Sensitivity and Specificity of Laboratory Parameters to Detect Early/Prefibrotic Myelofibrosis in 857 Patients with Essential Thrombocythemia. A Diagnostic Algorithm

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5148-5148
Author(s):  
Alessandra Carobbio ◽  
Guido Finazzi ◽  
Juergen Thiele ◽  
Hans-Michael Kvasnicka ◽  
Francesco Passamonti ◽  
...  

Abstract Abstract 5148 INTRODUCTION. Patients presenting with a clinical picture of essential thrombocythemia (ET) can actually have an early/prefibrotic myelofibrosis (PMF), according to current WHO criteria, in about 18% of cases. Laboratory tests which are significantly different in early/prefibrotic PMF as compared with histologically confirmed ET (WHO-ET) include decreased gender-matched hemoglobin (Hb), increased white blood cell (WBC), platelet (PLT) counts and lactate dehydrogenase (LDH) values. AIM. To evaluate sensitivity (SE) and specificity (SP) of blood cell counts and LDH, at presentation, for the diagnosis of early/prefibrotic PMF vs. WHO-ET. METHODS. Five hundred thirty-six cases (50%) who had complete laboratory data measured at diagnosis constituted the exploratory set of our study and were derived from an international ET database. The discriminatory ability of Hb, WBC, PLT and LDH in correctly classifying patients in the early/prefibrotic PMF or WHO-ET groups was initially tested by plotting their Receiving Operating Characteristic (ROC) curves and comparing the relative Areas Under the Curve (AUC) with the value of 0.50 (which stands for the completely useless of the test). Three parameters with statistically significant discriminatory power were chosen (Hb, WBC and LDH) and thresholds searched in order to guarantee at least 90% of SE or SP. Finally, a diagnostic algorithm was designed. The validation set of this analysis was constituted by 321 patients with WHO-ET (n=62) or early/prefibrotic PMF (n=259) diagnosed by the same pathologist who confirmed the training set cohort and collected in the Institute for Pathology, University of Cologne, Germany. SE and SP for the same parameters and thresholds as well as the final diagnostic algorithm were applied to this set of patients to demonstrate the results' reproducibility. RESULTS. Sensitivity and specificity to recognize early/prefibrotic PFM have been evaluated by ROC curves. The best performance was found for LDH (AUC = 0.7059). WBC and Hb had super imposable curves, with AUC of 0.6279 and 0.6257, respectively. The worst performance was registered for PLT count: its AUC was only 0.5628, not significantly different from the reference value of 0.50 (p=0.154). Thresholds of Hb, WBC and LDH were searched to achieve at least 90% of SE or SP. HB < 12 g/dL for women or <13 g/dL for men, and WBC >= 13 x109/L had higher SP (92% and 91%, respectively). High SP is highly related to the presence of early/prefibrotic PMF (true positives). On the contrary, LDH < 200 mU/mL and WBC < 7 x109/L had good sensitivity (91% and 94%, respectively). High SE is highly related to the absence of early/prefibrotic PMF (true negatives). By applying these SE and SP values in a step-by-step algorithm, nearly half of patients (48%) could be classified as WHO-ET or early/prefibrotic PMF, assuming at each step a margin of error of less than 10%. For the remaining 50% of patients, laboratory results didn't allow to suspect or exclude the presence of early/prefibrotic PMF. In the validation set of 321 patients classified by WHO 2008 as true ET or early/prefibrotic PMF (Cologne cohort) SP of anemia was 84%, WBC < 7 x109/L or >= 13 x109/L had 91% and 81% of SE and SP, respectively. LDH values < 200 mU/mL had 85% of SE. By applying the same flow-chart, 46% of patients were classified as WHO-ET or early/prefibrotic PMF. CONCLUSIONS. The present study provides clinicians with laboratory parameters that should increase suspicion of early/prefibrotic PMF in a patient with a working clinical diagnosis of ET. In fact, while patients presenting clinically with ET can now be discriminated as true ET or early/prefibrotic PMF by adopting the WHO 2008 criteria that require bone marrow histology, an algorithm including baseline anemia, WBC count and LDH, allows this differentiation in about 50% of patients with a good approximation. However, for a definitive proof, bone marrow histology is still an integral part for final diagnosis. Disclosures: Vannucchi: Novartis: Honoraria.

