Objective
Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or ...hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome.
Methods
A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n = 162), were judged by experts to not have reactive hemophagocytic syndrome (n = 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n = 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets.
Results
Nine variables (3 clinical i.e., known underlying immunosuppression, high temperature, organomegaly, 5 biologic i.e., triglyceride, ferritin, serum glutamic oxaloacetic transaminase, and fibrinogen levels, cytopenia, and 1 cytologic i.e., hemophagocytosis features on bone marrow aspirate) were retained in the HScore. The possible number of points assigned to each variable ranged from 0–18 for known underlying immunosuppression to 0–64 for triglyceride level. The median HScore was 230 (interquartile range IQR 203–257) for patients with a positive diagnosis of reactive hemophagocytic syndrome and 125 (IQR 91–150) for patients with a negative diagnosis. The probability of having hemophagocytic syndrome ranged from <1% with an HScore of ≤90 to >99% with an HScore of ≥250.
Conclusion
The HScore can be used to estimate an individual's risk of having reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/).
Abstract Objectives Current knowledge in reactive hemophagocytic syndrome mainly relies on single-center case series including a relatively small number of patients. We aimed to identify a ...multicenter large cohort of adult patients with reactive hemophagocytic syndrome and to describe relevant clinical and laboratory features, underlying conditions, and outcome. Methods We conducted a multicenter study in 3 tertiary care centers in France over a 6-year period. The medical files of 312 patients with suspected hemophagocytic syndrome were retrospectively reviewed. Patients were classified with a positive, negative, or undetermined diagnosis of hemophagocytic syndrome by experts' consensus. Results Among the 312 patients fulfilling our inclusion criteria, 162 were classified with positive hemophagocytic syndrome (male, 67%; median age, 48 35-62 years). Compared with patients without hemophagocytic syndrome, patients with hemophagocytic syndrome more frequently had an underlying immunodepression (45% vs 33%, P = .03) and exhibited higher temperature, ferritin, triglycerides, aspartate transaminase, bilirubin, lactate dehydrogenase, and C-reactive protein, and lower hemoglobin, leukocytes, platelets, and sodium levels. Only 70% of them had hemophagocytosis features on bone marrow aspiration. Hematologic malignancies, especially non-Hodgkin lymphomas, were the main trigger of hemophagocytic syndrome, accounting for 56% of cases. The early mortality rate (ie, within 1 month after diagnosis) was 20%. Patients with hematologic malignancies-associated hemophagocytic syndrome had a poorer early outcome than those with underlying infection. Conclusions In this large, multicenter study, hematologic malignancies are the main disease associated with hemophagocytic syndrome in adults. Early mortality is high, and outcome is influenced by the underlying disease.
Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a ...wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN.
•Enrichment of atypical MPL mutations in essential thrombocythemia.•MPLS204P and MPLY591N mutants are weak gain-of-function mutants.
In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability ...to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.
The diagnosis of the reactive form of hemophagocytic syndrome in adults remains particularly difficult since none of the clinical or laboratory manifestations are specific. We undertook a study in ...order to elicit which features constitute helpful criteria for a positive diagnosis. In this Delphi study, the features investigated in the questionnaire and the experts invited to participate in the survey were issued from a bibliographic search. The questionnaire was iteratively proposed to experts via a web-based application with a feedback of the results observed at the preceding Delphi round. Experts were asked to label each investigated criterion in one of the following categories: absolutely required, important, of minor interest, or not assessable in the routine practice environment. A positive consensus was a priori defined as at least 75% answers observed in the categories absolutely required and important. The questionnaire investigated 26 criteria and 24 experts originating from 13 countries participated in the second and final Delphi round. A positive consensus was reached for the nine following criteria: unilineage cytopenia, bicytopenia, pancytopenia, presence of hemophagocytosis pictures on a bone marrow aspirate or on a tissue biopsy, high ferritin level, fever, organomegaly, presence of a predisposing underlying disease, and high level of lactate dehydrogenase. A negative consensus was reached for 13 criteria, and an absence of consensus was observed for 4 criteria. The study constitutes the first initiative to date for defining international guidelines devoted to the positive diagnosis of the reactive form of hemophagocytic syndrome.
Molecular aspects of myeloproliferative neoplasms Delhommeau, François; Jeziorowska, Dorota; Marzac, Christophe ...
International journal of hematology,
03/2010, Volume:
91, Issue:
2
Journal Article
Peer reviewed
During these past 5 years several studies have provided major genetic insights into the pathogenesis of the so-called classical myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential ...thrombocythemia (ET), and primary myelofibrosis (PMF). The discovery of the
JAK2V617F
mutation first, then of the
JAK2
exon 12 and
MPLW515
mutations, have modified the understanding of these diseases, their diagnosis, and management. Now it is established that almost 100% of PV patients present a
JAK2
mutation. Nearly 60% of ET patients and 50% of patients with PMF have the
JAK2V617F
mutation. The
MPLW515
mutations are also present in a small proportion of ET and PMF patients. These mutations are oncogenic events that cause these disorders; however, they do not explain the heterogeneity of the entities in which they occur. Genetic defects have not been yet identified in around 40% of ET and PMF. There are likely additional somatic genetic factors important for the MPN phenotype like the recently described
TET2
,
ASXL1
, and
CBL
mutations. Moreover, polymorphisms in the
JAK2
gene have been recently described as associated with MPN. Additional studies of large cohorts are required to dissect the genetic events in MPNs and the mechanisms of these oncogenic cooperations.
Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features of CALR-mutated essential thrombocythemia and myelofibrosis ...patients. In most cases, CALRm were found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1 CALRm spreads more easily than the type 2 CALRm in lymphoid cells. The CALRm were also associated with an early clonal dominance at the level of hematopoietic stem and progenitor cells (HSPC) with no significant increase during granulo/monocytic differentiation in most cases. Moreover, we found that half of type 2 CALRm patients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2 CALRm progenitors. When associated mutations were present, CALRm were the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1 CALRm led to a greater increased number of all types of progenitors compared with the type 2 CALRm. However, both types of CALRm induced an increase in megakaryocytic progenitors associated with a ruxolitinib-sensitive independent growth and with a mild constitutive signaling in megakaryocytes. At the transcriptional level, type 1 CALRm seems to deregulate more pathways than the type 2 CALRm in megakaryocytes. Altogether, our results show that CALRm modify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2 CALRm.
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