Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Simple Summary AML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients. Abstract Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients

Initial joint stability affects the outcome after conservative treatment of simple elbow dislocations: a retrospective study

Background: Conservative treatment of simple elbow dislocations can lead to complications such as persisting pain and restricted joint mobility. The current aim was to identify patients with deteriorated outcome after conservative treatment and to investigate a possible association with initial joint (in)stability. Methods: Sixty-eight patients (mean age 37.1 ± 17.2 years) with simple elbow dislocations received conservative treatment. After closed reduction, joint stability was tested by varus and valgus stress under fluoroscopy. According to the findings under fluoroscopy, three different groups of instability could be identified: (1) slight instability (joint angulation <10°; n = 49), (2) moderate instability (angulation ≥10°; n = 19) and (3) gross instability. Patients with gross instability (re-dislocation under stability testing) were treated with primary surgical ligament repair and therefore excluded from this study. Additionally, MRIs and radiographs were analysed regarding warning signs of instability such as the drop sign and joint incongruence. Main outcome parameters were the Mayo Elbow Performance Score (MEPS), range of motion (ROM), complications and revision rates. Results: After 40.7 ± 20.4 months, the overall MEPS was excellent (94.2 ± 11.3) with a trend of slightly worse clinical results in group 2 (95.8 ± 9.0 vs. 90.0 ± 15.2 points; p = 0.154). In group 1, significantly more patients achieved an excellent result regarding the MEPS scoring system (77.6 vs. 52.6 %; p = 0.043) and elbow extension was significantly worse in group 2 (5.3 ± 9.9° vs. 1.4 ± 3.0°; p = 0.015). Seven treatment complications occurred in group 2 (36.8 %) compared with two in group 1 (4.1 %, p < 0.0001). Six patients (8.8 %) needed secondary surgery with an 8.4-fold higher risk for revision surgery in group 2 (p = 0.007). The presence of a positive drop sign or joint incongruence led to higher odds ratio (OR) for complications (OR = 15.9) and revision surgery (OR = 10.3). Conclusions: This study demonstrates that patients with moderate joint instability after simple elbow dislocation have a significantly worse clinical outcome, more complications and a higher need for secondary revision surgery following conservative treatment compared to patients with slight elbow instability

Normal values of distal radioulnar translation assessed by three-dimensional C-arm scans: a cadaveric study

We investigated whether mobile C-arm cone beam computer tomography (CBCT) could be used to measure radioulnar translation. The study was conducted on 31 Thiel-fixed intact cadaver arms. Three-dimensional scans of each wrist were carried out in pronation and supination. Four established measurement methods were used (radioulnar line, subluxation ratio, epicentre and radioulnar ratio methods) to measure radioulnar translation. The intraclass correlation coefficient for inter-observer and intra-observer reliability were excellent in three of four methods (>0.94). The reference ranges for physiological radioulnar translation were between -30% and 91% (radioulnar line method), -32% and 87% (subluxation ratio method), -40% and 23% (epicentre method), and 2% and 73% (radioulnar ratio method). Our results indicate that radioulnar translation in the distal radioulnar joint can be determined reliably using mobile C-arm CBCT. The normal values provide a basis for further experimental and clinical studies

Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance

OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies

Return to work after acromioclavicular joint stabilization: a retrospective case control study

Background: Considering the epidemiology of acromioclavicular (AC) dislocation related to young and active patients, the impact on working capacity is highly relevant. The purpose of this study was to determine the capacity of work and time to return to work (RTW) after AC joint stabilization. We hypothesized that manual working patients show more restrictions returning to work. Methods: In this retrospective case series, pre- and posttraumatic working capacity of 54 patients (FU-rate 80.1%, FU time 23, range 18–45 month) stabilized in single TightRope technique was analyzed. Clinical outcome (DASH, Constant-Murley score) and complications were evaluated in addition. Results: Fifty one of 54 patients (94.5%) were returned to work at final follow-up. The median time to return was 13 (5–143) weeks. Manual working patients showed lower RTW-rates (91.2% vs. 100%; p = .151), longer RTW-time (15.5 vs. 6 weeks; p = .008), and more often persistent shoulder symptoms at work (55.9% vs. 5%; p &lt; .001). Conclusion: After stabilization of AC joint dislocation, the majority of patients returned to work, needing substantial time to return. Manual working patients required more time and often suffer under persistent symptoms at work

