RESUMO
Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.
RESUMO
Acute myelogenous leukemia (AML) is an aggressive disorder with an overall disease-free survival of 40-50% even for the younger patients under 60 years of age who can receive the most intensive treatment. The median age at the time of diagnosis is 60-65 years, and the large majority of elderly patients usually receive less intensive chemotherapy or only supportive therapy due to the high treatment-related mortality when using intensive therapy for elderly individuals. Thus, there is a need for new therapeutic approaches to improve the treatment in younger patients and to make AML-directed therapy with acceptable toxicity possible in elderly individuals. Angiogenesis seems to be important both for leukemogenesis and susceptibility to intensive chemotherapy, and antiangiogenic strategies are therefore considered for the treatment of AML. The two proangiogenic mediators vascular endothelial growth factor (VEGF) and interleukin 8, (IL-8, also referred to as CXCL8) seem to be important in human AML: VEGF is released at increased levels due to interactions between AML cells and neighboring nonleukemic cells, whereas IL-8 is released at high levels by native human AML cells. Thus, VEGF as a therapeutic target in AML is suggested both by experimental and clinical observations, whereas IL-8 as a target is mainly suggested by experimental evidence. In the present review we describe and discuss (i) the angioregulatory network of soluble mediators in AML, including both the systemic levels and local release by native human AML cells; and (ii) various therapeutic approaches to target VEGF and IL-8. Although single angioregulatory mediators can be targeted, it should be emphasized that the final effect of soluble mediators on angioregulation is determined by a complex angioregulatory network that varies between AML patients, and the final effect of targeting single mediators may therefore differ between patient subsets.
