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Background Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. Objective The aim of this study was to assess patient preference for ravulizumab or eculizumab. Methods Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. Results Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). Conclusion This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts.

In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS ( p  = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH−, p  = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH− for HSCT; in AA: 78 vs. 50% for IST, p  < 0.0001, and 97 vs. 77%, p  = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p  < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p  = 0.01), leukemic evolution (6.8 vs. 12.7%, p  = 0.01 in MDS), and overall survival [73% (95% CI 68–77) vs. 51% (48–54), p  < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8–3.1; p  < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.

The C5 targeting monoclonal antibody eculizumab has changed the natural history of paroxysmal nocturnal hemoglobinuria (PNH) in the last 10 years. However, some unmet clinical needs persist, including persistent anemia with some patients requiring transfusions, incomplete C5 inhibition with breakthrough hemolysis (because of pharmacokinetic or pharmacodynamic issues such as infections, as well as conditions increasing complement activity), the underlying bone marrow failure, and the significant burden on patient quality of life (intravenous route of administration and frequency of infusions). Moreover, a subclass of patients carries C5 polymorphisms resistant to eculizumab inhibition. Several second-generation C5 inhibitors are under active study to overcome unmet clinical needs with eculizumab. Current strategies encompass increasing drug half‐life, developing small molecule inhibitors of C5, and exploring new routes of administration (including subcutaneous and oral agents). In this review, we summarize available data on second-generation C5 inhibitors in PNH, including novel monoclonal antibodies, a small interfering RNA, and small molecules.

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.

Histopathological analysis of samples of skin biopsies from the chin and lower eyelid showed superficial and deep perifollicular and periadenexal lymphocytic inflammation as well as ectatic blood vessels in the superficial dermis: indicative of the clinical diagnosis of rosacea. Notably, the patient had a family history of both myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML): his mother was diagnosed with MDS aged 27 years, AML aged 36 years, and she died aged 37 years; a maternal aunt was diagnosed with MDS aged 26 years and had an allogeneic transplant; his maternal grandmother was diagnosed with AML aged 24 and died one year later; and a maternal great aunt, who was diagnosed at an unknown age, with AML. Putting the findings together—monocytopenia, human papilloma viral infection, lymphoedema, and family history of myelodysplastic syndromes—we suspected the patient had GATA2 deficiency.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.

Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34 + CD38 − CD45RA − CD90 + CD49f + HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.

Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS)1. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant2 within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients3. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation4,5. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1–GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.Martinez-Hoyer et al. identify recurrent TP53 or RUNX1 variants in patients with lenalidomide-resistant myelodysplastic syndromes that are associated with impaired RUNX1/GATA2-mediated megakaryocytic differentiation and cell death.