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Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted in vitro by endothelial cells and vascular smooth muscle cells, and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects, ADM transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express ADM. ADM was overexpressed in AML cells versus normal CD34+ cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of ADM expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of ADM in FLT3-ITD, NPM1-mutated AML and FLT3-ITD/NPM1-mutated cases compared with wild-type ones. Moreover, ADM expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with ADM levels in the bone marrow cells of at least two AML cohorts. Moreover, ADM was upregulated in CD4+ T and CD8+ T cells from AML patients compared with healthy controls and some ADM co-expressed genes participate in a signature of immune tolerance that characterizes CD4+ T cells from leukemic patients. Overall, our study shows that ADM expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.

BackgroundThe anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019.MethodsWe conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs.ResultsA total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol.ConclusionsOur findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.

The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors. Since genetic lesions are necessary but not sufficient for Multiple Myeloma (MM) evolution, several authors hypothesized that immune dysfunction involving both B and T cell counterparts plays a key role in the pathogenesis of the disease. The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma into immune system shaping. A large series of 976 bone marrow samples from 735 patients affected by PCD was studied by flow analysis to identify discrete immune subsets. Treated MM samples displayed a reduction of CD4+ cells (p<0.0001) and an increase of CD8+ (p<0.0001), CD8+/DR+ (p<0.0001) and CD3+/CD57+ (p<0.0001) cells. Although these findings were to some extent demonstrated also following bortezomib treatment, a more pronounced cytotoxic polarization was shown after exposure to autologous stem cell transplantation (ASCT) and Lenalidomide (Len) treatment. As a matter of fact, samples of patients who received ASCT (n=110) and Len (n=118) were characterized, towards untreated patients (n=138 and n=130, respectively), by higher levels of CD8+ (p<0.0001 and p<0.0001, respectively), CD8+/DR+ (p=0.0252 and p=0.0001, respectively) and CD3+/CD57+ cells (p<0.0001 and p=0.0006, respectively) and lower levels of CD4+ lymphocytes (p<0.0001 and p=0.0005, respectively). We demonstrated that active MM patients are characterized by a relevant T cell modulation and that most of these changes are therapy-related. Current Myeloma treatments, notably ASCT and Len treatments, polarize immune system towards a dominant cytotoxic response, likely contributing to the anti-Myeloma effect of these regimens.

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