Fostamatinib is available in France since October 2021 for the treatment of adult chronic immune thrombocytopenia (ITP). French health authorities requested a 3-year, prospective, multicenter registry to provide real-world evidence about the effectiveness and safety of fostamatinib. Patients' characteristics, treatment response (ongoing exposure to fostamatinib and a platelet count ≥ 30 × 109/L with no rescue in the previous 4 weeks) after 3, 6, 12, and 24 months (M); bleeding; fostamatinib discontinuation; adverse drug reactions (ADRs) and other events of interest have been analyzed. In total, 164 patients were included (median age: 59 years; 55.5% women; 84.1% had previous bleeding; 30 had secondary ITP; 89.0% had chronic ITP). The median ITP duration was 7.2 years and the median number of previous ITP treatments was 6. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Concomitant treatment (mostlyTPO-RA) was used in > 60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpointwas, respectively, 27.0%, 44.6%, 55.9%, and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding duringfostamatinib exposure; none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%)patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%). Seven thrombosis (4.3%) and40 infections (12 serious) were reported in 25 patients (15.2%), mostly in patients with known risk factors. In conclusion,fostamatinib in combination with TPO-RA should be considered in difficult-to-treat ITP patients. No new safety signal was observed.

ABSTRACTAdvanced genomic technologies are revolutionizing our ability to understand complex diseases. Large‐scale population studies are needed to realize the potential of using individual genetic information to personalize treatments for better patient outcomes for chronic non‐communicable diseases, such as sickle cell disease (SCD). SCD is recognized as a benchmark genetic disorder for study both in Africa and globally due to its unmet health burden and the potential utilization of genomic knowledge for improving the health outcomes for individuals living with the disease. Over the past two decades, groundbreaking genomic research in SCD has led to the discovery, fine mapping, and validation of genetic and epigenetic variants of importance for SCD. These include variants in genes such as BCL11A, HBG, MYB, KLF1, and FLT1, which are all associated with fetal hemoglobin expression, a major modifier of disease severity in SCD. There has also been increased genomic knowledge of other SCD modifiers, including the distribution of alpha‐ and beta‐thalassemia variants in Africa, and infectious disease related markers such as APOL1. Pioneering pharmacogenomics studies for hydroxyurea are promising and have unveiled the importance of the implementation of such studies for all SCD therapeutics, including small molecules and recent gene‐based therapies. Genomic research for the development of personalized medicine for SCD must involve countries in Africa due to the high prevalence of the disease in these countries, the high African genetic diversity that influences disease progression, and the potential to follow treatment outcomes in large cohorts of patients. These findings hold great promise to lead to a better understanding of SCD biology and treatment responses, the discovery of new therapies, and informing the design and execution of much needed clinical trials.

Idiopathic multicentric Castleman disease (iMCD)-TAFRO (Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/renal dysfunction, Organomegaly) is the most severe clinical subtype of iMCD characterized by a catastrophic cytokine storm. Currently, iMCD-TAFRO is regarded as incurable which needs "indefinite" treatment. However, long-term data are sparse, and treatment discontinuation may be possible in a subset of patients. This multicenter, retrospective study analyzed 27 patients who discontinued treatment. All patients had biochemical complete response (CR) at the time of drug discontinuation. Most patients were treated with myeloma-like treatment (59.3%) and only 11.1% received anti-IL-6 therapy. With a median follow-up of 31 months (range, 12-108) after treatment discontinuation, only four patients (14.8%) suffered from progression of disease (PD) and the others (85.2%) maintained biochemical CR. Patients who suffered from PD had a significantly lower pretreatment CRP level than patients maintaining responses (43.7 ± 39.3 vs. 126.4 ± 62.5 mg/L, p = 0.018). No significant impacts of different treatment approaches or duration of treatment on the likelihood of achieving long-term remission were observed. The median time between drug discontinuation to PD (n = 4) was 9.5 months (range, 5-12). These patients all achieved treatment responses again with the same or similar treatment approaches. The estimated PFS at 6 months, 1 year, and 3 years were 96.3%, 85.2%, and 85.2%, respectively. All patients remained alive with a median of 31 months follow-up after drug discontinuation. This study suggests that some iMCD-TAFRO patients might maintain long-term remission after treatment discontinuation. For patients who achieved biochemical CR, an attempt at treatment discontinuation could be considered.

ABSTRACTAcute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or frequent episodes. Epidemiological studies have found an association between asthma and ACS, but whether this link is causal is unclear. We used polygenic scores (PGS) to analyze whether the genetic propensity for asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that PGS for asthma (PGSasthma) was associated with ACS rate (number of episodes per year), but not ACS occurrence, in both the CSSCD (n = 1278) and the GEN‐MOD (n = 406) prospective SCD cohorts, independently of fetal hemoglobin (HbF) (β = 0.17, standard error = 0.06, p = 0.006). This effect was most pronounced in patients with low HbF levels. Combining PGSasthma and HbF identified a population at high risk of frequent ACS after a first episode: individuals within the highest PGSasthma quintile and the lowest HbF quintile. Finally, we found that the genetic correlation between these two conditions only partially overlapped. This suggests that genetically determined asthma is not the unique contributor to the genetic propensity for ACS and that other genetic determinants may also play a role. In sum, our results suggest that patients with a high genetic propensity for asthma are prone to frequent ACS if not protected by high HbF levels. Combining PGSasthma and HbF may allow identifying patients at high risk of frequent ACS after a first episode for personalized management.

AL amyloidosis is a clonal plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include HFpEF, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or MGUS." Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required. Organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T (or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four stages; 5 year survivals are 82%, 62%, 34%, and 20% respectively. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a ≥ VGPR. In patients failing to achieve this depth of response, options for consolidation include pomalidomide, stem cell transplantation, and venetoclax. T-cell redirecting therapies, both bispecific antibodies and car T, show high level activity and may soon become standard second-line therapy. Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. An antibody to deplete deposited κ fibrils has reported benefit in patients with cardiomyopathy.