2009 ◽  
Vol 27 (18) ◽  
pp. 2991-2999 ◽  
Author(s):  
Peter J. Campbell ◽  
David Bareford ◽  
Wendy N. Erber ◽  
Bridget S. Wilkins ◽  
Penny Wright ◽  
...  

PurposeEssential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology reflects underlying disease activity in ET but many morphological features show poor reproducibility.Patients and MethodsWe evaluated the clinical significance of bone marrow reticulin, a measure previously shown to have relatively high interobserver reliability, in a large, prospectively-studied cohort of ET patients.ResultsReticulin grade positively correlated with white blood cell (P = .05) and platelet counts (P = .0001) at diagnosis. Elevated reticulin levels at presentation predicted higher rates of arterial thrombosis (hazard ratio [HR], 1.8; 95% CI, 1.1 to 2.9; P = .01), major hemorrhage (HR, 2.0; 95% CI, 1.0 to 3.9; P = .05), and myelofibrotic transformation (HR, 5.5; 95% CI, 1.7 to 18.4; P = .0007) independently of known risk factors. Higher reticulin levels at diagnosis were associated with greater subsequent falls in hemoglobin levels in patients treated with anagrelide (P < .0001), but not in those receiving hydroxyurea (P = .9). Moreover, serial trephine specimens in patients randomly assigned to anagrelide showed significantly greater increases in reticulin grade compared with those allocated to hydroxyurea (P = .0003), and four patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea. These data suggest that patients receiving anagrelide therapy should undergo surveillance bone marrow biopsy every 2 to 3 years and that those who show substantially increasing reticulin levels are at risk of myelofibrotic transformation and may benefit from changing therapy before adverse clinical features develop.ConclusionOur results demonstrate that bone marrow reticulin grade at diagnosis represents an independent prognostic marker in ET, reflecting activity and/or duration of disease, with implications for the monitoring of patients receiving anagrelide.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5208-5208
Author(s):  
Li Xia Zhou ◽  
Jieyu Ye ◽  
En Yu Liang ◽  
Chunfu Li ◽  
Beng H Chong ◽  
...  

Abstract Our previous studies have demonstrated that PDGF (Platelet-derived growth factor) has a potential effect in the regulation of hematopoiesis and megakaryopoiesis (Yang et al, Thromb Haemastasis, 1997; Ye et al, Haematologica, 2010). Essential Thrombocythemia (ET) is characterized by persistently elevated platelet counts in the context of a normal red cell mass. However, the physiopathologic mechanism of ET is still under investigation. Here, we tested the bone marrow plasma levels of PDGF-BB in essential thrombocythemia patients (n=16) and normal control (n=8), and found an increased PDGF-BB levels in ET patients (2070.92±123.98 pg/ml), compared with normal control (1381.85±128.37pg/ml) (P=0.002). Furthermore, we have demonstrated the presence of functional PDGF receptors (PDGFR) in human megakaryocytes, and their ability to mediate a mitogenic response by bone marrow colony-forming unit-megakaryocyte (CFU-MK) formation assay (n=6). PDGF-BB stimulated in vitro megakaryopoiesis via PDGFR. It also showed a direct stimulatory effect of PDGF-BB on c-Fos expressions in megakaryocytic cells, CHRF. We speculate that these transcription factors might be involved in the signal transduction of PDGF on the regulation of megakaryopoiesis. PDGF also enhanced platelet recovery in mice model with radiation-induced thrombocytopenia. Studies showed that PDGF, like thrombopoietin (TPO), significantly promoted platelet recovery and the formation of bone marrow CFU-MK in this irradiated-mouse. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow histology sections. We also demonstrated that PDGF activated the p- Akt, p-Jak2 and p-Stat3 expression, while addition of imatinib mesylate reduced p-Akt, p-Jak2 and p-Stat3 expression in CHRF cells. Our findings suggested that the PDGF-initiated megakaryopoiesis is likely to be mediated via PDGF receptors with subsequent activation of the Akt and Jak2/ Stat3 pathways. These studies provide a possible explanation that PDGF/PDGFR may be involved in the physiopathologic mechanism of essential thrombocythemia. Disclosures Yang: National Natural Science Foundation of China(81270580): Research Funding.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5239-5239
Author(s):  
Mi Kwon ◽  
Santiago Osorio Prendes ◽  
Carolina Muñoz ◽  
Jose Manuel Sanchez ◽  
Monica Ballesteros ◽  
...  

