Impact of pharmacokinetics to reduce bleeding in a cohort of patients with severe hemophilia A in a personalized comprehensive management program

Introduction: In recent decades, hemophilia A treatment has been focused on body weight, without taking pharmacokinetic parameters into account. Previous research has shown that the individual pharmacokinetic response is more effective in predicting the required dose of clotting factor. We want to evaluate the impact on reducing the frequency of bleeding in patients treated with recombinant factor VIII, based on a personalized comprehensive management program. Objective: Our aim was to compare the results of a standard comprehensive treatment program (stage I) vs. a personalized pharmacokinetic - based treatment program (stage II) in a cohort of 60 patients with severe hemophilia without inhibitors. Results:The median age was 15.5 years (3 - 68). The ABR was 1.03 (62 episodes) in the first stage and 0.58 (35 episodes) in the second one, (p = 0.004). By type of bleeding, the impact of the intervention differs significantly in spontaneous bleeding (p = 0.007) and a 73% reduction in the first stage. There were no significant differences in traumatic bleeding. Conclusions: The use of pharmacokinetics for personalized dosing of patients with severe hemophilia A, significantly reduces ABR and spontaneous bleeding, improving the patient's quality of life and costs for the health system.

Direct oral anticoagulants; a review for the non-specialist

Thrombin inhibitors and direct factor Xa inhibitors represent a major breakthrough in the field of anticoagulation pharmacotherapy. These novel agents have replaced warfarin as the oral anticoagulant of choice in certain indications, as they possess equal or superior efficacy and better safety profiles. They have a quick onset of action, predictable pharmacokinetic properties and minimal drug and food interactions. So they do not require frequent blood monitoring and dose adjustments as with warfarin. Considering all the advantages, there seems to be a rapid increase in the number of patients who are started on these novel anticoagulants. In this review, we highlight the pharmacology of these direct oral anticoagulants and the evidence-based indications for their use. We aim to provide a clinical overview for the non-specialist who may be called upon to manage a patient who is currently on one of these novel anticoagulants.

Therapeutic innovation for multi-resistant candidemics: synergy of isavuconazole and caspofungin association

Fungal infections occurring in immunocompromised patients after immuno-chemotherapy treatment, are often difficult to eradicate and capable of even being fatal. Systemic mycoses affecting severely immunocompromised patients often manifest acutely with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination. Opportunistic fungal infections (mycoses) include several pathogens elements, as Candidiasis, Aspergillosis, Mucormycosis (zygomycosis) and Fusariosis. Prompt diagnosis and effective therapy are needed to improve the associated morbidity and mortality, especially in cases with non-canonical fungal localizations and not responsive to the available antifungal drugs.

LSD1 inhibition enhances robust fetal hemoglobin induction in human β0-thalassemia/HbE erythroid cells

Induction of fetal hemoglobin (HbF) ameliorates the clinical severity of β-thalassemias. Histone methyltransferase LSD1 enzyme removes methyl groups from the activating chromatin mark histone 3 lysine 4 at silenced genes, including the γ-globin genes. LSD1 inhibitor RN-1 induces HbF levels in cultured human erythroid cells. Here, the HbF-inducing activity of RN-1 was investigated in erythroid progenitor cells derived from β0-thalassemia/HbE patients. The significant and reproducible increases in γ-globin transcript and HbF expression upon RN-1 treatment was demonstrated in erythroid cells with divergent HbF baseline levels, the average of HbF induction was 17.7 + 0.8%. RN-1 at low concentration did not affect viability and proliferation of erythroid cells, but decreases in cell number was observed in cells treated with RN-1 at high concentration. Delayed terminal erythroid differentiation was revealed in β0-thalassemia/HbE erythroid cells treated with RN-1 as similar to other compounds that target LSD1 activity. Downregulation of repressors of γ-globin expression; NCOR1 and SOX6, was observed in RN-1 treatment. These findings provide a proof of concept that a LSD1 epigenetic enzymes is a potential therapeutic target for β0-thalassemia/HbE patients.

