A Postpartum Rebound of Platelet Count in Patient with Type 2 Calreticulin -Mutant Essential Thrombocythemia: A Case Report

Pegylated Interferon ◽

Young Lady ◽

Management Approach ◽

Optimal Management ◽

Acceptable Range

Abstract Essential thrombocythemia (ET) is an uncommon myeloproliferative neoplasm (MPN). It is more commonly encountered in females; around 20% of them are below 40 years old. The optimal management of ET during pregnancy and after delivery is still not well established. Here, we report a case of a young lady with ET who developed a marked rebound in her platelet count two weeks after delivery. She was on Pegylated Interferon (PEG-IFN) alfa 2-a during pregnancy, but she had stopped it on her own one month before delivery. We resumed her therapy, and subsequently, her platelet count reduced dramatically within four weeks to the acceptable range. This case emphasizes the importance of platelet count follow-up after delivery and outlines the management approach in such cases.

Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort

Blood ◽

10.1182/blood-2012-04-424911 ◽

2012 ◽

Vol 120 (7) ◽

pp. 1409-1411 ◽

Cited By ~ 98

Author(s):

Peter J. Campbell ◽

Cathy MacLean ◽

Philip A. Beer ◽

Georgina Buck ◽

Keith Wheatley ◽

...

Keyword(s):

Platelet Count ◽

Vascular Complications ◽

Complication Rates ◽

Normal Range ◽

Major Hemorrhage ◽

Confounding Variables ◽

Wbc Count

Abstract Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782.

The Platelet COUNT at Diagnosis of Essential Thrombocythemia Is a Prognostic Factor for Thrombosis-Free Survival: Retrospective Analysis on 1201 Patients

Blood ◽

10.1182/blood.v126.23.2815.2815 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2815-2815

Author(s):

Marco Montanaro ◽

Roberto Latagliata ◽

Michele Cedrone ◽

Ambra Di Veroli ◽

Cristina Santoro ◽

...

Keyword(s):

Platelet Count ◽

Retrospective Analysis ◽

Protective Factor ◽

Thrombotic Event ◽

Free Survival ◽

Significant Difference ◽

Wbc Count ◽

Spleen Enlargement

Abstract The protective effect of higher platelet count at diagnosis of Essential Thrombocythemia (ET) was reported in some papers (Carobbio A. 2011, Palandri F. 2012, Montanaro M., 2014). As at our knowledge, there is no study specifically addressing this point; in this retrospective analysis we have examined 1201 ET patients (pts) followed in 11 Hematological centers of our region from 1/1978 to 12/2010. The diagnosis of ET was made with PVSG, WHO 2001 and WHO 2008 criteria, respectively, according to the period of 1st observation. The main features of our cohort were as follows: median age 62,9 yrs (19-96), male/female 435/766 (36.2%/63.8%), median WBC count 8,8 x 106/L (1.2-57.7), median Hb level 14.0 g/dl (6.0-20.5), median platelet count 813 x 106/L (457-3582), JAK-2V617F mutation in 498/834 performed pts (59,7 %) with a median allele burden of 19.6% (0.2-99.9%), spleen enlargement in 226 pts (18.7%), previous thrombosis in 17.9% of pts (arterial 14.1%, venous 3.8%). The median follow-up of the entire cohort was 7.75 