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single-agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry., Methods: Patients between 18 and 64 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high-dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting., Results: Six-hundred-forty-two patients received HiDAC consolidation with median dosage of 17.6 (IQR (interquartile range), 16.5-18.0) g/m 2 for a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7-8.6) g/m 2 for a median of 2 cycles (IQR, 1-3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients (HR = 0.935, p = 0.69). Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%, HR = 1.101, p = 0.65). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p < 0.001). Censoring for allogeneic hematopoietic cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only of European LeukemiaNet (ELN) favorable-risk AML patients, there was no significant difference in outcome. Of note, significantly more patients treated with HiDAC suffered from ≥ 3 CTCAE infectious complications (56.7 [95%-CI 52.8-60.6%] vs. 44.1% [95%-CI 36.6-51.7%]; p = 0,004). The rate of other ≥ 3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups., Conclusions: This retrospective analysis suggests no significant benefit of high-dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group., Trial Registration: NCT03188874., (© 2022. The Author(s).)

Background: While the "7+3" regimen of cytarabine + anthracycline has been the backbone of acute myeloid leukemia (AML) treatment for four decades, several novel drugs have been approved in the past five years. Despite these promising novel therapeutic options, treatment of AML remains challenging, given the biologically heterogenous character of the disease., Aim: This review provides an update on novel treatment strategies for AML., Material and Methods: This article is based on the current European LeukemiaNet (ELN) recommendations and the DGHO «Onkopedia» guideline on AML treatment., Results and Conclusion: The treatment algorithm is based on patient-related and disease-specific factors, such as patient age and fitness as well as AML molecular profile. Younger patients considered fit for intensive chemotherapy receive 1-2 courses of induction therapy ("7+3" regimen, eg. cytarabine/daunorubicin, or CPX-351 for patients with myelodysplasia-related AML or therapy-related AML). For CD33+ patients or those with evidence of an FLT3 mutation "7+3" in combination with Gemtuzumab-Ozogamicin (GO) or Midostaurin is recommended, respectively. For consolidation, patients receive either high-dose chemotherapy (± GO/± Midostaurin) or undergo allogeneic hematopoietic cell transplantation (HCT), based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or FLT3 inhibitor is indicated. Patients experiencing relapse should receive chemotherapy-based re-induction therapy or, in case of an FLT3 mutation, Gilteritinib and subsequently undergo allogeneic HCT. For older patients or those considered unfit for intensive therapy, azacytidine in combination with Venetoclax is a promising novel treatment strategy. Although not yet approved by the European Medical Agency (EMA), for patients with IDH1 IDH1 or IDH2 mutations treatment with the IDH1 and IDH2 inhibitors Ivosidenib and Enasidenib should be considered., Competing Interests: Leo Ruhnke: Beigene, Inc., Reisekostenunterstützung Neovii Biotech GmbH, Reisekostenunterstützung Jan Moritz Middeke: Beratungstätigkeit: Janssen, Roche, Gilead, Abbvie, Jazz, Pfizer, Astellas, Novartis, AstraZeneca Honorare: Novartis, Roche, Janssen, Abbvie, Pfizer, Sanofi, Astellas Finanzierung wissenschaftlicher Untersuchungen: Janssen, Jazz, Astellas, (Thieme. All rights reserved.)

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell-mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 × 106 to 20 × 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade ≤2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Inflammation plays an important role in chimeric antigen receptor (CAR) T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. We evaluated the prevalence of CHIP, using a targeted deep sequencing approach, in a cohort of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma before and after CAR T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia, and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34%) before CAR T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR T-cell treatment but had an improved overall survival (not reached vs 265 days, P = .003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic use of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (with the exception of ferritin), or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR T-cell therapy and is not associated with an inferior outcome., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4 + /CD34 + short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC <95% at ≥12 months post-HCT). Median follow-up was 11 years. All patients had received combined ex vivo/in vivo T cell-depleted (TCD) peripheral blood stem cells; none experienced ≥grade 2 acute graft-versus-host disease (GVHD). The mean total PBMC, CD4 + , and CD34 + DC of all patients were 95.88%, 85.84%, and 90.15%, respectively. Reduced-intensity conditioning (RIC) was associated with a trend to lower mean total DC. Of note, two patients who experienced relapse had lower CD34 + DC but higher CD4 + DC as compared with patients in continuous remission. Bone marrow evaluation revealed increased CD4 + /FOXP3 + cells in patients with MC, which might indicate expansion of regulatory T cells (T regs ). Our results support known predictive factors associated with MC such as RIC and TCD, promote the value of CD34 + MC as a potential predictor of relapse, highlight the potential association of CD4 + MC with reduced risk of GVHD, and indicate a possible role of T regs in the maintenance of immune tolerance post-HCT., Competing Interests: Author CT was employed by AgenDix GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ruhnke, Stölzel, Oelschlägel, von Bonin, Sockel, Middeke, Röllig, Jöhrens, Schetelig, Thiede and Bornhäuser.)

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. SIGNIFICANCE: Rare cancers are difficult to treat; in particular, molecular pathogenesis-oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659 ., (©2021 American Association for Cancer Research.)

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., (© 2021. The Author(s).)

Immunofluorescent staining is a widespread tool in basic science to understand organ morphology and (patho-) physiology. The analysis of imaging data is often performed manually, limiting throughput and introducing human bias. Quantitative analysis is particularly challenging for organs with complex structure such as the kidney. In this study we present an approach for automatic quantification of fluorescent markers and histochemical stainings in whole organ sections using open source software. We validate our novel method in multiple typical challenges of basic kidney research and demonstrate its general relevance and applicability to other complex solid organs for a variety of different markers and stainings. Our newly developed software tool "AQUISTO", applied as a standard in primary data analysis, facilitates efficient large scale evaluation of cellular populations in various types of histological samples. Thereby it contributes to the characterization and understanding of (patho-) physiological processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Endothelial cells (EC) frequently undergo primary or secondary injury during kidney disease such as thrombotic microangiopathy or glomerulonephritis. Renin Lineage Cells (RLCs) serve as a progenitor cell niche after glomerular damage in the adult kidney. However, it is not clear whether RLCs also contribute to endothelial replenishment in the glomerulus following endothelial injury. Therefore, we investigated the role of RLCs as a potential progenitor niche for glomerular endothelial regeneration. We used an inducible tet-on triple-transgenic reporter strain mRen-rtTAm2/LC1/LacZ to pulse-label the renin-producing RLCs in adult mice. Unilateral kidney EC damage (EC model) was induced by renal artery perfusion with concanavalin/anti-concanavalin. In this model glomerular EC injury and depletion developed within 1 day while regeneration occurred after 7 days. LacZ-labelled RLCs were restricted to the juxtaglomerular compartment of the afferent arterioles at baseline conditions. In contrast, during the regenerative phase of the EC model (day 7) a subset of LacZ-tagged RLCs migrated to the glomerular tuft. Intraglomerular RLCs did not express renin anymore and did not stain for glomerular endothelial or podocyte cell markers, but for the mesangial cell markers α8-integrin and PDGFRβ. Accordingly, we found pronounced mesangial cell damage parallel to the endothelial injury induced by the EC model. These results demonstrated that in our EC model RLCs are not involved in endothelial regeneration. Rather, recruitment of RLCs seems to be specific for the repair of the concomitantly damaged mesangium., Competing Interests: The authors have declared that no competing interests exist.