Christen Lykkegaard Andersen

A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia

Inhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator‐initiated, non‐randomized, open‐label phase II multi‐centre study included 63 patients (19 essential thrombocythaemia, 44 polycythaemia vera) from 15 centres. The primary objective was to evaluate if vorinostat was followed by a decline in clonal myeloproliferation as defined by European Leukaemia Net. Thirty patients (48%) completed the intervention period (24 weeks of therapy). An intention‐to‐treat response rate of 35% was identified. Pruritus was resolved [19% to 0% (P = 0·06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0·03). Sixty‐five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0·006). Thirty‐three patients (52% of patients) discontinued study drug before end of intervention due to adverse events (28 patients) or lack of response (5 patients). In conclusion, vorinostat showed effectiveness by normalizing elevated leucocyte and platelet counts, resolving pruritus and significantly reducing splenomegaly. However, vorinostat was associated with significant side effects resulting in a high discontinuation rate. A lower dose of vorinostat in combination with conventional and/or novel targeted therapies may be warranted in future studies.

A phase II study of vorinostat (MK-0683) in patients with primary myelofibrosis and post-polycythemia vera myelofibrosis

The Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) primary myelofibrosis (PMF) is characterized by progressive accumulation of connective tissue and endothelial proliferation in the bone marrow accompanied by extramedullary hematopoiesis with enlargement of the spleen and liver.[

Somatic mutations of the CREBBP and EP300 genes affect response to histone deacetylase inhibition in malignant DLBCL clones

Heterogeneous clinical responses to histone deacetylase inhibitors (HDACi) in diffuse large B-cell lymphoma (DLBCL) have prompted a need for evaluating the impact of mutations in the histone acetyl transferases (HAT) CREBBP and EP300 on HDACi treatment outcome. We identified four DLBCL cell lines; Toledo, with mutations in CREBBP and EP300, SUDHL-7 with mutation of CREBBP and wild-type (wt) EP300, RL with mutation of EP300 and wt CREBBP, and U2932 with wt CREBBP and wt EP300. Vorinostat treatment induced apoptosis significantly more rapid and profound in the CREBBP/EP300 double mutant cell line. Our results suggest that pre-treatment stratification according to HAT defects may be relevant in DLBCL.

Circulating YKL-40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state

Chronic myeloproliferative neoplasms (MPN), encompassing essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (PMF), are featured by a chronic inflammatory state which is pronounced in myelofibrosis The value of YKL‐40 as a biomarker of disease burden has been demonstrated in several different diseases, including cancer, diabetes mellitus and cardiovascular diseases. A state of chronic inflammation is shared by them all, YKL‐40 also being involved in the severity of chronic endothelial inflammation, which today is considered of crucial importance for the development of atherosclerosis. The MPNs being cancers with a heavy burden of cardiovascular diseases we hypothesised that circulating YKL‐40 might reflect the inflammatory process and potentially serve as a novel disease marker. Using ELISA, we measured YKL‐40 in 15 patients with ET, 16 patients with PV, 17 patients with PMF and 30 healthy controls. YKL‐40 was significantly elevated in PMF vs. control subjects, PMF levels median 43 ng/mL vs. controls median 28 ng/mL, P = 0.033. An increase from ET over PV may reflect the integrated impact of disease processes in MPNs.

A systematic review of health-related quality of life in longitudinal studies of myeloma patients

Multiple myeloma (MM) patients report high symptom burden and reduced health‐related quality of life (HRQoL) compared to patients with other haematological malignancies. The aim of this review was to analyse published longitudinal studies including MM patients according to a change in HRQoL scores, which is perceived as beneficial to the patient according to two published guidelines.

Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat

YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P<0.0001) and 1.7 times higher than in ET (P=0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms.

Lack of somatic mutations in the catalytic domains of CREBBP and EP300 genes implies a role for histone deacetylase inhibition in myeloproliferative neoplasms.

Somatic mutations of the two genes coding for the histone acetyltransferase genes, CREEBP and EP300 have been identified as a pathogenetic mechanism shared by common forms of B-cell non-Hodgkińs lymphomas. A screening for somatic mutations in CREEBP and EP300 genes in patients with myeloproliferative neoplasms (MPNs) has not previously been performed. DNA was purified from diagnostic samples of 56 MPN patients. We designed a mutation screening assay based on denaturing gradient gel electrophoresis and direct sequencing. Our results suggest that CREBBP and EP300 mutations are not major pathogenetic mechanisms of MPNs. The rationale for using HDACi in these patients seems reasonable.

The Danish National Chronic Myeloid Neoplasia Registry

Aim The Danish National Chronic Myeloid Neoplasia Registry (DCMR) is a population-based clinical quality database, introduced to evaluate diagnosis and treatment of patients with chronic myeloid malignancies. The aim is to monitor the clinical quality at the national, regional, and hospital departmental levels and serve as a platform for research. Study population The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable myeloproliferative neoplasms, chronic myelomonocytic leukemia, and chronic myeloid leukemia. Main variables Data are collected using standardized registration forms (so far up to four forms per patient), which are consecutively filled out online at time of diagnosis, after 2-year and 5-year follow-ups, and at end of follow-up. The forms include variables that describe clinical/paraclinical assessments, treatment, disease progression, and survival – disease-specific variables – as well as variables that are identical for all chronic myeloid malignancies. Descriptive data By the end of 2014, the DCMR contained data on 2,690 patients with an inclusion rate of ∼500 patients each year. Since the registry was established, annual reports have shown consistently high national coverage and data completeness, ≥90% and ≥88%, respectively. Conclusion The DCMR is a national database used for monitoring the quality of patient care in patients with chronic myeloid malignancies, but until validation has been conducted, the data must be used with caution. However, the DCMR is a valuable data source accessible to clinicians and researchers.

The prevalence and prognostic value of concomitant eosinophilia in chronic graft-versus-host disease after allogeneic stem cell transplantation

The prognostic significance of eosinophilia after myeloablative allogeneic stem cell transplantation (ASCT) remains to be established. Patients, whom developed chronic graft-versus-host disease (cGVHD) after ASCT, were included (n = 142). Eosinophil count was analyzed at cGVHD onset. We observed no significant association between EO and the grade of cGVHD, thrombocytopenia, nor extensive skin involvement. Importantly, we observed no significant association between cGVHD with concomitant eosinophilia and long-term clinical outcomes, and subgroup analyses revealed a considerable confounding effect of ongoing steroid treatment. In conclusion, we advocate that prognostic conclusions regarding cGVHD with concomitant eosinophilia after ASCT should be interpreted with caution.

A Randomized Placebo-Controlled Phase II Study of Clarithromycin or Placebo Combined with VCD Induction Therapy Prior to High-Dose Melphalan with Stem Cell Support in Patients with Newly Diagnosed Multiple Myeloma

BackgroundThe objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib–cyclophosphamide–dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.MethodsPatients were randomized to receive tablet clarithromycin 500xa0mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.ResultsThe study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (nu2009=u200927) or placebo (nu2009=u200931). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5–64.7) and in 16 patients (51.6%, 33.1–69.8) (pu2009=u20090.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥u2009grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.ConclusionThe study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9)