Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal ...gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell-cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.
1 SRH Kurpfalzkrankenhaus Heidelberg gGmbH and Hemophilia Center, Heidelberg, Germany
2 Thrombosis and Hemostasis Unit, Niguarda Hospital, Milan, Italy
3 Arthur Bloom Haemophilia Centre, University ...Hospital of Wales School of Medicine, Cardiff University, Cardiff, UK
4 Center for Hemophilia and Thrombosis, Skejby University Hospital, Department of Clinical Biochemistry, Aarhus, Denmark
5 Georgetown University Hospital, Lombardi Cancer Center, Division of Hematology/Oncology, Washington, DC, USA
6 Department of Internal Medicine, Centre Hospitalier Universitaire de Rouen-Boisguillaume, Rouen, France
7 Regional University Hospital Carlos Haya, Division of Hematology, Málaga, Spain
8 Department of Pediatrics, Nara Medical University, Nara, Japan
9 Hématologie-Oncologie, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
Correspondence: Angela Huth-Kühne, SRH Kurpfalzkrankenhaus and Hemophilia Center Heidelberg gGmbH Bonhoefferstrasse 5, 69123 Heidelberg. E-mail: angela.huth-kuehne{at}kkh.srh.de
Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group.
Key words: acquired hemophilia, bleeding, inhibitors, treatment, recommendations.
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Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression ...results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.
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•Combined Egfr/Raf1 ablation results in complete regression of a subset of PDACs•Mouse mutant Kras/Trp53-induced PDACs display distinct transcriptional profiles•PDAC transcriptional profiles determine their response to Egfr/Raf1 ablation•EGFR/c-RAF inhibition also prevents proliferation of PDX-derived tumor cells
Blasco et al. show that ablation of Egfr and Raf1 results in complete regression of a subset of mutant Kras/Trp53-induced pancreatic ductal adenocarcinomas (PDAC) without overt toxicity. Inhibition of EGFR and c-RAF expression also blocks the progression of patient-derived PDAC xenografts with mutant KRAS/TP53.
Objectives
To report the final results of the 2‐year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry®/BAY 81–8973) used in standard clinical practice in patients ...with moderate‐to‐severe haemophilia A.
Methods
TAURUS (NCT02830477) is a phase 4, multinational, prospective, non‐interventional, single‐arm study in patients of any age with moderate or severe haemophilia A (≤5% factor FVIII activity). TAURUS was designed to primarily investigate weekly prophylaxis dosing regimens used in standard clinical practice. Annualised bleeding rates (ABRs), treatment satisfaction and adherence, and safety were also assessed.
Results
Of 302 patients included in the full analysis set, 84.4% (n = 255) maintained their octocog alfa prophylaxis baseline regimen throughout the study, with a majority of patients (76.5%, n = 231) on two times or three times weekly regimens at the end of the observation period (≥1–≤2 years). ABRs, treatment satisfaction, and adherence remained stable during the observation period. Octocog alfa was well tolerated and there were no new or unexpected adverse events.
Conclusions
These data show that a smooth transition is observed when switching to octocog alfa from a previous FVIII treatment, with no safety issues and stable bleeding rates in a real‐world setting of patients with moderate‐to‐severe haemophilia A.
Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no ...signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short
in vivo
persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.
Patients with multirefractory immune thrombocytopenia (ITP) have limited treatment options. Recent data suggest that specific anti-platelet antibodies may cause destruction of platelets by favoring ...platelet loss of sialic acid. In this multicenter study 35 patients with ITP, including 16 with multirefractory disease, were analyzed for antiplatelet-antibodies, thrombopoietin (TPO) levels, and platelet desialylation. In selected cases, responses to a novel treatment strategy using oseltamivir were tested.
We found that antibodies against GPIbα were overrepresented in multirefractory patients compared to responders (n = 19). In contrast to conventional ITP patients, multirefractory patients exhibited a significant increased platelet activation state (granule secretion) and desialylation (RCA-1 binding) (p < 0.05), and a trend toward higher plasma TPO concentrations. The decreased sialic acid content seemed to be restricted to platelet glycoproteins, since other plasma proteins were not hypoglycosylated. A total of 10 patients with multirefractory ITP having remarkable loss of platelet terminal sialic acids were given oseltamivir phosphate. When the antiviral drug was combined with TPO receptor agonists (TPO-RAs) or with immunosuppressant drugs, platelet responses were observed in 66.7% of patients. All responding patients presented with antibodies reactive only against GPIbα.
These findings suggest that desialylation may play a key pathogenic role in some multirefractory ITP patients, and provide diagnostic tools for the identification of such patients. Furthermore, we show that sialidase inhibitor treatment in combination with therapies that help to increase platelet production can induce sustained platelet responses in some patients with anti-GPIbα -mediated thrombocytopenia that have failed previous therapies.
Objectives
To report interim data from TAURUS, a study assessing real‐world prophylactic treatment with unmodified, full‐length recombinant FVIII BAY 81‐8973 (Kovaltry®; Bayer) indicated for ...haemophilia A.
Methods
TAURUS (NCT02830477) is an international, open‐label, prospective, non‐interventional, single‐arm study with a one‐year observation period (target N = 350). Patients have moderate or severe haemophilia A (FVIII ≤5% or ≤1%) and ≥50 exposure days to any FVIII product. Clinician‐ and patient‐reported outcomes are captured on previous product use, changes in prophylaxis dose and dosing frequency, FVIII consumption, reported bleeding rates, treatment satisfaction and adherence, pharmacokinetic (PK) data (if available) and safety data.