yrs. Thrombosis-free survival curves were plotted according to Kaplan-Meier method and independent risk factors were identified with the Cox proportional-hazards method. At the multivariate analysis, negative prognostic factors for TFS resulted: previous thrombotic events (p= 0.012), age ≥60 yrs (p= 0.008) and spleen enlargement (p= 0.039): on the contrary, platelet count ≥ 944.109/L resulted a protective factor for TFS [p= 0.031 with an HR 0,57 (C.I. 95% 0,35-0,95)]. Receiver operating characteristic (ROC) analyses based on thrombotic events during follow-up were used to identify the baseline platelet count of 944 x 109/L as the best threshold for predicting thrombotic events. Thrombotic events according to this cutoff were 40/384 (10.3%) in pts with platelet count ≥ 944 x 109/L and 109/817 (13.3%) in pts with platelet count < 944 x 109/L. The sites of thrombosis are reported in the table. A comparison of the main features in these two populations showed that pts with PLT count < 944 x 109/L were older (median age 60.4 yrs vs 57.1 yrs, p= 0.016), had a lower median WBC count (8.8 x 109/L vs 10.6 x 109/L, p< 0.0001), an higher median Hb level (14.1 g/dL vs 13.6 g/dL, p< 0.0001) and an higher rate of JAK-2V617F mutation (67.2% vs 41.6%, p< 0.0001); no differences were observed between the two groups as to thrombotic events before diagnosis, spleen enlargement and cardiovascular risk factor (p=NS). As to the treatment, both groups resulted equally treated with anti-aggregant agents (84,6% vs 87,4%, p= 0,76) while in pts with platelet count <944 x 109/L the oral anticoagulants (7.1% vs. 3.1%, p= 0.01) were more often used. Pts with higher platelet count were more frequently treated with cyto-reductive drugs (90,4 % vs 76,4 %, p< 0.0001). No significant difference resulted for Hydroxyurea (70,8 % vs 64,3%, p= 0,34) and Interferon ( 11,7% vs 6,9%, p= 0,07); on the contrary, more pts with higher platelet count were treated with anagrelide (10.7% vs 5.0%, p= 0.001) and alkylating agents (8.9% vs 5.1%, p= 0.03). In conclusion, our retrospective analysis confirmed the protective role for thrombosis of an higher platelet count at diagnosis. Pts with platelet count ≥ 944 x 109/L were more frequently treated with cyto-reductive drugs and this could possibly explain the better TFS, even if the platelet count closer to the occurrence of a thrombotic event resulted near the normal values in both groups. On the other hand, the higher rate of JAK-2V617F mutation in the group of pts with a baseline lower platelet count could be responsible of this counterintuitive finding: it is worth of note, however, that in our series the JAK-2V617F mutation did not result a significant factor for TFS. Table 1.TYPESITEPLTs ≥ 944PLTs <944ARTERIALCardiac10 (2.6%)20 (2.5%)CNS*9 (2.3%)39 (4.8%)Peripheral2 (0.5%)6 (0.7%)Splanchnic1 (0.3%)1 (0.1%)Total22/384 (5.7%)66/817 (8.1%)VENOUSPeripheral17 (4.4%)32 (3.9%)Atypical03 (0.4%)Splanchnic1 (0.2%)7 (0.9%)Total18/384(4.6%)42/817(5.2%)*Central Nervous System; ° Non tested Disclosures No relevant conflicts of interest to declare.

