In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.

Ruxolitinib is a recommended second-line treatment for the prevention of thrombosis in patients with polycythemia vera who become resistant or intolerant to hydroxyurea; however, evidence regarding its efficacy in terms of thrombosis reduction is uncertain. We searched Medline, Embase, and archives of abstracts from the European Hematology Association and the American Society of Hematology annual congresses from 2014 onward for randomized controlled trials comparing the treatment vs best available therapy (BAT). Our search retrieved 80 records; after screening of abstracts and full text, the total was reduced to 16. Evidence came from 4 randomized controlled trials, including 663 patients (1057 patients per year). We estimated a thrombosis risk ratio of 0.56 for ruxolitinib BAT, corresponding to an incidence of 3.09% and 5.51% patients per year, respectively. The number of thrombotic events reported with ruxolitinib was consistently lower than that with BAT in our sample, but, globally, the difference did not reach significance (P = .098). Hard evidence in favor of ruxolitinib is lacking; a clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable.

Hydroxyurea is the standard treatment in high risk patients with polycythemia vera. Yet, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematological transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in contemporary patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using WHO diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow-ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9, 3.6 and 6.8% persons/year at median ages 60, 70 and 80 respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0·4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at 5 year and 33.7% at 10 years; overall mortality was 12.6% and 56.2% at 5 and 10 years respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using hard endpoints for efficacy, such as major thrombosis.

The main cause of intestinal failure is short bowel syndrome (SBS). The management goal for children with SBS is to promote intestinal adaptation while preserving growth and development with the use of parenteral nutrition (PN). This study evaluated the intestinal absorption rate in children with SBS, focusing on the role of the remnant colon. In addition, the relation between intestinal absorption rate, citrulline concentration, and small bowel length was studied. Thirty-two children with SBS on PN were included. They were divided into 3 groups according to the European Society for Clinical Nutrition and Metabolism (ESPEN) anatomical classification system: type 1 SBS (n = 9), type 2 (n = 13), and type 3 (n = 10). Intestinal absorption rate was assessed by a stool balance analysis of a 3-d collection of stools. Plasma citrulline concentrations were measured and the level of PN dependency was calculated. The total energy absorption rate did not differ significantly between the 3 groups: 68% (61-79% ) for type 1, 60% (40-77%) for type 2, and 60% (40-77%) for type 3 ( P = 0.45). Children with type 2 or 3 SBS had significantly shorter small bowel length than children with type 1: 28 cm (19-36 cm) and 16 cm (2-29 cm), respectively, compared with 60 cm (45-78 cm) ( P = 0.04). Plasma citrulline concentrations were lower in type 3 SBS but not significantly different: 15 µmol/L (11-25 µmol/L) in type 1, 14 µmol/L (7-21 µmol/L) in type 2 , and 9 µmol/L (6-14 µmol/L) in type 3 ( P = 0.141). A multivariate analysis confirmed the role of the remnant colon in providing additional energy absorption. This study demonstrated the importance of the colon as a salvage organ in children with SBS. Plasma citrulline concentrations should be interpreted according to the type of SBS. Efforts should focus on conservative surgery, early re-establishment of a colon in continuity, and preserving the intestinal microbiota.

In the 2016 revised classification of myeloproliferative neoplasms pre-fibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity, distinct from essential thrombocythemia (ET). Owing that the majority of cases falling in the pre-PMF category were previously diagnosed as ET, one may question about the need to re-evaluate the results of epidemiologic, clinical, and molecular studies, and the results of clinical trials in the two entities. Based on a critical review of recently published studies, pre-PMF usually presents with a distinct clinical and hematological presentation and higher frequency of constitutional symptoms. JAK2V617F and CALR mutations in pre-PMF patients are superimposable to ET, whereas non-driver high-risk mutations are enriched in pre-PMF compared with ET. Thrombosis is not significantly different, whereas bleeding is more frequent in pre-PMF. Median survival is significantly shorter in pre-PMF and 10-year cumulative rates progression to overt myelofibrosis is 0–1% vs. 10–12%, and leukemic transformation is 1–2% vs. 2–6%, in ET and pre-fibrotic-PMF, respectively. Most patients fall in the lower prognostic IPSS group in which observation alone can be recommended. Patients at intermediate risk may require a symptom-driven treatment for anemia, splenomegaly or constitutional symptoms while cytoreductive drugs are indicated in the high-risk category.