Recent insights into the role of the microbiome in malignant and benign hematologic diseases.

Growing evidence suggests the impact of microbiome alteration, named dysbiosis, on the development of neoplasms, infections, inflammatory diseases, and immuno-mediated disorders. Regarding hematologic diseases, most data regard hematopoietic stem cell transplant (HSCT). In this review, we systematically evaluate the studies concerning microbiome in malignant and benign hematologic disorders beyond HSCT. A permissive microbiota is associated to the development of hematologic malignancies (including acute leukemia, lymphoma, and multiple myeloma), as well as of iron deficiency anemia, autoimmune cytopenias, and aplastic anemia. This happens through various mechanisms; chronic inflammatory triggering, epithelial barrier alteration, antigen dissequestration, and molecular mimicry. Hematologic therapies (chemo and immunosuppression) may induce/worsen dysbiosis and favour disease progression and infectious complications. Antibiotics may also induce dysbiosis with possible long-term consequences. Finally, novel target therapies are likely to alter microbiome, inducing gut inflammation (i.e. small molecules such as tyrosine-kinase-inhibitors) or enhancing host's immune system (as observed with CAR-T cells and checkpoint inhibitors)

Cytokine polymorphisms in patients with autoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features

The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe warm-antibody AIHA, there is evidence for the upfront addition of rituximab to prednisolone in the first line. Novel agents targeting B-cells, extravascular hemolysis, or removing IgG will offer further options in the acute and relapsed/refractory settings. In cold agglutinin disease, the development of complement inhibitors and B-cell targeting agents makes it possible to individualize therapy, based on the disease profile and patient characteristics. For most AIHAs, the optimal treatment remains to be found, and there is still a need for more evidence-based therapies. Therefore, prospective clinical trials should be encouraged

Use and positioning of fostamatinib in the management of primary chronic immune thrombocytopenia: an Italian expert opinion

Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, represents a new therapeutic opportunity for patients with immune thrombocytopenia (ITP) in Europe and Italy. However, the positioning of this drug in patient's therapeutic sequence is undefined within the most recent international guidelines. The conclusions from a consensus meeting between Italian experts, whose task was to outline the profile of the ideal candidate to receive fostamatinib, are reported here. A modified Delphi methodology was used to achieve shared statements, which were reported in a narrative form. In particular, the panelists examined the strengths and weaknesses of the registration studies in terms of clinical outcomes, the safety profile of fostamatinib, the drug's impact on the quality of life of patients with chronic ITP, and the potential benefits of its use in the pandemic era. Although the experience with thrombopoietin receptor agonists (TPO-RAs) and the amount of data from real-world studies suggest the preferential use of these drugs as a second-line treatment in most patients, the absence of an increased thrombotic risk in the clinical trials could make fostamatinib a reasonable choice in patients with an increased risk of vascular events. An unstable platelet count during TPO-RAs might also justify a switch to the Syk inhibitor, which is more likely to stabilize the platelet count in responders. Fostamatinib may be preferred to immunosuppressors during the SARS-CoV-2 pandemic, in patients at infectious risk, or in case of contraindication to splenectomy. Finally, the novel mechanism of action makes it an attractive drug in multi-refractory patient

Severe autoimmune hemolytic anemia; epidemiology, clinical management, outcomes and knowledge gaps

Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low grade hemolysis to severe life-threatening cases. The rarity, heterogeneity and incomplete understanding of severe AIHA complicate the recognition and management of severe cases. In this review, we describe how severe AIHA can be defined and what is currently known of the severity and outcome of AIHA. There are no validated predictors for severe clinical course, but certain risk factors for poor outcomes (hospitalisation, transfusion need and mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA (warm AIHA with complement positive DAT, mixed, atypical) are associated with lower hemoglobin levels, higher transfusion need and mortality. Currently, there is no evidence-based therapeutic approach for severe AIHA. We provide a general approach for the management of severe AIHA patients, incorporating monitoring, supportive measures and therapeutic options based on expert opinion. In cases where steroids fail, there is a lack of rapidly effective therapeutic options. In this era, numerous novel therapies are emerging for AIHA, including novel complement inhibitors, such as sutimlimab. Their potential in severe AIHA is discussed. Future research efforts are needed to gain a clearer picture of severe AIHA and develop prediction models for severe disease course. It is crucial to incorporate not only clinical characteristics but also biomarkers that are associated with pathophysiological differences and severity, to enhance the accuracy of prediction models and facilitate the selection of the optimal therapeutic approach. Future clinical trials should prioritize the inclusion of severe AIHA patients, particularly in the quest for rapidly acting novel agents

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease

Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.</p

Hematological and Extra-Hematological Autoimmune Complications after Checkpoint Inhibitors

Checkpoint inhibitors (CPI) represent a novel therapeutical strategy with a high efficacy both in solid and hematological cancers. They act by reactivating the immune system against neoplastic cells but may, in turn, cause immune-related adverse events (IRAEs) involving several organs with variable frequency and severity. Up to 10% of CPI-treated patients experience hematological IRAEs, mainly cytopenias. The differential diagnosis is challenging due to underlying disease, previous treatments and the variable liability of available tests (i.e., the direct antiglobulin test, anti-platelet antibodies, etc.). Among extra-hematological IRAEs, cutaneous and endocrine ones are the most frequent (up to 30&ndash;50%), ranging from mild (pruritus, eczema and thyroid dysfunctions) to severe forms (bullous disorders, hypophysitis and diabetes), mostly requiring topic or replacement therapy. Gastroenteric and kidney toxicities occur in about 5% of patients, biopsies may support the diagnosis, and immunosuppressive treatment is required in severe cases. Finally, neurologic and cardiologic IRAEs, although rare, may be life-threatening and require prompt intervention. By reviewing the most recent literature on post-CPI IRAEs, it emerged that clinical suspicion and monitoring of laboratory markers of organ damage is pivotal to a prompt diagnosis. In severe cases, CPI should be discontinued and immunosuppressive therapy started, whilst rechallenge is anecdotal and should be carefully evaluated

Diagnosis and Management of Autoimmune Hemolytic Anemias

Autoimmune hemolytic anemia (AIHA) is usually categorized, as other immune-mediated cytopenias, in so-called benign hematology, and it is consequently managed in various settings, namely, internal medicine, transfusion centers, hematology and, more rarely, onco-hematology departments [...