A Heterogeneous Response Pattern to Interferon-alpha2 with Induction of a Significant Decrease in the Calreticulin Mutant Allele Burden in a Subset of Patients with Essential Thrombocythemia and Primary Myelofibrosis

Blood ◽

10.1182/blood.v126.23.4057.4057 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4057-4057

Author(s):

Sabrina Cordua ◽

Lasse Kjaer ◽

Morten Orebo Holmström ◽

Niels Pallisgaard ◽

Vibe Skov ◽

...

Keyword(s):

Mutant Allele ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Allele Burden ◽

Travel Grant ◽

Ifn Treatment

Abstract Introduction The discovery of mutations in the calreticulin (CALR) gene in the majority of JAK2 -V617F negative patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Klampfl et al., 2013; Nangalia et al., 2013) has improved the diagnostic accuracy considerably, and most recently distinct clinical and hematological characteristics according to mutational status have been described (Park et al., 2015). The perspective is to personalize and optimize treatment according to the molecular and clinical landscape. This may be achieved by obtaining more information on responses in myeloproliferative neoplasms (MPN) to existing treatment strategies as assessed by the allele burden. Mutations in the CALR gene have proven to play a major role in oncogenic and immunologic processes (Lu, Weng, & Lee, 2015). In this context, it is highly relevant to explore the effectiveness of interferon-alpha2 (IFN) in reducing the CALR -mutated clone. Until now, only one paper has reported a decrease in allele burden in two patients during IFN treatment (Cassinat, Verger, & Kiladijan, 2014). The objective of this report is to expand current knowledge on this important topic by describing the mutant CALR allele burden over time in a larger group of IFN-treated patients. Method Clinical data were collected retrospectively from a single institution on all IFN-treated CALR positive MPN patients with sequential determinations of the mutant allele burden. Type 1 and type 2 mutations were initially identified by a previously published fragment analysis (Klampfl et al 2013). We have developed a Taqman qPCR assay for precise determination of the mutant allele burden of type 1 and type 2 mutations. Stored DNA was subsequently analysed to increase follow-up time. Results Twenty-one patients were included. Fifteen patients had a diagnosis of PMF; 7 of these were diagnosed with prefibrotic myelofibrosis. Six patients had ET. The type 1 and 2 mutations were found in 15 and 6 patients, respectively. Median age was 60 years (range 42-79) and the sex ratio (M/F) was 8/13. Fifteen patients (71%) were in ongoing treatment with IFN, whereas treatment was discontinued in 6 (29%) because of side effects. Median time of IFN treatment was 756 days (range 42-3927). The IFN prescribed was either subcutaneous injection of Pegasys® (median: 45 microgram (ug) per week), PegIntron® 25-50 ug per week, or Multiferon® 3 x 3 million IU per week. Median follow up time since the first CALR measurement was 756 days (range 294-2108). Fourteen patients (67%) maintained an unchanged allele burden during follow up; 1 patient (5%) presented a temporary decrease (from 39% to 27% in allele burden) but increased to the initial level within months while still on IFN treatment (presumably due to low compliance); 1 patient (5%) displayed an increase in allele burden during transformation to acute myelogenous leukemia (Figure 1); and 5 patients (24%) exhibited a marked decrease in allele burden (median decrease: 32%, range 18-45) during treatment with IFN (Figure 2). All 5 patients with decreasing allele burden (Table 1) normalized their platelet counts within a median time of 5 weeks (range 4-20) after initiating treatment with IFN. Conclusion Using a novel sensitive assay for the CALR mutant allele burden, we have demonstrated and substantiated the effectiveness of IFN to reduce the allele burden in a larger series of CALR positive patients with PMF and ET. Importantly, we report for the first time on highly heterogeneous response patterns. Our observation of one fourth of the CALR positive patients responding to treatment with IFN strongly suggests that IFN significantly influences the CALR mutational load. Further clinical and molecular studies are urgently needed to explore the mechanisms behind the heterogeneous response patterns and the clinical implications in regard to clonal evolution and disease progression in non-responding patients. We are currently analysing these issues to assess the definite role of IFN in future treatment strategies in CALR positive MPN patients. Table 1. Patients responding to interferon-alpha2 Characteristics Number/median (range) Patients 5 Age, years 53 (42-62) Sex (M/F) 1/4 Diagnosis- Essential thrombocythemia- Primary myelofibrosis- Prefibrotic myelofibrosis 221 Calreticulin mutation type- type 1- type 2 50 Duration of interferon-alpha2 treatment, days 960 (177-2790) Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cordua: Janssen-Cilag: Other: travel grant. Off Label Use: interferon alpha2 for myeloproliferative neoplasms. Holmström:La Roche Ltd: Other: travel grant. Pallisgaard:Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Novartis: Other: travel grant, Research Funding, Speakers Bureau; Roche: Other: travel grant. Hasselbalch:Novartis: Research Funding.

EXTENSIVE NECROTIC TROPHIC FOOT AND LEG ULCER IN THE PRESENCE OF ESSENTIAL THROMBOCYTHEMIA

Wounds and wound infections The prof B M Kostyuchenok journal ◽

10.25199/2408-9613-2014-1-1-41-45 ◽

2015 ◽

Vol 1 (1) ◽

pp. 41-45

Author(s):

V. O. Tsvetkov ◽

V. V. Malovichko ◽

A. S. Stupin ◽

S. O. Arkhireev

Keyword(s):

Platelet Count ◽

Surgical Treatment ◽

Excellent Result ◽

Skin Grafting ◽

Blood Platelet ◽

Ulcer Recurrence ◽

Rare Occurrence ◽

Blood Platelet Count

We are to present a rare occurrence of large limb-threatening ulcer of the leg and foot in patient with thrombocytosis. Essential thrombocythemia was diagnosed based on peripheral blood platelet count and gen test findings. The improving of platelet count was obtained by oral hydroxyurea. Complex surgical treatment, including free-skin grafting, was performed with the excellent result. Two-year follow-up was retraced without any sign of ulcer recurrence.

A Phase 3, Double-Blind, Placebo-Controlled, Randomized Study Evaluating Navitoclax in Combination with Ruxolitinib in Patients with Myelofibrosis (TRANSFORM-1)

Blood ◽

10.1182/blood-2020-139758 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Jalaja Potluri ◽