N-Octanoyl Dopamine, a Non-Hemodyanic Dopamine Derivative, for Cell Protection during Hypothermic Organ Preservation

BACKGROUND: Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects. METHODOLOGY/PRINCIPAL FINDINGS: To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects. CONCLUSIONS/SIGNIFICANCE: In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors

Development and validation of a novel questionnaire for self-determination of the range of motion of wrist and elbow

Background: The aim of this study was to develop and validate a novel self-administered questionnaire for assessing the patient’s own range of motion (ROM) of the wrist and the elbow. Methods: In a prospective clinical study from January 2015 to June 2015, 101 consecutive patients were evaluated with a novel, self-administered, diagram-based, wrist motion assessment score (W-MAS) and elbow motion assessment score (E-MAS). The questionnaire was statistically evaluated for test-retest reliability, patient-physician agreement, comparison with healthy population, and influence of covariates (age, gender, affected side and involvement in workers’ compensation cases). Results: Assessment of patient-physician agreement demonstrated almost perfect agreement (k > 0.80) with regard to six out of eight items. There was substantial agreement with regard to two items: elbow extension (k = 0.76) and pronation (k = 0.75). The assessment of the test-retest reliability revealed at least substantial agreement (k = 0.70). The questionnaire revealed a high discriminative power when comparing the healthy population with the study group (p = 0.007 or lower for every item). Age, gender, affected side and involvement in workers’ compensation cases did not in general significantly influence the patient-physician agreement for the questionnaire. Conclusion: The W-MAS and E-MAS are valid and reliable self-administered questionnaires that provide a high level of patient-physician agreement for the assessments of wrist and elbow ROM. Level of evidence: Diagnostic study, Level I

Vascular Impulse Technology versus elevation in the treatment of posttraumatic swelling of extremity fractures: study protocol for a randomized controlled trial

Background: Fractures of the extremities are often complicated by a variable degree of swelling secondary to hemorrhage and soft tissue injury. Patients typically require up to 7 days of inpatient bed rest and elevation to reduce swelling to an acceptable level for operative treatment with internal fixation. Alternatively, an intermittent pneumatic compression device, such as the Vascular Impulse Technology (VIT) system, can be used at the injured extremity to reduce the posttraumatic swelling. The VIT system consists of a pneumatic compressor that intermittently rapidly inflates a bladder positioned under the arch of the hand or the foot, which results in compression of the venous hand or foot plexus. That intermittent compression induces an increased venous velocity and aims to reduce the soft tissue swelling of the affected extremity. Methods/design: The VIT study is a prospective, monocenter, randomized controlled trial to compare the VIT system with elevation in the treatment of posttraumatic swelling in the case of a fracture of the upper and lower extremity. This study will include 280 patients with fractures of the upper and the lower extremity with nine different injury types. For each of the nine injury types a separate randomization to the two intervention groups (VIT group or control group) will be performed. The primary outcome parameter is the time taken for the swelling to resolve sufficiently to permit surgery. A separate analysis for each of the nine injury types will be performed. Discussion: In the proposed study, the effectiveness of the VIT system in the treatment of posttraumatic swelling of upper and lower extremity fractures will be evaluated. Trial registration: German Clinical Trial Register, No. DRKS00010510. Registered on 17 July 2016

In Vivo Emergence of UL56 C325Y Cytomegalovirus Resistance to Letermovir in a Patient with Acute Myeloid Leukemia after Hematopoietic Cell Transplantation

CMV associated tissue-invasive disease is associated with a considerable risk of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recently, the terminase inhibitor letermovir (LMV) has been approved for prophylaxis of CMV infection in HSCT. We hereby report a 60-year-old female experiencing CMV reactivation after HSCT in a CMV seronegative donor-constellation. Due to ongoing elevated CMV viral load and drug-associated myelosuppression, which prevented ganciclovir therapy, treatment was replaced by foscarnet. Due to nephrotoxicity, foscarnet was switched to LMV. The patient developed skin GvHD and prednisolone was started. Subsequently, CMV viremia worsened despite LMV therapy. Genotyping revealed the mutation C325Y of the CMV UL56 terminase being associated with high-level resistance against LMV. Prolonged uncontrolled low-level viremia due to prednisolone treatment may have favored the selection of drug-resistant CMV. Despite the excellent toxicity profile of LMV, physicians should be aware of risk factors for the emergence of resistance