Abstract WHO criteria defines platelet counts above 600×109/L as the threshold for essential thrombocythemia (ET) diagnosis. It has been argued that such threshold excludes a number of patients with ET with platelet counts below 600×109/L. Recently, a proposal for revision of the World Health Organization (WHO) diagnostic criteria for ET has been published, which includes the combination of histological bone marrow study and testing of JAK2 mutation. Design and methods: Retrospective analysis of 92 patients with ET diagnosis between 1989 and February 2008, isolating the subgroup of patients with platelet counts below 600×109/L. The aim of this study was to analyze the applicability of the 2008 WHO criteria in this subgroup. Results: Of the 92 patients, 30 patients did not fulfill the WHO criteria due to platelet counts &lt;600×109/L and in some cases also due to the coexistence of alternative causes of thrombocytosis. There were no significant differences between the entire group and the borderline platelet count subgroup in demographics, clinical and laboratory parameters (Table 1). The median age of the borderline platelet count group was 51 years (range 19–83 years) and 20 were female (70%). At diagnosis their median platelet count was 527×109/L (range 424–597). Fifteen patients (50%) showed the presence of JAK2 mutation. Remarkably, 74% of the patients presented as high-intermediate risk at diagnosis. From the 30 patients who did not fulfill the WHO criteria due to low platelet counts, 26 (87%) satisfied the modified criteria allowing ET diagnosis. Among them, 1 patient showed an alternative cause of thrombocytosis, however JAK2 mutation was positive confirming the primary cause of the disorder. Four patients remained not fulfilling the new criteria due to insufficient bone marrow sample or incompatible histology, however one of these patients showed JAK2 mutation confirming ET. The median follow-up was 2.54 years (range 0.07–18.7). During this period, none of the 30 patients had a spontaneous decrease of platelet count to within the normal range. Furthermore, transformation from ET to IMF was observed in 2 cases supporting the diagnosis of ET. During follow-up, 27 out of 30 patients were treated with antiaggregating drugs, 3 with antithrombotic therapy, and 20 with myelosuppressive therapy. The 11 patients who did not receive myelosuppressive therapy remained with platelet counts above 400×109/L. Conclusions: In our study, patients with platelet counts below 600×109/L did not show significant differences compared with the whole ET patients group. This subgroup can be diagnosed as having ET following the 2008 WHO criteria. The detection of JAK2 mutation in this setting enables the accurate diagnosis not only in cases with borderline thrombocytosis but more importantly in cases with alternative potential causes and also in cases where bone marrow sample is not available or incompatible. This observation raises de question of the role of bone marrow histology as a subjective diagnostic tool in ET diagnosis as opposed to JAK2 mutation detection. In JAK2 negative patients, subsequent follow-up of untreated patients confirmed the diagnosis since platelet counts remained high. The modified criteria facilitates the clinician to make an early diagnosis of ET in this subgroup of patients. Furthermore, a high proportion of these patients may be at risk of vascular complications, who may beneficiate from being correctly treated. TABLE 1 Total of patients Platelet count &lt;600×10e9/L Number 92 30 Female (number, %) 59 (64%) 20 (70%) Age (median, range) 51 (19–84) 51 (19–83) Risk Low 26 (28%) 8 (26%) Intermediate 21(22%) 6 (19%) High 45 (48%) 16 (53%) Platelets ×10e9/L 693 (424–2,777) 527 (424–597) Hb g/dL 14.5 (11–18) 14.3 (11–16.8) Leucocytes ×10e9/L 8,5 (3,6–24,2) 8,5 (5,2–13,8) LDH UI/L 380 (39–1413) 337 (39–938) Splenomegaly 16 (17%) 5 (17%) JAK2 mutation 47 (51%) 15 (50%) Bone Marrow histology Celullarity &gt;3.5 30/88 (34%) 8/28 (29%) Fibrosis grade I 2/90 (2%) 0 Compatible histology 79/89 (86%) 21/28 (75%) Abnormal Cytogenetics 2/26 (8%) 0 Symptoms 13 (14%) 4 (13%) Thrombotic event 16 (18%) 5 (17%) Haemorrhagic event 3 (4%) 0


