Essential Thrombocythemia in Patients with Platelet Counts below 600×109/L: Applicability of the 2008 World Health Organization Diagnostic Criteria Proposal

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5239-5239
Author(s):  
Mi Kwon ◽  
Santiago Osorio Prendes ◽  
Carolina Muñoz ◽  
Jose Manuel Sanchez ◽  
Monica Ballesteros ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Essential Thrombocythemia ◽  
World Health ◽  
Jak2 Mutation ◽  
Who Criteria ◽  
Platelet Counts ◽  
Bone Marrow Histology ◽  
Health Organization

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 <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 <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 >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

JAK2 V617F Mutation Identifies a Biologically Distinct Subtype of Essential Thrombocythemia Which Resembles Polycythemia Vera.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 253-253 ◽  
Author(s):  
Anthony Green ◽  
Peter Campbell ◽  
Linda Scott ◽  
Georgina Buck ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Response To Therapy ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Cell Counts ◽  
V617f Mutation

Abstract An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera (PV) but only half of those with essential thrombocythemia (ET) and idiopathic myelofibrosis. It is not known whether mutation-bearing patients are biologically distinct from those lacking the mutation, or why the same mutation is associated with different phenotypes. Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with ET, including 776 from the MRC PT-1 trial and two other prospective studies. The combined cohort provides a unique resource for studying ET, particularly in view of its large size, centralized review of end-points and comprehensive follow-up. The involvement of a large number of secondary and tertiary centers, together with the inclusion of patients in all risk categories, suggest the results are of general relevance. JAK2 mutation status divided the cohort into two distinct subgroups. Mutation-positive patients (53.4%) displayed multiple features resembling PV, with significantly increased hemoglobin levels (p<0.0001), neutrophil counts (p<0.0001), bone marrow erythropoiesis (p=0.001) and granulopoiesis (p=0.005). They suffered more venous thromboses in the year before diagnosis (p=0.04) and during follow-up (p=0.06), together with a higher incidence of polycythemic transformation (p=0.01). To explore the resemblance between V617F-positive ET and PV further, we analysed factors that might constrain erythropoiesis. Compared to mutation-negative patients with ET, mutation-positive patients had lower serum epo (p<0.0001), lower ferritin (p=0.01), and were more likely to be microcytic (p<0.0001). V617F-positive patients were more sensitive to hydroxyurea, requiring lower doses to control platelet count than V617F-negative patients (p<0.0001), a pattern not seen with anagrelide. Despite lower doses of hydroxyurea, V617F-positive patients had greater reductions in hemoglobin, platelet and white cell counts than V617F-negative patients, with no analogous differences noted between V617F-positive and negative patients randomized to anagrelide (p=0.004, p=0.04, p=0.0003 for platelet count, Hb and WCC). Mutation-negative patients did exhibit many clinical and laboratory features characteristic of a myeloproliferative disorder, including cytogenetic abnormalities, hypercellular bone marrow, abnormal megakaryocyte morphology, PRV1 over-expression, growth of epo-independent erythroid colonies, and a risk of myelofibrotic or leukemic transformation. JAK2 mutation status defines two biologically distinct subgroups of ET with differences in presentation, outcome and response to therapy. Our results suggest a model in which V617F-positive ET and PV form a continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers, including iron stores, epo homeostasis, gender and V617F-homozygosity. This concept has major implications for the classification, diagnosis and management of MPDs.

Prospective Evaluation of the World Health Organization Criteria for the Diagnosis of Polycythemia Vera,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3837-3837 ◽  
Author(s):  
Richard T. Silver ◽  
William Chow ◽  
Katherine Vandris ◽  
Ivy Tam ◽  
Anita Narayan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Hemoglobin Concentration ◽  
World Health ◽  
Red Cell ◽  
Jak2 Mutation ◽  
Who Criteria ◽  
The World ◽  
Health Organization ◽  
Minor Criteria

