In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are ...undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.
Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for ...related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease.
Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized ...placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL.sub.CO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change + or - SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL.sub.CO increased by 28.0 + or - 6.2%, spleen volume decreased by 36.0 + or - 3.0% and liver volume decreased by 30.7 + or - 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DL.sub.CO increased by 28.5 + or - 6.2%, spleen volume decreased by 47.0 + or - 2.7%, and liver volume decreased by 33.4 + or - 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy.
Background
The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B‐cell lymphoma (DLBCL) diagnosis is uncertain.
...Methods
We performed a 5‐year retrospective single‐center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB−/FC− (75.6%), BMB+/FC+ (13.4%), and BMB−/FC+ (11%).
Results
Median infiltration by FC analysis of the BMB−/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event‐free survival (EFS) after 18 months was 82, 23, and 27% for BMB−/FC−, BMB−/FC+, and BMB+/FC+, respectively (p < .001). After 18 months of observation, OS was 87, 46, and 55% for BMB−/FC−, BMB−/FC+, and BMB+/FC+, respectively (p = .001). In multivariate analysis (BM infiltration vs. cell‐of‐origin according to Hans algorithm and standard IPI), BM infiltration was independently associated with EFS (HR: 1.94, 95% CI: 1.3–2.9) and overall survival (HR: 1.69, 95% CI: 1.1–2.7).
Conclusion
In summary, minimal BM infiltration, detected by FC but not by BMB, has same prognostic implications than overt BM infiltration and should be considered as extranodal involvement regardless the infiltration quantity.
In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and ...frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.
Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of ...blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0–2 % and >2– < 5 %. This distinction is critical for establishing prognosis, but the reproducibility of this threshold is still not demonstrated. The objectives of our study were to explore the reliability of the 2008 WHO classification, regarding unilineage vs. multilineage dysplasia, by reviewing 110 cases previously diagnosed with MDS, and to study whether the threshold of ≤2 % BM blasts is reproducible among different observers. We used the same methodology as in our previous paper Font et al. (2013) Ann Hematol 92:19–24, by encouraging investigators to include patients with <5 % BM blasts. Samples were collected from 11 hospitals and were evaluated by 11 morphologists. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. Discordance was observed in 36/108 suitable cases (33 %, kappa test 0.503). Diagnosis of MDS with unilineage dysplasia (refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS) or unclassifiable MDS) was assessed in 33 patients, by either of the two observers. We combined this series with the cases with RCUD or RARS included in our 2013 paper, thus obtaining 50 cases with unilineage dysplasia by at least one of the observers. The whole series showed very low agreement regarding RCUD (5/23, 21 %) and RARS (5/28, 18 %). Regarding BM blast count, the threshold of ≤2 % was not reproducible (discordance rate 32/108 cases, kappa test 0.277). Our study shows that among MDS WHO 2008 categories, interobserver discordance seems to be high in cases with unilineage dysplasia. We also illustrate that the threshold of ≤2 % BM blasts as settled by the R-IPSS may be not easy to reproduce by morphologists in real practice.
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