2020 ◽  
Author(s):  
Jing Wang ◽  
Jinyu Su ◽  
Yuan Yuan ◽  
Xiaxia Jin ◽  
Bo Shen ◽  
...  

Abstract Background: Axial spondyloarthritis (axial SpA)is a chronic inflammatory disorder involving the sacroiliac joints, that could lead to disability due to the failure of timely treatment. The lymphocyte-to-monocyte ratio (LMR) is an indicator of disease progression. However, its role in axial SpA remains unclear. The aim of this study was to investigate the role of LMR in axial SpA diagnosis, disease activity classification and sacroiliitis staging. Methods: Seventy-eight axial SpA patients and 78 healthy controls (HCs) were enrolled in this study. The diagnosis of axial SpA was performed according to the New York criteria or the Assessment of Spondyloarthritis international Society (ASAS) classification criteria, whereas the staging of sacroiliitis in axial SpA patients was determined by X-ray examination. Comparisons of LMR levels between groups were performed using t test. Pearson or Spearman correlation analysis were used to assess correlations between LMR and other indicators. Receiver operating characteristic (ROC) curves were used to determine the role of LMR in the diagnosis of axial SpA.Results: Higher neutrophil-to-lymphocyte ratio(NLR), red blood cell distribution width(RDW), platelet-to-lymphocyte ratio(PLR), mean platelet volume(MPV), erythrocyte sedimentation rate (ESR), and C-reactive protein(CRP) levels and lower red blood cell (RBC), hemoglobin (Hb), Hematocrit (Hct), LMR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin/globulin (A/G) levels were noted in axial SpA patients compared to HCs. Positive correlations were observed between LMR and RBC, Hb, Hct and A/G, whereas negative correlations were found between LMR and NLR, PLR, AST, and TBIL (P< 0.05). ROC curves showed that the area under the curve(AUC) for LMR in the diagnosis of ankylosing spondylitis was 0.803 (95% CI =0.734-0.872) with a sensitivity and specificity of 62.8% and 87.2%, respectively, and the AUC (95% CI) for the combination of ESR, CRP and LMR was 0.975 (0.948-1.000) with a sensitivity and specificity of 94.9% and 97.4%, respectively. LMR levels were lower (P<0.05) and significant differences in LMR values were observed among different stages (P<0.05). Conclusions: Our study suggested that LMR might be an important inflammatory marker to identify axial SpA and assess disease activity and X-ray stage of sacroiliitis.


2020 ◽  
Author(s):  
Jing Wang ◽  
Jinyu Su ◽  
Yuan Yuan ◽  
Xiaxia Jin ◽  
Bo Shen ◽  
...  