Abstract Abstract 3837 Introduction The World Health Organization (WHO) published consensus criteria (2007) for the diagnosis of polycythemia vera (PV), which have never been objectively evaluated prospectively. Concern regarding limitations of these criteria and treatment algorithms based upon them has been documented. The WHO diagnosis for PV includes 2 major criteria, (1) increased red cell volume (RCV), now most often measured by an increased hemoglobin value, and (2) JAK2 mutation, and 3 minor criteria, hypercellular bone marrow with trilineage hyperplasia, low serum erythropoietin (EPO) level, and endogenous erythroid colony (EEC) formation in vitro. Diagnosis of PV requires that either both major criteria and 1 minor criterion, or increased RCV and 2 minor criteria must be met. Increased red cell volume was arbitrarily defined as: hemoglobin concentration (Hgb) >18.5 g/dL in men and >16.5 g/dL in women, or hematocrit value (Hct) >99th percentile of institutional normal range, or Hgb >17g/dL in men and >15 g/dL in women if a true sustained increase ≥2 g/dL from baseline exists, or elevated red cell mass (RCM) value >25% above mean normal predicted value according to Pearson, et al. Patients and Methods We prospectively evaluated 30 patients with a clinical phenotype of PV using the WHO criteria for diagnosis. For measuring RCV, simultaneous Cr51 RCM and I125 plasma volume analyses were performed. The RCM of overweight patients (BMI >25 kg/m2) was determined by using a BMI of 22 kg/m2 (20% fat) for adjusted weight. JAK2V617F allele burden was determined both qualitatively by ARMS PCR assay and quantitatively by pyrosequencing. Bone marrow biopsy slides were prepared routinely and stained for reticulin and collagen. The Manoharan scale was used for evaluating fibrosis. Marrow interpretation by 2 observers was initially “blinded”. EEC assays were not performed. All patients have been followed regularly at our institution for a median of 4 years to allow confirmation of diagnosis. Results Of the 30 patients, 28 were diagnosed as PV because of an increased RCM and JAK2 positivity. The median phlebotomy requirement during the first year was 4 (range 2–13). The remaining 2 patients met the WHO criterion of JAK2 positivity and an increased hematocrit value but had a normal RCM and were diagnosed as essential thrombocythemia (ET), subsequently confirmed clinically by no increase in Hct or Hgb and no need for phlebotomy in the succeeding years. Eighteen PV patients, 4 women and 14 men, met major criterion #1 by elevated RCM only, but not by the WHO criteria for increased Hgb. The median Hgb count was 15.2 g/dL for the 4 women (range: 14.4–16.4) and 17.2 g/dL for the 14 men (range: 15.6–18.1). All 28 patients had marrow findings consistent with PV; the marrows of the 2 ET patients were interpreted as nonspecific myeloproliferative disease. Only 21 patients had a low EPO level (<5 mU/mL), as did 1 ET patient. There was no correlation between RCM and white blood cell, red blood cell, or platelet counts, or between RCM and JAK2V617F %, age, phlebotomy requirement, spleen size, or grade of myelofibrosis. Although in general, RCM increased with increasing Hgb and Hct, it was not possible to correlate RCM with a unique Hgb or Hct. Conclusion We conclude, as have others, that Cr51 RCM determination remains critical for distinguishing absolute erythrocytosis and the subsequent diagnosis of PV. Using Hgb as a single criterion, 18 patients (64.3%) would not have been diagnosed as PV and using Hct as a single criterion, 9 patients (32.1%) would have not. We confirm marrow evaluation is highly valuable when performed by skilled hematopathologists. However, serum EPO levels are not diagnostic. EEC assays are rarely performed except in experimental laboratories. The frequency of performing RCM studies has decreased due to a reliance on hemoglobin concentration, but this is incorrect. Informal review of hematocrit ranges shows institutional variability. We recommend immediate revision of the WHO criteria for the diagnosis of PV patients with “early stage” disease, especially to distinguish it from ET. Criteria for the unequivocal diagnosis of PV should be increased RCM, as opposed to any form of increased RCV, and JAK2 mutation. In the rare cases of increased RCM and JAK2 negativity, marrow morphology plus other minor criteria to be discussed can be diagnostic. Since the therapies for myeloproliferative disorders differ, our data has major clinical implications. Disclosures: No relevant conflicts of interest to declare.

