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Purpose: The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. Methods: Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. Results: Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels. Conclusions: Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed and compared the efficacy and toxicity of azacitidine ( AZA) and low-dose cytarabine ( LD- Ara- C) in 65 palliative patients with acute myeloid leukemia ( AML) showing high bone marrow blast counts (≥30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD- Ara- C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD- Ara- C group. AZA and LD- Ara- C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD- Ara- C groups, respectively, without statistically significant difference. In multivariate analysis ( n = 65), previous treatment ( HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics ( HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the prospective studies on the effect of pretransplant imatinib in patients with blast crisis of chronic myeloid leukemia (BC-CML) after myeloablative allogeneic stem cell transplantation (allo-SCT).

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59–0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic threatens patients with a compromised immune and endothelial system, including patients who underwent allogeneic stem cell transplantation (alloSCT). Thus, there is an unmet need for optimizing vaccination management in this high-risk cohort. Here, we monitored antibodies against SARS-CoV-2 spike protein (anti-S1) in 167 vaccinated alloSCT patients. Humoral immune responses were detectable in 81% of patients after two vaccinations with either mRNA-, vector-based, or heterologous regimens. Age, B-cell counts, time interval from vaccination, and the type of vaccine determined antibody titres in patients without systemic immunosuppression (sIS). Similar to a healthy control cohort, mRNA vaccine-based regimens induced higher titres than vector-based vaccines. Patients on two or more immunosuppressants rarely developed immunity. In contrast, 62% and 45% of patients without or on only one immunosuppressant, respectively, showed a strong humoral vaccination response (titre > 100). Exacerbation of cGVHD upon vaccination was observed in 6% of all patients and in 22% of patients receiving immunosuppression for cGVHD. cGVHD exacerbation and low antibody titres were both associated with higher angiopoietin-2 (ANG2) serum levels. In conclusion, mRNA-based vaccines elicit strong humoral responses in alloSCT patients in the absence of double sIS. Biomarkers such as ANG2 might help with weighing cGVHD risk versus beneficial responses. [ABSTRACT FROM AUTHOR]

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We present algorithms that allow for real-time rendering of 3D-scenes with a watercolor painting appearance. Our approach provides an appropriate simplification of the visual complexity, imitates characteristic natural effects of watercolor, and provides two essential painting techniques: the wet-on-wet and the wet-on-dry painting. We concentrate on efficient algorithms based on image space processing rather than on an exact simulation. This allows for the real-time rendering of 3D-scenes. During an animation a high frame-to-frame coherence can be achieved due to a stable segmentation scheme. Finally, we seamlessly integrate a smooth illumination into the watercolor renderings using information from the 3D-scene. [ABSTRACT FROM AUTHOR]

Simocyclinone D8 is a potent inhibitor of bacterial gyrase, produced by Streptomyces antibioticus Tü 6040. It contains an aminocoumarin moiety, similar to that of novobiocin, which is linked by an amide bond to a structurally complex acyl moiety, consisting of an aromatic angucycline polyketide nucleus, the deoxysugar olivose and a tetraene dicarboxylic acid. We have now investigated the enzyme SimL, responsible for the formation of the amide bond of simocyclinone. The gene was cloned, expressed in S. lividans T7, and the protein was purified to near homogeneity, and characterized. The 60 kDa protein catalyzed both the ATP-dependent activation of the acyl component as well as its transfer to the amino group of the aminocoumarin ring, with no requirement for a 4′-phosphopantetheinyl cofactor. Besides its natural substrate, simocyclinone C4, SimL also accepted a range of cinnamic and benzoic acid derivatives and several other, structurally very diverse acids. These findings make SimL a possible tool for the creation of new aminocoumarin antibiotics. [ABSTRACT FROM AUTHOR]

The left ends of the biosynthetic gene clusters of novobiocin (nov), clorobiocin (clo) and coumermycin A1 (cou) from Streptomyces spheroides (syn. S. caeruleus) NCIMB 11891, S. roseochromogenes var. oscitans DS 12.976 and S. rishiriensis DSM 40489 were cloned and sequenced. Sequence comparison suggested that novE, cloE and couE, respectively, represent the borders of these three clusters. Inactivation of novE proved that novE does not have an essential catalytic role in novobiocin biosynthesis, but is likely to have a regulatory function. The gene products of novF and cloF show sequence similarity to prephenate dehydrogenase and may produce 4-hydroxyphenylpyruvate (4HPP) as a precursor of the substituted benzoate moiety of novobiocin and clorobiocin. Coumermycin A1 does not contain this benzoate moiety, and correspondingly the coumermycin cluster was found not to contain a functional novF homologue. The coumermycin biosynthetic gene cluster apparently evolved from an ancestral cluster similar to those of novobiocin and clorobiocin, and parts of the ancestral novF homologue have been deleted in this process. No homologue to novC was identified in the gene clusters of clorobiocin and coumermycin, questioning the postulated involvement of novC in aminocoumarin biosynthesis. Heterologous expression of novDEFGHIJK in Streptomyces lividans resulted in the formation of 2,4-dihydroxy-α-oxy-phenylacetic acid, suggesting that at least one of the proteins encoded by these genes may participate in a hydroxylation reaction. [ABSTRACT FROM AUTHOR]

