Howard S. Oster

Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions : could it be beneficial in early disease?

Erythropoietin (Epo) is the main growth regulator of red blood cells, and recombinant human erythropoietin (rHuEpo) is thus used in clinical practice for the treatment of anaemia, primarily in kidney disease and cancer. rHuEpo treatment was found to be associated with prolonged survival of multiple myeloma (MM) patients. This clinical observation was then supported by studies on murine myeloma models. It thus appeared that rHuEpo had an anti‐myeloma effect, causally related to an immunomodulatory function of rHuEpo. The present study investigated whether rHuEpo‐treated MM patients acquire improved immunological functions. Treatment with rHuEpo, prescribed for anaemia that occurs in advanced disease, was associated with effects on a variety of immunological parameters and functions. This was expressed in an actual normalisation of the CD4:CD8 cell ratio, enhanced T cell phytohaemagglutinin‐mediated activation and proliferation potential, T cell expression of the costimulatory CD28 and inhibitory CTLA‐4 molecules, as well as reduced interleukin‐6 serum values to normal levels. Furthermore, it was demonstrated that immunological abnormalities manifest in patients even in the early stages of MM. Our findings thus suggest that rHuEpo treatment might be effective in the early stages of MM, before anaemia develops. It is expected that this would boost the immune system, consequently achieving an anti‐myeloma function; affecting disease progression and improving the prognosis.

Erythropoietin: The swinging pendulum

Erythropoiesis stimulating agents (ESAs) have been used widely for anemic patients, especially those on dialysis and with cancer. However, reports have suggested shorter survival in erythropoietin (EPO)-treated cancer patients. The purpose of this review is to summarize and evaluate critically the current information about ESA treatment and its possible association with mortality in cancer patients. The pendulum that initially swung in the direction of widespread ESA treatment, and then in the direction of no treatment, is swinging back toward a stable position. This review also provides tools to decide how and when to use ESAs safely, according to accepted guidelines.

Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation

Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been controversial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that several of these specifically recognize EPOR by Western blot, immunoprecipitation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment.

Is bone marrow examination always necessary to establish the diagnosis of myelodysplastic syndromes? A proposed non-invasive diagnostic model

Abstract A non-invasive myelodysplastic syndromes (MDS) diagnostic model would allow for care while avoiding invasive bone marrow examinations (BME). BME-established MDS patients were compared to non-MDS (BME-excluded) patients. Variables (gender, age, hemoglobin (Hb), mean red blood cell corpuscular volume (MCV), platelet (PLT), and white blood cell (WBC)) were combined with multivariate logistic regression; a probability score (Y) was calculated. MDS (n = 48) and non-MDS (n = 63) patients were used to establish the model. The ROC was drawn, giving an AUC of 0.748 (95% CI: 0.656–0.84). Two cutoff values were used for Y. Y ≥ 0.633: high likelihood (positive predictive value (PPV) = 85%); Y ≤ 0.288: low likelihood (negative predictive value (NPV) = 81%) of MDS. The first group is defined as probable MDS (pMDS); the second, probably not MDS (pnMDS). The model was validated with 40 additional patients (20 with and 20 without MDS). Using clinical and lab data, we could diagnose or exclude MDS in about half of the patients, avoiding BME. Future work will use larger cohorts of patients to improve and further validate the model.

Cytokines in MDS: Abnormalities and Treatment

Myelodysplastic syndromes (MDS) are associated with quantitative and qualitative hematopoietic defects. The cytokine abnormalities have led to the introduction of recombinant products into clinical practice. This chapter reviews the biology and therapeutic use of cytokines.

Can bone marrow cellularity help in predicting prognosis in myelodysplastic syndromes

To ascertain the relevance of bone marrow cellularity (BMC) to the interpretation of blast percentage (blast%) in MDS prognostication.