Low diagnostic accuracy and inter-observer agreement on CT and MRI in diagnosis of spinal fractures in multiple myeloma

Skeletal disease is common in multiple myeloma. We investigated the inter-observer agreement and diagnostic accuracy of spinal fractures diagnosed by computer tomography (CT) and magnetic resonance imaging (MRI) from 12 myeloma patients. Two radiologists independently assessed the images. CT, MRI, and other images were combined to a gold standard. The inter-observer agreement was assessed with Cohen’s kappa. Radiologist 1 diagnosed 20 malignant spinal fractures on CT and 26 on MRI, while radiologist 2 diagnosed 12 malignant spinal fractures on CT and 22 on MRI. In comparison the gold standard diagnosed 10 malignant spinal fractures. The sensitivity for malignant fractures varied from 0.5 to 1 for CT and MRI, and the specificity varied from 0.17 to 0.67. On MRI, the specificity for malignant spinal fractures was 0.17 for both radiologists. The inter-observer agreement for malignant spinal fractures on CT was -0.42 (Cohen’s kappa) and -0.13 for MRI, while for osteoporotic fractures it was -0.24 for CT and 0.53 for MRI. We conclude that malignant spinal fractures were over-diagnosed on CT and MRI. The inter-observer agreement was extremely poor.

Germline CEBPA mutation in familial acute myeloid leukemia

Myeloid Neoplasms with germline predisposition become part of 2016 World Health Organization (WHO) classification of hematological malignancies since 2016. CCAAT/enhancer binding protein-alpha (CEBPA) is a myeloid transcription factor located in chromosome 19q. Acute myeloid leukemia (AML) with biallelic mutations of CEBPA AML with recurrent genetic abnormalities according to WHO classification. The inheritance of a germline CEBPA mutation predisposes to the development of AML with autosomal dominant inheritance. Familial CEBPA AML share characteristics with somatic CEBPA AML. However, a higher relapse incidence is reported. We present the case of a 46-years-old male with family history of acute leukemia who was diagnosed with single mutated CEBPA acute myeloid leukemia. The same mutation was found in two of his siblings. The clinical suspicion and proper diagnosis of familial cases is necessary, especially when a related allogenic transplant is indicated in order to select an adequate donor.

Abstract Book of the SOHO 3rd Italian Conference | 27-30 September 2021

This Book of Abstract contains oroginal contributions presented at the 3rd SOHO Italian Conference 27-30 September 2021 | Hybrid event

How I manage systemic light chain amyloidosis

Light chain amyloidosis (AL) is a protein deposition disorder with a heterogenous pattern of organ involvement and dysfunction that varies by affected patient. Often diagnosed late after the onset of symptoms, appropriate and correct diagnosis, and prompt initial management, typically with anti-plasma cell therapy targeting the underlying cell producing the aberrant light chain protein, can lead to significant improvement in patient symptoms, organ function and lifespan. With recent publication of phase III studies focused on AL, and a changing regulatory landscape providing greater availability of novel therapies, the management of AL is in some ways more complex with greater options to consider. In this clinical review, a discussion of the diagnosis, staging, and goals of therapy transitions to a focus on contemporary management questions to outline our clinical approach to multi-disciplinary management and long term follow up for patients with suspected or confirmed AL.

Apixaban and eftrenonacog alfa treatment in a patient with moderate hemophilia B and cardiovascular disease

In developed countries, the life expectancy of patients with hemophilia (PwH) is now close to that of the unaffected male population. This means that these patients are at risk of developing age-related comorbidities, including cardiovascular disease. Managing cardiovascular disease in PwH patients can be particularly challenging, due to their high bleeding risk. To our knowledge, this is the first report of a male patient with moderate hemophilia B and hypertensive ischemic heart disease complicated by arrhythmia due to nonvalvular atrial fibrillation, who was treated with apixaban and left atrial appendage closure while receiving concomitant anti-hemorrhagic prophylaxis with eftrenonacog alfa.

Transformation of low-grade follicular lymphoma with partial marginal zone differentiation: Two cases

Two cases of low-grade follicular lymphoma, with marginal zone differentiation and/or with high proliferation rate in one of them, are reported with transformation into high grade B-cell and B-lymphoblastic lymphomas. The contribution of these features to the transforming process, although previously described, is infrequent, and has not been deciphered to date.