Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.

Background: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2, causing constitutive activation of the kinase and activation of downstream signalling.

Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

Objective: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

Background: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies.

Methods: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies.

Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.

Lipodystrophy syndromes are rare diseases primarily affecting the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, often leading to reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmunity in the vast majority of cases. While many subtypes are now recognized and classified, the disease remains remarkably underdiagnosed.

From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy.

Aims: Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise.

Delayed diagnosis resulting in increased disease burden in multiple myeloma: the legacy of the COVID-19 pandemic.

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood.

Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy.

Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease.

Vaccine subtype and dose interval determine immunogenicity of primary series COVID-19 vaccines in older people.

Age is the strongest determinant of COVID-19 mortality, and over 2 billion people have received primary series vaccination with BNT162b2 (mRNA) or ChAdOx1 (adenoviral vector). However, the profile of sustained vaccine immunogenicity in older people is unknown. Here, we determine spike-specific humoral and cellular immunity to 8 months following BNT162b2 or ChAdOx1 in 245 people aged 80-98 years.

Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia.

Background: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses.

Method: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms.

Results: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.

Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.

Background: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia.

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy.

Azacitidine for the treatment of steroid-refractory chronic graft-versus-host disease: the results of the phase II AZTEC clinical trial.

Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy.

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors.

Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy.

Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as a major cause of death in CGL2 patients, leading us to examine whether loss could directly affect the innate immune response.