Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

Cementless Total Hip Arthroplasty in Primary Myelofibrosis - a Case Report.

There is a great deal of data available, in part contradictory, on the best fixation technique to use for total hip arthroplasty (THA) in hip osteoarthritis. Both the cementless and the cemented versions offer excellent long-term outcomes - if the respective technique is applied correctly. However, as far as we know, no recommendation has been made regarding cemented vs. cementless THA in primary myelofibrosis. The case described here concerns a very active 76-year-old patient with primary myelofibrosis. This is a rare hematological disease. It develops from clonal hematopoiesis with impaired blood formation and progressive bone marrow fibrosis. An MRI scan of the patients pelvis showed a marked spotted change over all of the imaged bone. Ultimately, in preoperative planning we decided in favor of a proven cementless implant (Allofit Alloclassic cup and the CLS Spotorno stem from Zimmer). Complication-free osseous integration of the cementless implants was observed. Histologic analysis of the bone showed a focally sclerotically altered bone structure. Neither osteoporosis nor osteopenia were found. In our opinion, taking into account all other indication criteria, there is no reason not to perform a cementless THA implantation in the presence of primary myelofibrosis. Key words: hip, primary myelofibrosis, cementless, THA, total hip replacement.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.

[Acute leukemia in adults]. / Akute Leukämien des Erwachsenen.

BACKGROUND: The prognosis of adult patients with acute leukemia has continuously improved over the years due to the introduction of new diagnostic and therapeutic procedures and progress in the field of supportive therapy. METHODS: This article gives an overview of the currently available options and the clinical approach to the diagnostics and therapy of acute leukemia. RESULTS: The standardization as well as improvements in diagnostic procedures, in particular by immunocytological and genetic procedures, allow a more rapid determination of the exact diagnosis. In addition to age and performance status of patients, an established panel of cytogenetic and molecular markers allows an individual risk stratification for selecting the most appropriate therapeutic procedure for each patient. In acute myeloid leukemia (AML) younger patients with genetically determined intermediate and poor risk status benefit from allogeneic stem cell transplantation whereas patients in the low risk group are still primarily treated with conventional induction chemotherapy with anthracycline and cytarabine. The poor prognosis of elderly patients with AML has been improved by the development of stem cell transplantation procedures with reduced intensity conditioning and for patients not suitable for stem cell transplantation, the introduction of less toxic demethylating substances allows a substantial improvement in outcome and quality of life compared to cytoreductive therapy alone. The additional role of targeted therapies in AML is still under investigation. In adult patients with acute lymphoblastic leukemia (ALL), the standard systemic therapy still consists of complex cytotoxic regimens which have been modified from pediatric protocols. Biologically and genetically determined subgroups of ALL patients as well as poor responders, who can be identified by the detection of significant molecular determined residual disease (MRD) after standard therapy, benefit from allogeneic transplantation in first remission. In patients with bcr-abl positive ALL, the implementation of first and second generation tyrosine kinase inhibitors has led to rapidly rising response rates and less toxicity. Patients with relapsed ALL may benefit from new molecular options, e.g. bispecific antibodies. Additionally, improved standardization and supportive care, particularly due to the introduction of modern antimycotic agents, increase the treatment options and improve the prognosis of patients with acute leukemia. CONCLUSION: The improved diagnostic and therapeutic options for patients with acute leukemia require a complex management. Currently only subgroups of patients benefit from molecular targeted therapeutic strategies. Due to this increasing complexity in the management, patients with acute leukemia should be treated in academic centers and within clinical trials.

[Chronic myelogenous leukemia]. / Chronische myeloische Leukämie.

The advent of tyrosine kinase inhibitors (TKI) has improved the prognosis and outcome of patients with chronic myelogenous leukemia (CML) considerably. Compared with imatinib, the first-line use of second-generation inhibitors nilotinib and dasatinib has led to faster and deeper molecular remissions accompanied by a differential adverse effect profile. An essential part of the management of CML patients is the guideline-based application of cytogenetics and standardized polymerase chain reaction techniques to regularly assess the remission status. Long-lasting treatment-free remission in a minority of patients led to hopes for the curability of CML in a significant minority of patients. The use of interferon alpha combined with or after TKI therapy is associated with the induction of an immune response toward the leukemic clone. This innovative treatment approach is currently under prospective investigation to improve long-term response. The coordinated cooperation of academic and regional hospitals, office-based hematologists, laboratories, and patient representatives allows for up-to-date patient care and the early use of new therapeutic options in patients at risk.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.

To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.

In vivo activity of 11ß-hydroxysteroid dehydrogenase type 1 in man: effects of prednisolone and chenodesoxycholic acid.

The 11ß-hydroxysteroid dehydrogenases (11ß-HSDs) play a pivotal role in glucocorticoid (GC) action. 11ß-HSD1 is a predominant reductase, activating GCs from inert metabolites, whereas 11ß-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic effects of GCs, a selective inhibition of 11ß-HSD1 represents a potential target for therapy of impaired glucose tolerance, insulin insensitivity and central obesity. In vitro, 11ß-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone on hepatic 11ß-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone (E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers within a randomised cross-over trial before and after oral administration of 12.5 mg E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11ß-HSD1 activity, hepatic reduction of 25 mg E acetate before and after treatment with prednisolone (30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined using a fully automated liquid chromatographic system. CDCA had no effect on the activity of 11ß-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11ß-HSD1, which could not be extinguished by a parallel increase of IGF-1 under prednisolone. CDCA does not affect in vivo activity of 11ß-HSD1 when given in therapeutic dosages. During GC treatment, increased hepatic activation of E to F may aggravate metabolic side effects of GCs such as seen in the metabolic syndrome.

Pharmacodynamics and pharmacokinetics of synthetic mineralocorticoids and glucocorticoids: receptor transactivation and prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases.

Glucocorticoid (GC) and mineralocorticoid (MC) action in target tissues is determined by prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases (HSDs) and receptor transactivation. We characterized these parameters for steroids often used in clinical practice. HSD activity was examined in human liver (HSD1) and kidney microsomes (HSD2) and in CHO cells stably transfected with both enzymes. GC and MC transcriptional activity was tested by luciferase assay in CV-1 cells transfected with human GC or MC receptor expression vectors. The 11-hydroxy-group is necessary for GC and MC receptor transactivation. As HSD2 oxidizes 11-hydroxysteroids to inactive 11-dehydrosteroids, GC and MC activity in HSD2-expressing tissues (kidney, colon) is regulated by this enzyme. As 9alpha-fluorination (such as in 9alpha-fluorocortisol) decreases oxidation by HSD2 and increases both GC and MC receptor transactivation, this modification leads to optimal, but non-selective transactivation of both receptors. Increased GC receptor and decreased MC receptor transactivation leading to more selective GC activity is reached using the following substituents: 16beta-methyl (in betamethasone), 16alpha-methyl (in dexamethasone) and triangle up 1-dehydro-configuration (in prednisolone). Whereas the modifications in position 16 decrease oxidation by HSD2, the triangle up 1-dehydro-configuration increases HSD2-activity leading to an enhanced inactivation of prednisolone compared to all other steroids. 9alpha-fluorocortisol, the most frequently used substance for MC-substitution, seems to be the best choice of available steroids for this purpose. Whereas GC selectivity can be improved by hydrophobic substituents in position 16 and the triangle up 1-dehydro-configuration, maximal GC activity needs additional fluorination in position 9alpha (such as in dexamethasone). For GC therapy directed to HSD2-expressing organs, widely used prednisolone does not seem to be the optimal recommendation.

Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig.

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.