Multistep pathogenesis of chronic myelomonocytic leukemia in patients.

Background: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients.

Methods: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14).

Results: Median survival was 90, 45, and 9 months, respectively (p = .

Impact of age on the cumulative risk of transformation in patients with chronic myelomonocytic leukaemia.

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients.

Myelomonocytic skewing in chronic myelomonocytic leukemia: phenotypic, molecular and biologic features and impact on survival.

Background: Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined.

Methods: Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures.

Results: There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%).

Retrospective analysis of the prevalence of specialised palliative care services for patients with metastatic breast cancer.

Background: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear.

Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia.

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients.

Myelomonocytic Skewing In Vitro Discriminates Subgroups of Patients with Myelofibrosis with A Different Phenotype, A Different Mutational Profile and Different Prognosis.

Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E.

Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype.

Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients.

Genotypic and phenotypic evolution in a patient with chronic myelomonocytic leukemia.

The correlation of molecular and phenotypic evolution in individual patients with chronic myelomonocytic leukemia (CMML) is poorly investigated. The longitudinal follow up of a CMML patient for more than 10 years illustrates that the emergence of clones harboring mutations in and finally in multiple genes, respectively, was mirrored by thrombocytopenia, thrombocytosis, myeloproliferation and transformation into acute myeloid leukemia. Moreover, molecular aberrations of the genes were associated with markedly increased spontaneous in vitro myeloid colony formation which has been shown to be a functional indicator of RAS pathway hyperactivation.

The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML.

Evaluation of efficacy of alemtuzumab in 5 patients with aplastic anemia and/or myelodysplastic neoplasm.

Patients with aplastic anemia or hypoplastic myelodysplastic syndrome (MDS) may respond to immunosuppressive therapy, including the anti-CD52 antibody alemtuzumab. We analyzed treatment responses to alemtuzumab in 5 patients with MDS or aplastic anemia (AA) evolving to MDS. Two patients with hypoplastic MDS (hMDS) showed a partial response (PR) to alemtuzumab.

In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia.

In chronic myelomonocytic leukemia (CMML), colony-forming units granulocyte/macrophage (CFU-GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM-CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML.

Interleukin-10 inhibits autonomous myelopoiesis in patients with myelofibrosis.

The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis.

Evaluation of treatment responses and colony-forming progenitor cells in 50 patients with aplastic anemia after immunosuppressive therapy or hematopoietic stem cell transplantation: a single-center experience.

We analyzed the clinical course and outcome in 50 patients (27 males, 23 females) suffering from aplastic anemia (AA), treated in our department between 1987 and 2007. The median age was 37 years (range: 14-70 years). A total of 42 patients received antithymocyte globulin and cyclosporine A (CSA).

High spontaneous granulocyte/macrophage-colony formation in patients with myelofibrosis.

Unstimulated methylcellulose cultures in 25 myelofibrosis (MF) patients were performed to better understand the role of cytokines in the proliferation of MF cells. Compared to controls MF patients show a variable but highly increased spontaneous CFU-GM formation (66 vs 4.8/10(5) PBMNC).

CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin.

Background: CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.

Design And Methods: We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction.

Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis.

Minimal diagnostic criteria for myelodysplastic syndromes (MDS) include constant cytopenia recorded for at least 6 months, dysplasia, and exclusion of other causes of cytopenia and dysplasia. However, there are patients with dysplastic bone marrow features with or without a karyotype, who have only mild if any cytopenia. This condition has been termed idiopathic dysplasia of unknown significance (IDUS).

Targeted drug delivery by gemtuzumab ozogamicin: mechanism-based mathematical model for treatment strategy improvement and therapy individualization.

Gemtuzumab ozogamicin (GO) is a chemotherapy-conjugated anti-CD33 monoclonal antibody effective in some patients with acute myeloid leukemia (AML). The optimal treatment schedule and optimal timing of GO administration relative to other agents remains unknown. Conventional pharmacokinetic analysis has been of limited insight for the schedule optimization.

Circulating hematopoietic progenitor cells predict survival in patients with myelofibrosis with myeloid metaplasia.

Background And Objectives: The levels of circulating hematopoietic progenitor cells are often increased in myelofibrosis with myeloid metaplasia (MMM). The prognostic relevance of this phenomenon is largely unknown.

Design And Methods: We determined the number of circulating myeloid (CFU-GM), erythroid (BFU-E), and pluripotent (CFU-GEMM) progenitors, in 110 patients with MMM at diagnosis using a semi-solid colony assay.

Relation of in vitro growth characteristics to cytogenetics and treatment outcome in acute myeloid leukemia: prognostic significance in patients with a normal karyotype.

We analyzed in vitro growth characteristics of bone marrow mononuclear cells (BMMCs) from 322 patients with acute myeloid leukemia (AML) in relation to cytogenetic abnormalities. Median colony growth was low in each of the cytogenetic changes associated with a favorable outcome. Most karyotypic abnormalities in the intermediate prognosis group were associated with low growth potential, but 11 q23 abnormalities exhibited 8 times higher in vitro growth.