Prefibrotic myelofibrosis: is this diagnosis valid?

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 1-2 ◽  
Author(s):  
LoAnn Peterson
Keyword(s):  
Bone Marrow ◽  
World Health Organization ◽  
Diagnostic Criteria ◽  
Essential Thrombocythemia ◽  
World Health ◽  
Substantial Variation ◽  
Bone Marrow Histology ◽  
The World ◽  
Health Organization

Wilkins and colleagues evaluate the utility of the World Health Organization (WHO) diagnostic criteria intended to separate cases previously classified as essential thrombocythemia (ET) into 2 groups: “true ET” and “prefibrotic myelofibrosis.” Focusing on bone marrow histology, the authors found substantial variation in classification of cases.

Comprehensive Cytokine Profiling in Systemic Mastocytosis: Prognostic Relevance of Increased Plasma IL-2R Levels.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2836-2836 ◽  
Author(s):  
Animesh Pardanani ◽  
Christy Finke ◽  
Terra L Lasho ◽  
Ayalew Tefferi
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Mast Cell ◽  
Median Survival ◽  
Systemic Mastocytosis ◽  
B Cell Lymphoma ◽  
World Health ◽  
Serum Tryptase ◽  
Who Criteria

Abstract Abstract 2836 Background: The clinical phenotype of systemic mastocytosis (SM) is highly variable; establishing prognosis in terms of overall survival or risk of transformation to aggressive disease for those with non-indolent and indolent disease variants, respectively, is not trivial. Similar to other clonal hemopathies, mast cell (MC) activation and/or stromal response to clonal MC expansion likely results in a dysregulated immuno cellular/cytokine profile; analysis of this aspect of SM may provide additional prognostic information within the context of well established parameters such as the World Health Organization (WHO) SM classification system. Here, we conducted a comprehensive analysis of circulating cytokines/chemokines with clinicopathologic and clinical outcome correlations in a cohort of SM patients seen at our institution. Methods: The diagnosis of SM and its subclassification were established according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Follow up information including data on survival and disease progression were updated in July 2012. Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Forty six SM patients met the above stipulated criteria; 25 (54%) were male and the median age at referral was 61 years (range 21–85). Subclassification of patients per WHO criteria was: indolent SM (ISM) 23 (50%), aggressive SM (ASM) 8 (17%) and SM with associated clonal hematological non-MC lineage disease (SM-AHNMD) 15 (33%). When the distribution of 30 cytokines was considered across the 3 SM sub groups, only interleukin (IL)-8 was significantly different (SM-AHNMD > ISM/ASM; p=0.0002). For ISM patients, increased levels of sIL-2R were associated with presence of B-findings (p=0.0046) including splenomegaly (p=0.001) and serum tryptase levels >200 ng/mL (p=0.0046), and decreased levels of IL-8 and hepatocyte growth factor (HGF) with MC mediator-release symptoms (p <0.05). Increased levels of sIL-2R (r2=0.6; p<0.0001) and RANTES (r2=0.37; p=0.0013) were correlated with bone marrow MC burden, and sIL-2R (r2=0.34; p=0.004) and MIG (r2=0.42; p=0.0012) with serum tryptase levels in ISM patients; similar findings were noted for the overall cohort. At a median follow up of 28 months (range 0–116), 20 (43%) deaths, and 3 (13%) and 1 (2%) transformations to ASM and mast cell leukemia, respectively, were recorded for the overall cohort. In univariate analysis, increased sIL-2R levels were predictive for inferior overall survival (p=0.005); this prognostic significance was maintained in multivariate analysis after adjusting for other known prognostic variables individually (i.e. WHO SM subtypes, age >65 years, hemoglobin <10 g/dL, thrombocytopenia, weight loss or hypoalbuminemia) (all p <0.05). Increased sIL-2R (>75th percentile) effectively stratified patients in the overall cohort into 2 well-delineated risk groups for overall survival (median survival 109 vs. 26 months; p=0.0004) (Figure). This sIL-2R threshold was also able to risk stratify patients within ISM (median survival not reached vs. 38 months) and non-ISM (median survival 31 vs. 5 months) categories (p <0.0001). Conclusions: The current study demonstrates s-IL2R to be a key inflammatory cytokine in SM; it is significantly correlated with a phenotype of high systemic MC burden and in this regard, is an attractive surrogate for treatment response in clinical practice, if validated. The predictive value of sIL-2R for overall survival is akin to similar observations in primary myelofibrosis and diffuse large B-cell lymphoma; in this study, it was noted to be independent of conventional measures of organopathy from MC infiltration, and thus may reflect a novel pathogenetic process in SM, mediated by dysregulated inflammatory and/or immuno cellular pathways. Disclosures: No relevant conflicts of interest to declare.

