Platelet Count Predicts Co-occurrence of Driver Mutations in Essential Thrombocythemia and Myelofibrosis with a Low JAK2 Allele Burden

2019 ◽  
Vol 19 ◽  
pp. S352-S353
Author(s):  
Barbara Mora ◽  
Margherita Maffioli ◽  
Daniela Barraco ◽  
Michele Merli ◽  
Rosario Casalone ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Driver Mutations ◽  
Allele Burden

Platelet count predicts driver mutations’ co-occurrence in low JAK2 mutated essential thrombocythemia and myelofibrosis

Leukemia ◽  
2020 ◽  
Author(s):  
Barbara Mora ◽  
Claudia Siracusa ◽  
Elisa Rumi ◽  
Margherita Maffioli ◽  
Ilaria Carola Casetti ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Driver Mutations

scholarly journals Impact of Underlying Mutational Profile, and Changes during Treatment, in MPN Patients Treated with JAK Inhibitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 353-353
Author(s):  
Paola Guglielmelli ◽  
Annalisa Pacilli ◽  
Giada Rotunno ◽  
Francesca Gesullo ◽  
Alessandro Pancrazzi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Clinical Response ◽  
Mutational Analysis ◽  
Jak2 V617f ◽  
Symptomatic Improvement ◽  
Driver Mutations ◽  
Jak Inhibitors ◽  
Advisory Committees ◽  
Allele Burden ◽  
Calr Mutations

Abstract Background. Most patients (pts) with MPN derive clinical benefits from treatment with JAK inhibitors (JAKi) but predictors of response or loss of response have not been clearly identified. Aims. To address the impact of underlying mutational profile of driver mutations (JAK2V617F, CALR, MPL), including other genes of JAK/STAT pathway, and "subclonal" (epigenetic, spliceosome) mutations, and their modifications under treatment, on the response to JAKi. Methods. 100 patients with WHO2008-diagnosis of MPN, 39 PV, 14 ET, 64 MF (37 PMF, 27 PPV/PET-MF), were included. 25 (12PV, 13 MF) had received hydroxyurea (HU), 75 (20 PV, 7 ET, 48 MF) a JAKi (67 ruxolitinib, 8 fedratinib). Response criteria were as by IWG-MRT (Blood 2013; 121:4778; Blood 2013; 122:1395). Mutations in 22 genes (JAK1, JAK2, JAK3, EZH2, ASXL1, TET2, IDH1, IDH2, CBL, SRSF2, DNMT3A, NFE2, SOCS1, SOCS2, SOCS3, SH2B3, STAT1, STAT3, STAT5A, STAT5B, SF3B1, U2AF1) were analyzed in blood DNA at baseline (bl) and at the latest available sample by deep sequencing with Ion Torrent-PGM. CALR mutations were analyzed by capillary electrophoresis; JAK2 V617F allele burden was measured by RT-qPCR assays. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier method and Cox regression, were used for statistical analysis. Results. A. Impact of baseline mutational profile. PV and ET:At bl, 17/40 (42.5%) pts had subclonal mutations. Spleen volume reduction (SVR) by IWG-MRT criteria was obtained in 100% of pts without subclonal mutations compared to 66% of those with >1 mutations (P=0.04). Presence of NFE2 mutations uniformly predicted for lack of SVR (P=0.03). Loss of SVR was predicted by ASXL1 mut (67% vs 12% in un-mutated; P<0.05). No correlation of mutations with symptomatic improvement, normalization of leukocyte and platelet count, and control of hematocrit to <45% in PV pts was noticed. A trend to lower pruritus responses were seen in PV pts harboring >1 subclonal mutations (P=0.06). JAK2 V617F homozygous pts were more prone to have platelet count control (81%) compared to heterozygous (30%; P<0.04). MF:At bl, 33/64 (51.5%) pts had subclonal mutations. No correlation of mutations with symptomatic improvement, normalization of leukocyte and platelet count was found. SVR was not predicted by a high molecular risk status (Leukemia 2013;27:1861; Blood 2014;123:2157); however, harboring >1 of the 22 mutations was negatively associated with SVR (P=0.02) (HR 1.9, 95% CI 1.0-4.6). No correlation of JAK2 V617F or CALR mutations, or the allele burden, on SVR or loss of SVR was discovered. B. Changes during treatment. PV and ET:follow-up mutational analysis was performed at median treatment duration of 2.9y HU, 4.7y ruxolitinib, 1.7y fedratinib in 50 pts for driver mutation and 40 pts for subclonal genes. Of HU pts (n=12), 33% each had JAK2 V617F allele burden stable, increased and reduced by >10%. Median reduction of allele burden was -18.3%. 1 pt acquired 2 novel subclonal mutations (ASXL1, EZH2) and 2 showed increased allele burden of ASXL1 and TET2 by >10%. Among JAKi pts (n=30), 20 pts (66.7%) had JAK2 V617F allele burden reduction by a median of -33.3% (-13.6 to -100%), stable in 9. Degree of allele burden reduction was positively correlated with length of JAKi treatment (P=0.04). 1 pt acquired novel ASXL1, 2 pts had increase (ASXL1, EZH2) and 6 pts reduction of >10% of allele burden (4 TET2, 1 DNMT3A, 1 SH2B3). No correlation was seen with clinical response over time. MF: follow-up mutational analysis was performed at median treatment duration of 2.4y HU, 1.9y ruxolitinib, 1.4y fedratinib. HU pts (n=13): of the 7 JAK2 V617F mut, 4 increased and 1 decreased the allele burden, and 1 of 3 CALR mutated reduced allele burden, by >10%. 1 pt acquired CBL mutation, other mutations (n=7) were stable. Among JAKi treated pts, of the 41 JAK2 V617F mutated, 51% showed a median allele burden reduction of -14.8% (-10.5% to -53.9%). Of 10 pts with subclonal mutations at baseline, 4 clones (3 ASXL1 and 1 NFE2) increased and 2 (EZH2, ASXL1) decreased by >10%. Only 1 pt acquired a novel mutation in EZH2. No correlation was seen with clinical response over time. Discussion. These data suggest that only minimal influence on clinical response is provided by driver mutations and their allele burden, or subclonal mutations, in MPN patients receiving JAKi. The clinical relevance of different clone fluctuations over treatment with conventional therapy and JAKi remains to be addressed. Disclosures Vannucchi: Baxalta: Membership on an entity's Board of Directors or advisory committees; Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Clinical Characteristics and Cardioavscular Events in Patients with Esential Thrombocythemia with <10% Vs. ≥10% JAK2 V617F Allele Burden