Results
At cut‐off, baseline data were available from 160 patients (89 had ≥6 months of follow‐up data). Most patients had severe haemophilia A (85%), infused BAY 81‐8973 ≥ 3×/wk (59%) and experienced a median number of total bleeds of 2.0 (non‐annualised; 246 days median documentation period). Good levels of treatment satisfaction (Hemo‐SATA,P) and adherence (VERITAS‐Pro) were maintained. TAURUS demonstrated a favourable PK profile of BAY 81‐8973 in comparison with other standard half‐life rFVIIIs and supported the WAPPS PopPK model. No patients developed inhibitors.
Conclusions
TAURUS data demonstrate effective prophylaxis with BAY 81‐8973 in the real world without compromising patient satisfaction or adherence.
Introduction
The Haemophilia Early Arthropathy Detection with Ultrasound (HEAD‐US) system and scoring scale has proven to be an accurate and time‐efficient imaging method for identifying joint damage ...in patients with haemophilia.
Aim
Observational, multicentre, cross‐sectional study conducted in 8 centres in Spain that assessed the joint status of adult patients with severe haemophilia A (SHA) using HEAD‐US.
Methods
Joint status of the elbow, knee and ankle was evaluated in adults with SHA receiving on‐demand (OD) treatment, or primary (PP), secondary (SP), tertiary (TP) or intermittent (IP) prophylaxis.
Results
Of the 95 patients enrolled, 87 received prophylaxis (6.3% PP, 38.9% SP, 43.2% TP and 3.2% IP). Mean age was 35.2 years, and 59% of patients had not undergone image testing in the last year. The HEAD‐US score was 0 in all joints in 6.3% of patients. The ankle was the most affected joint, regardless of treatment regimen. Patients receiving OD treatment, TP or IP had the overall worst scores, mainly in the ankles and elbows; a similar but milder profile was observed in patients on SP; and patients on PP had the best score in all joints.
Conclusion
Joint function may be effectively preserved in patients with SHA on PP, but OD treatment or later initiation of prophylaxis does not seem to prevent progression of arthropathy. Disease worsening was observed in patients OD, TP or IP, most often affecting ankles and elbows. Closer ultrasound imaging monitoring may improve management of these patients.
Objectives
This study estimated the cost of prophylaxis with activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa) in surgical patients with haemophilia A ...and inhibitors in Spain.
Methods
A decision‐analytic model was developed to estimate the cost to the Spanish National Health System of providing haemostatic coverage in this haemophilia population, with age distribution and average weight derived from the literature, and the annual number of surgeries (0.33 per patient) from local data. Drug costs were calculated from official ex‐factory prices with a 7.5% mandatory deduction and recommended dosing regimens.
Results
The estimated average costs per patient were €10 100.73 (aPCC) and €14 265.89 (rFVIIa) for dental extraction, €24 043.88 (aPCC) and €62 301.08 (rFVIIa) for minor surgery and €126 595.81 (aPCC) and €347 731.09 (rFVIIa) for major surgery. Assuming an estimated 23 annual surgeries in this population (N = 69), distributed as 19% dental extraction, 50% minor surgery and 31% major surgery, the total annual cost of prophylaxis was €1 209 682.35 with aPCC and €3 221 929.28 with rFVIIa.
Conclusions
aPCC costs were 62.5% lower than rFVIIa. Assuming potential clinical equivalence, aPCC is a potentially cost‐saving option for surgical patients with haemophilia A and inhibitors.
Adherence to prophylaxis in adult patients with severe haemophilia A Bonanad, Santiago; García‐Dasí, María; Aznar, José A. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
September 2020, 2020-09-00, 20200901, Letnik:
26, Številka:
5
Journal Article
Recenzirano
Introduction
Adherence is a cornerstone of factor VIII prophylactic treatment. Information regarding the factors with potential influence on adherence is limited, particularly in adult patients.
Aim
...To assess adherence in adult patients with severe haemophilia A receiving prophylactic treatment in a real‐life setting, and investigate the factors influencing adherence.
Methods
Observational, prospective study including adult patients receiving factor VIII therapy in 15 Spanish centres. Patients recorded infusion doses on a logbook and answered various questionnaires to assess their health beliefs. Adherence rate was the percentage of infused doses over the prescribed ones. Self‐perceived adherence was assessed using the VERITAS‐Pro questionnaire, the psychometric properties of which were validated in the Spanish population. The relationship between adherence rate and treatment, clinical and demographic characteristics, health beliefs and perceived self‐efficacy was investigated.
Results
A total of 66 patients were followed up for 12 months. Mean adherence rate at the end of follow‐up was 82.5%. Most of the study patients (n = 53, 80.3%) showed a moderate‐to‐high adherence rate (>70%). The VERITAS‐Pro revealed a high perception of adherence. Multivariate analyses to predict treatment adherence identified the knee as a target joint and longer treatment duration as variables with significant (negative) influence on adherence. Adherence rate was not influenced by the patient's health beliefs or perceived self‐efficacy.
Conclusion
Most adult patients receiving factor VIII prophylactic treatment in Spain have moderate‐to‐high treatment adherence. Treatment duration and the knee as a target joint are factors with a moderate negative influence on treatment adherence.
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