Simple Summary: Asunercept showed promising clinical efficacy in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome. In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response in order to propose a hypothetical responder serum profile. Response to asunercept was associated with improved overall survival. Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept. Non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk myelodysplastic syndrome patients most likely to benefit from asunercept treatment. Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: We have previously shown that high pre-conditioning levels of Interleukin-18 were associated with worse survival after allogeneic stem cell transplantation due to increased non-relapse mortality. While no correlations with acute graft-versus-host disease were observed, interleukin-18-related excess mortality was mainly driven by fatal infectious complications. In multiple studies, delayed hematopoietic recovery and poor graft function following allogeneic stem cell transplantation has been demonstrated as a powerful predictor of non-relapse mortality. The present study links high interleukin-18 to delayed platelet recovery in allografted patients. Given the functions of interleukin-18 in regulating the quiescence of hematopoietic stem/progenitor cells, our findings may be explained by Interferon gamma-independent inhibitory effects of interleukin-18 on stem cell proliferation and hematopoietic reconstitution in allografted patients. Importantly, considering recent successful interleukin-18-neutralizing approaches in autoimmune disorders, our results provide a rationale to explore modulation of interleukin-18 for improving hematopoietic recovery and outcomes in allogeneic stem cell transplantation recipients. Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes. [ABSTRACT FROM AUTHOR]

Diminishing potential to replace damaged tissues is a hallmark for ageing of somatic stem cells, but the mechanisms remain elusive. Here, we present proteome-wide atlases of age-associated alterations in human haematopoietic stem and progenitor cells (HPCs) and five other cell populations that constitute the bone marrow niche. For each, the abundance of a large fraction of the ~12,000 proteins identified is assessed in 59 human subjects from different ages. As the HPCs become older, pathways in central carbon metabolism exhibit features reminiscent of the Warburg effect, where glycolytic intermediates are rerouted towards anabolism. Simultaneously, altered abundance of early regulators of HPC differentiation reveals a reduced functionality and a bias towards myeloid differentiation. Ageing causes alterations in the bone marrow niche too, and diminishes the functionality of the pathways involved in HPC homing. The data represent a valuable resource for further analyses, and for validation of knowledge gained from animal models. Ageing causes an inability to replace damaged tissue. Here, the authors perform proteomics analyses of human haematopoietic stem cells and other cells in the bone marrow niche at different ages and show changes in central carbon metabolism, reduced bone marrow niche function, and enhanced myeloid differentiation. [ABSTRACT FROM AUTHOR]

Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4–12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness [VO2peak], muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients. [ABSTRACT FROM AUTHOR]

Patient numbers for EASIX calculation are listed in following order (no neutropenic fever or sepsis / neutropenic fever without sepsis/neutropenic fever with sepsis) for the different timepoints: prior conditioning n = 125/200/27, day-3 n = 85/159/23, day 0 n = 84/159/23, day 3 n = 86/157/23, day 5 n = 87/153/22, day 7 n = 89/157/22, day 14 n = 108/161/20, day 21 n = 119/185/21, day 28 n = 120/194/17. As numbers of patients with sepsis were still small, these results warrant confirmation in larger multicenter trials with more sepsis patients. Sepsis patients were subgrouped by no neutropenic fever or sepsis, and neutropenic fever without and with sepsis. [Extracted from the article]

Background: Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant‐associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. Methods: Statin‐based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. Results: SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38–0.96) and better overall survival (OS) after acute graft‐versus‐host disease (HR 0.59, 95% CI 0.37–0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post‐alloSCT, patients receiving SEP had significantly higher levels of the rate‐limiting enzyme of tryptophan metabolism, indoleamine 2,3‐dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p =.055). No significant differences in interferon‐gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. Conclusions: Together, these data suggest that SEP improves NRM and OS post‐alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action. [ABSTRACT FROM AUTHOR]

Background: Graft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present "Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD" - Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients.Methods: IRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion.Discussion: To our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment.Trial Registration: ClinicalTrials.gov : NCT05111834 . Registered 8 November 2021 - Retrospectively registered. [ABSTRACT FROM AUTHOR]