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Fetal Genotype-Phenotype Intercourse Discordance: A Case of 5-Alpha-Reductase Deficit.
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versus-host disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and low-dose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.Various allogeneic (allo) stem cell transplantation platforms have been developed over the last 2 decades. In this review we focus on the impact of in vivo and ex vivo graft manipulation on immune reconstitution and clinical outcome. Strategies include anti-thymocyte globulin- and post-transplantation cyclophosphamide-based regimens, as well as graft engineering, such as CD34 selection and CD19/αβT cell depletion. Differences in duration of immune suppression, reconstituting immune repertoires, and associated graft-versus-leukemia effects and toxicities mediated through viral reactivations are highlighted. In addition, we discuss the impact of different reconstituting repertoires on donor lymphocyte infusions and post allo pharmacological interventions to enhance tumor control. We advocate for precisely counting all graft ingredients and therapeutic drug monitoring during conditioning in the peripheral blood, and for adjusting dosing accordingly on an individual basis. In addition, we propose novel trial designs to better assess the impact of variations in transplantation platforms in order to better learn from our diversity of "counts" and potential "adjustments." This will, in the future, allow daily clinical practice, strategic choices, and future trial designs to be based on data guided decisions, rather than relying on dogma and habits.Driver mutations occur in Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), and calreticulin (CALR) in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). From mutations leading to one amino acid substitution in JAK2 or MPL, to frameshift mutations in CALR resulting in a protein with a different C-terminus, all the mutated proteins lead to pathologic and persistent JAK2-STAT5 activation. The most prevalent mutation, JAK2 V617F, is associated with the 3 entities polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), while CALR and MPL mutations are associated only with ET and MF. Triple negative ET and MF patients may harbor noncanonical mutations in JAK2 or MPL. One major fundamental question is whether the conformations of JAK2 V617F, MPL W515K/L/A, or CALR mutants differ from those of their wild type counterparts so that a specific treatment could target the clone carrying the mutated driver and spare physiological hematopoiesis. Of great interest, a set of epigenetic mutations can co-exist with the phenotypic driver mutations in 35%-40% of MPNs. These epigenetic mutations, such as TET2, EZH2, ASXL1, or DNMT3A mutations, promote clonal hematopoiesis and increased fitness of aged hematopoietic stem cells in both clonal hematopoiesis of indeterminate potential (CHIP) and MPNs. Importantly, the main MPN driver mutation JAK2 V617F is also associated with CHIP. Accumulation of several epigenetic and splicing mutations favors progression of MPNs to secondary acute myeloid leukemia. Another major fundamental question is how epigenetic rewiring due to these mutations interacts with persistent JAK2-STAT5 signaling. Answers to these questions are required for better therapeutic interventions aimed at preventing progression of ET and PV to MF, and transformation of these MPNs in secondary acute myeloid leukemia.Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. CK-586 cell line Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.
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