Novel Management of Immune Thrombocytopenia in Gaucher Disease Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5006-5006
Author(s):  
Hanna Rosenbaum
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Avascular Necrosis ◽  
Gaucher Disease ◽  
Immune Thrombocytopenia ◽  
High Dose ◽  
Type I ◽  
Platelet Counts ◽  
Skeletal Complications

Abstract Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases. Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis. Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes. Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis. Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. Disclosures Off Label Use: Romiplostim in gaucher patients.

scholarly journals Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2428-2428 ◽  
Author(s):  
Michael D. Tarantino ◽  
Jenny M. Despotovic ◽  
John Roy ◽  
John Grainger ◽  
Nichola Cooper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Claire N. Harrison ◽  
Rosemary E. Gale ◽  
Samuel J. Machin ◽  
David C. Linch
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Lower Risk ◽  
Study Group ◽  
Reactive Thrombocytosis ◽  
Age Related ◽  
Hemorrhagic Complications ◽  
Thrombotic Complications

Abstract Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

Cytogenetic Abnormalities in Essential Thrombocythemia: Prevalence and Prognostic Significance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3626-3626
Author(s):  
Alexandra P. Wolanskyj ◽  
Naseema Gangat ◽  
Susan M. Schwager ◽  
Rhett P. Ketterling ◽  
Ayalew Tefferi
Keyword(s):  
Overall Survival ◽  
Venous Thrombosis ◽  
Essential Thrombocythemia ◽  
Prognostic Significance ◽  
World Health ◽  
Study Cohort ◽  
Trisomy 8 ◽  
Abnormal Karyotype ◽  
Jak2 Mutation

Abstract Objectives: We conducted a study to describe the cytogenetic findings as well as clinical correlates and long-term prognostic relevance of abnormal cytogenetics at the time of diagnosis of Essential thrombocythemia (ET), in terms of clinical presentation, disease transformation into more aggressive myeloid disorders, and life expectancy. Patients and Methods: The study cohort consisted of a consecutive group of patients with ET who fulfilled the World Health Organization (WHO) diagnostic criteria, in whom bone marrow biopsy was performed at diagnosis, with interpretable cytogenetic analysis obtained in all cases. Results: A total of 403 patients were studied (median age, 56 years; median follow-up 64 months). The prevalence of abnormal cytogenetics at presentation was 6.7 % (27 of 403). The most common cytogenetic anomalies identified included trisomy 9 (4 patients), trisomy 8 (3 patients) and deletion 20q (3 patients). Parameters at diagnosis that were significantly associated with abnormal cytogenetics included palpable splenomegaly (p=0.03), current tobacco use (p=0.04); venous thrombosis (p= 0.019), extreme thrombocytosis (i.e., platelet count >1500 × 109/L, p = 0.03) and anemia with a hemoglobin of less than 10 g/dl (p=0.02); but did not include Jak2 mutation status, nor advanced age (≥ 60 years). During follow up, patients with abnormal cytogenetics were more likely to experience venous thrombosis (p=0.02) but not shorter survival [figure 1], transformation to AML, MDS or MMM, nor a greater requirement for cytotoxic therapy. Conclusion: Cytogenetic anomalies at presentation are relatively uncommon in ET, and do not predict a greater predilection towards evolution into more aggressive myeloid disorders, nor inferior survival. Fig. 1 Overall Survival According to Normal vs Abnormal Karyotype Fig. 1. Overall Survival According to Normal vs Abnormal Karyotype

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