Jason Harb ◽

Abdullah A. Masud ◽

Jessica E. Hutti

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Stock Options ◽

Bone Marrow Fibrosis ◽

Double Blind ◽

Starting Dose ◽

Secondary Endpoints ◽

Marrow Fibrosis

Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with poor clinical outcomes. It is characterized by bone marrow fibrosis and an array of constitutional symptoms that impair quality of life. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potential curative therapy for MF, but HSCT is only accessible to a minority of patients and is associated with high morbidity and high rates of transplant-related mortality. JAK inhibitors (JAKi), including the JAK1/2i ruxolitinib and JAK2i fedratinib, are approved for the treatment of primary and secondary MF based on reduction in splenomegaly and disease-related symptoms; however, they have little impact on bone marrow fibrosis and are not effective at managing all clinical manifestations of MF. Therefore, a substantial clinical need for novel therapies to improve the disease course of MF exists. Navitoclax is an oral, potent, small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family proteins BCL-XL, BCL-2, and BCL-w and has demonstrated cell-killing activity in myeloproliferative neoplasm-derived cell lines and primary specimens ex vivo. Preliminary data from a Phase 2 study (NCT03222609) of ruxolitinib-experienced patients with primary or secondary MF have shown favorable spleen responses and tolerability with navitoclax plus ruxolitinib (Harrison et al. EHA 2020. EP1081). TRANSFORM-1 aims to evaluate the combination of navitoclax and ruxolitinib vs placebo and ruxolitinib in adults with primary or secondary MF who have not previously received a JAK2i. Study Design and Methods: In this Phase 3, double-blind, placebo-controlled study (NCT04472598), patients aged ≥18 years with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior treatment with JAK2i, and Eastern Cooperative Oncology Group Performance Score ≤2 will be eligible for enrollment. Candidates for allo-HSCT and those who have received prior treatment with a BH3-mimetic compound or BET inhibitor will be excluded. Patients will be enrolled across 130 sites in approximately 17 countries. Planned target enrollment is 230 patients. Patients will be randomized 1:1 to receive navitoclax or placebo, plus ruxolitinib. Randomization stratification factors include intermediate-2 vs high-risk MF and platelet count ≤200 × 109/L vs >200 × 109/L. Navitoclax will be administered orally at a starting dose of 200 mg (platelet count >150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (platelet count ≤150 × 109/L). Ruxolitinib will be administered orally at a starting dose of 20 mg (platelet count >200 × 109/L) or 15 mg (platelet count 100-200 × 109/L) twice daily. Treatment may continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met. Patients who discontinue without progression will enter post-treatment follow-up; after disease progression or initiation of post-treatment cancer therapy, patients will enter survival follow-up. The primary endpoint of the study is ≥35% reduction in spleen volume from baseline (SVR35) at Week 24, as measured by magnetic resonance imaging or computed tomography, per International Working Group (IWG) criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24 (measured by Myelofibrosis Symptom Assessment Form v4.0), duration of SVR35, change in fatigue from baseline, time to deterioration of physical functioning, anemia response per IWG criteria, SVR35 per IWG, reduction in grade of bone marrow fibrosis from baseline, overall survival, leukemia-free survival, and overall response and composite response per IWG criteria. Exploratory endpoints include progression-free survival. Safety will be assessed throughout the study via adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram variables, and clinical laboratory testing. AEs will be graded per National Cancer Institute Common Terminology Criteria for AEs v5.0. The primary statistical analysis will be conducted using a stratified Cochran-Mantel-Haenszel test, and time-to-event secondary endpoints will be analyzed using a stratified log-rank test and Kaplan-Meier methodology. Hazard ratios will be estimated using stratified Cox proportional hazards model. Disclosures Potluri: AbbVie: Current Employment, Other: may hold stock or stock options. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Masud:AbbVie: Current Employment, Other: may hold stock or stock options . Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. OffLabel Disclosure: Navitoclax is an investigational drug for the treatment of myelofibrosis

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 ◽

10.1182/blood.v93.2.417 ◽

1999 ◽

Vol 93 (2) ◽

pp. 417-424 ◽

Cited By ~ 150

Author(s):

Claire N. Harrison ◽

Rosemary E. Gale ◽

Samuel J. Machin ◽

David C. Linch

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

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.

Essential thrombocythaemia first presenting as myocardial infarction in a 36-year-old male

BMJ Case Reports ◽

10.1136/bcr-2021-243842 ◽

2021 ◽

Vol 14 (9) ◽

pp. e243842

Author(s):

Shahid Bobat ◽

Paul Dunne

Keyword(s):

Myocardial Infarction ◽

Chest Pain ◽

Pegylated Interferon ◽

Coronary Event ◽

Essential Thrombocythaemia ◽

Clonal Proliferation ◽

History Of ◽

Artery Disease

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm where there is a clonal proliferation of thrombocytes. Whilst most often diagnosed incidentally, it can uncommonly present with arterial thrombosis. This is a case presentation of a 36-year-old male who was diagnosed with ET following myocardial infarction caused by multiple thrombotic emboli. The patient was initially misdiagnosed with viral myopericarditis based on an atypical history of chest pain with a viral prodrome. Reattendance a month later with further chest pain, dynamically raised troponin and ECG changes raised suspicions of ACS. Analysis of blood markers from both admissions showed consistently elevated platelet counts. A CMR scan revealed focal ischaemic scars in multiple cardiac segments consistent with an acute coronary event or coronary embolisation. A subsequent coronary angiography demonstrated minimal coronary artery disease. JAK2 gene V617F mutation was detected, confirming ET. The patient was commenced on pegylated interferon-alpha and dual antiplatelet therapy, and discharged with follow-up.