Abstract Background: Ankylosing spondylitis (AS)is a chronic inflammatory disorder involving the sacroiliac joints, that could lead to disability due to the failure of timely treatment. Therefore, early diagnosis is essential to for AS treatment. The lymphocyte-to-monocyte ratio (LMR) is an indicator of disease progression. However, its role in AS remains unclear. The aim of this study was to investigate the role of LMR in AS diagnosis, disease activity classification and sacroiliitis staging. Methods: Seventy-eight AS patients and 78 sex and age matched healthy controls (HCs) were enrolled in this study. The diagnosis of AS was performed according to the New York criteria or the Assessment of SpondyloArthritis international Society (ASAS) classification criteria, whereas the staging of sacroiliitis in AS patients was determined by X-ray examination. Comparisons of LMR levels between groups were performed using t test. Pearson or Spearman correlation analysis were used to assess correlations between LMR and other indicators. Receiver operating characteristic (ROC) curves were used to determine the role of LMR in the diagnosis of AS.Results: Higher neutrophil-to-lymphocyte ratio(NLR), red blood cell distribution width(RDW), platelet-to-lymphocyte ratio(PLR), mean platelet volume(MPV), erythrocyte sedimentation rate (ESR), and C-reactive protein(CRP) levels and lower red blood cell (RBC), hemoglobin (Hb), Hematocrit (Hct), LMR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin/globulin (A/G) levels were noted in AS patients compared to HCs. Positive correlations were observed between LMR and RBC, Hb, Hct and A/G, whereas negative correlations were found between LMR and NLR, PLR, AST, and TBIL (P< 0.05). ROC curves showed that the area under the curve(AUC) for LMR in the diagnosis of ankylosing spondylitis was 0.803 (95% CI =0.734-0.872) with a sensitivity and specificity of 62.8% and 87.2%, respectively, and the AUC (95% CI) for the combination of ESR, CRP and LMR was 0.975 (0.948-1.000) with a sensitivity and specificity of 94.9% and 97.4%, respectively. LMR levels were lower (P<0.05) and significant differences in LMR values were observed among different stages (P<0.05). Conclusions: Our study suggested that LMR could be an important inflammatory marker that can be used to diagnosis AS and identify disease activity and X-ray stage of sacroiliitis.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5583-5583
Author(s):  
Simon Mantha ◽  
Ross L. Levine ◽  
Raajit K. Rampal

Background: About 25% of individuals with essential thrombocythemia (ET) harbor a somatic mutation of the cal reticulin (CALR) gene which is thought to be the primary driving factor for the myeloid clone in those cases. Different secondary mutations have been described in association with CALR defects, however to our knowledge mixed-lineage leukemia (MLL) gene alterations have not been described before in this setting before progression to MDS or AML. Case Report: A 68 year old woman with a past medical history significant for thyroid cancer in remission following treatment with radioactive iodine was initially noted to have a platelet count of 629 K/mcL at the occasion of a routine CBC (normal=160-400 K/mcL). Total white blood cell count, differential and hemoglobin levels were normal. Platelet count had been normal at 377 K/mcL about one year prior to presentation. Testing for mutations of the JAK2 and MPL genes came back negative. There was no splenomegaly; initial bone marrow biopsy showed mild hypercellularity with maturing trilineage hematopoiesis and atypical megakaryocytosis without an increase in blasts. A very small population of clonal B-cells was detected (<2% of total). Cytogenetic analysis did not reveal any chromosomal rearrangement. The patient was started on hydroxyurea (HU) 500 mg PO daily one month after initial presentation. There was evidence of mild iron deficiency, which was corrected with administration of IV iron sucrose at a total dose of 400 mg. Four months after starting HU the platelet count had decreased to 543 K/mcL. Repeat bone marrow biopsy around that time showed mild hypocellularity (10-20%) along with persisting normal maturing trilineage hematopoiesis and atypical megakaryocytosis. There was no increase in reticulin fibers and blast count was normal. Stainable iron was present but no ring sideroblasts were noted. Karyotype was still normal and FISH revealed no evidence of deletion 5q, monosomy 5, deletion 7q, monosomy 7, trisomy 8, 11q23 translocation or 20q deletion. Given the absence of clonal defect and the lack of symptoms, HU was withheld following which the patient was observed closely. The platelet count then increased progressively, reaching a maximum of level of 977 K/mcL about 2 months after discontinuing cytotoxic treatment. The drug was then resumed and testing with the FoundationOne HemeTM panel was obtained, looking for a select list of base substitutions, insertions, deletions, copy number alterations and other DNA rearrangements for more than 400 genes known to be somatically altered in hematologic malignancies. This assay revealed the presence of an acquired anomaly of the MLL gene, consisting of a duplication of exons 4-8. Subsequent testing specific for the CALR gene also revealed an exon 9 insertion/deletion. HU was progressively increased, up to a dose of 1000 mg alternating with 1500 mg daily. With this treatment, the platelet count has decreased to 396 K/mcL one year after presentation. Total white blood cell count, differential and hemoglobin have remained normal. The patient is also taking aspirin 81 mg daily and remains clinically stable with no B symptoms, bleeding or thrombotic manifestations. Discussion: Since mutations of the CALR gene were found to be associated with ET and myelofibrosis, several secondary genetic defects were demonstrated. Those are thought to represent clonal evolution from a primary subset of cells carrying either the JAK2 V617F mutation or a CALR exon 9 alteration. To our knowledge, MLL gene mutations have not been described as early “hits” in myeloproliferative neoplasms. However they have been abundantly documented in myelodysplastic syndrome and acute myeloid leukemia (AML), where they are often a marker of poor prognosis. Conclusion: This is the first report of MLL exons 4-8 duplication in an individual with CALR-mutated ET. Interestingly, the patient presented here did not exhibit any neutrophilia, dysplasia or increase in bone marrow blasts. It remains unclear if in this setting such a genomic alteration confers an increased risk of progression to MDS or AML. Disclosures Levine: Foundation Medicine: Consultancy. Rampal:Foundation Medicine: Consultancy.