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

Blood ◽

10.1182/blood.v112.11.5239.5239 ◽

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 ◽

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

Survival Trends in Essential Thrombocythemia in the Face of Changing Treatment Practices

Blood ◽

10.1182/blood.v126.23.2805.2805 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2805-2805

Author(s):

A Kamel Abou Hussein ◽

Naseema Gangat ◽

Yoseph Elala ◽

Alexandra Wolanskyj ◽

Curtis A. Hanson ◽

...

Keyword(s):

Platelet Count ◽

Leukocyte Count ◽

Multivariable Analysis ◽

Controlled Study ◽

Free Survival ◽

Treatment Practices ◽

Group 3 ◽

The Impact

Abstract Background : Hydroxyurea has been the mainstay of cytoreductive therapy in essential thrombocythemia (ET) for over four decades. In 1988, anagrelide was first reported as an effective drug in ET (Silverstein et al. NEJM 1988;318:1292) and hundreds of patients were enrolled in clinical trials, which subsequently led to FDA approval in 1997. As a result, an increasing number of patients with ET were being treated with anagrelide until a subsequent controlled study suggested an inferior treatment outcome with anagrelide compared to hydroxyurea (Harrison et al. NEJM 2005;353:33). In the current study, we examined the impact of the corresponding practice changes on overall, myelofibrosis-free and leukemia-free survival, by comparing patients with ET diagnosed before 1988, between 1988 and 1997, and between 1998 and 2005 Methods: More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Survival was calculated from time of initial diagnosis to the time of last follow-up or death. For leukemia- or fibrosis-free survival, the time of the transformation events was considered as the uncensored variable. Conventional statistics was utilized for all analyses. Patients were divided into three groups commensurate with changes in treatment practices, corresponding to the aforementioned publications; Group 1 patients were diagnosed prior to 1988 (n =222), Group 2 1988 to 1997 (n =253), and Group 3 1998 to 2005 (n =264). Results : A total of 739 patients met the above-stipulated criteria (median age 57 years; 65% females). At a median follow-up of 12.2 years (range: 0.01-43.6 years), 368 (50%) deaths, 48 (6.5%) fibrotic transformations and 23 (3%) leukemic transformations were documented. Median overall survival (OS) was 18.6 years. On multivariable analysis, older age (P <0.001), increased leukocyte count (P <0.001), thrombosis history (P =0.04), and male sex (P<0.0001) were identified as predictors of inferior OS. Myelofibrosis-free survival (MFS) was predicted by platelet count <100 x 10(9)/L and lower hemoglobin level (multivariate P values 0.03 and <0.001, respectively). Leukemia-free survival (LFS) was predicted by increased leukocyte count, on multivariable analysis (P =0.002). Comparison of presenting features and outcome by period of diagnosis: Significant differences, in presenting features, between groups 1, 2, and 3 included age (median 55, 56, and 59 years, respectively; P =0.003), female preponderance (68, 69, and 58%, respectively; P =0.02), platelet count (1080, 995, and 890 x 10(9)/L, respectively; P <0.001), and leukocyte count (10, 9.6, and 8.4 x 10(9)/L, respectively; P <0.001). Median survival was 20.7 years, 19 years and 14.3 years, in groups 1, 2 and 3, respectively (P =0.02) (Figure 1). However, the difference in survival was no longer apparent during multivariable analysis that included age as a covariate (P=0.88). In univariate analysis, MFS was significantly shorter in group 3 patients (P=0.02; Figure 2); borderline significance was retained during multivariable analysis (p=0.13). LFS was similar among the three groups (P = 0.27). Conclusions : The results from the current retrospective study suggest increased rate of progression to myelofibrosis in ET patients diagnosed in the anagrelide era, an observation that is consistent with the results from a previous controlled study (Harrison et al. NEJM 2005;353:33). Regardless, survival in ET in the last four decades remains unchanged. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Pardanani: Stemline: Research Funding.

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 ◽

10.1182/blood.v93.2.417.402a33_417_424 ◽

1999 ◽

Vol 93 (2) ◽

pp. 417-424 ◽

Cited By ~ 8

Author(s):

Claire N. Harrison ◽

Rosemary E. Gale ◽

Samuel J. Machin ◽

David C. Linch

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Lower Risk ◽

Study Group ◽

Reactive Thrombocytosis ◽

Age Related ◽

Hemorrhagic Complications ◽

Thrombotic Complications

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.