2020 ◽  
Author(s):  
Jing Wang ◽  
Jinyu Su ◽  
Yuan Yuan ◽  
Xiaxia Jin ◽  
Bo Shen ◽  
...  

Abstract Background: Axial spondyloarthritis (axial SpA)is a chronic inflammatory disorder involving the sacroiliac joints, that could lead to disability due to the failure of timely treatment. The lymphocyte-to-monocyte ratio (LMR) is an indicator of disease progression. However, its role in axial SpA remains unclear. The aim of this study was to investigate the role of LMR in axial SpA diagnosis, disease activity classification and sacroiliitis staging.Methods: Seventy-eight axial SpA patients and 78 healthy controls (HCs) were enrolled in this study. The diagnosis of axial SpA was performed according to the New York criteria or the Assessment of Spondyloarthritis international Society (ASAS) classification criteria, whereas the staging of sacroiliitis in axial SpA patients was determined by X-ray examination. Comparisons of LMR levels between groups were performed using t test. Pearson or Spearman correlation analysis were used to assess correlations between LMR and other indicators. Receiver operating characteristic (ROC) curves were used to determine the role of LMR in the diagnosis of axial SpA.Results: Higher neutrophil-to-lymphocyte ratio(NLR), red blood cell distribution width(RDW), platelet-to-lymphocyte ratio(PLR), mean platelet volume(MPV), erythrocyte sedimentation rate (ESR), and C-reactive protein(CRP) levels and lower red blood cell (RBC), hemoglobin (Hb), Hematocrit (Hct), LMR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin/globulin (A/G) levels were noted in axial SpA patients compared to HCs. Positive correlations were observed between LMR and RBC, Hb, Hct and A/G, whereas negative correlations were found between LMR and NLR, PLR, AST, and TBIL (P< 0.05). ROC curves showed that the area under the curve(AUC) for LMR in the diagnosis of ankylosing spondylitis was 0.803 (95% CI =0.734-0.872) with a sensitivity and specificity of 62.8% and 87.2%, respectively, and the AUC (95% CI) for the combination of ESR, CRP and LMR was 0.975 (0.948-1.000) with a sensitivity and specificity of 94.9% and 97.4%, respectively. LMR levels were lower (P<0.05) and significant differences in LMR values were observed among different stages (P<0.05).Conclusions: Our study suggested that LMR might be an important inflammatory marker to identify axial SpA and assess disease activity and X-ray stage of sacroiliitis.


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