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4171-4171
Author(s):  
Blanca Xicoy ◽  
Natalia Estrada ◽  
Alberto Alvarez-Larran ◽  
Xavier Calvo Gonzalez ◽  
Beatriz Bellosillo ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Clinical Characteristics ◽  
Prognostic Score ◽  
Jak2 V617f ◽  
Advisory Committees ◽  
Allele Burden ◽  
Therapeutic Algorithm ◽  
Uncertain Significance

Introduction The clinical characteristics, treatment, cardiovascular events (CVE) and evolution of patients diagnosed with JAK2 V617F positive essential thrombocythemia (ET) with low allele burden (LAB) are scarcely studied. Its presence in people without a confirmed diagnosis of malignant hemopathy is called clonal hematopoiesis of uncertain significance (CHIP) and confers higher risk of developing CVE. The objective of this study was to compare the clinical characteristics and CVE of a series of JAK2 V617F-positive ET patients with <10% (LAB) vs. ≥10% allele burden (HAB), from the GEMFIN (Grupo Español de Enfermedades Mieloproliferativas Crónicas Filadelfia Negativas) Group. Methods From the database of the GEMFIN group, 410 ET patients were JAK2 V617F positive, 89 (21.7 %) with LAB and 321 (78.3%) with HAB. The clinical characteristics, treatment (cytoreduction, antiagregation, anticoagulation, JAK inhibitor), CVE (before, at and after diagnosis) and evolution to myelofibrosis (MF) or acute myeloid leukemia (AML) of these two groups of patients were compared. Results LAB and HAB groups did not significantly differ regarding the main clinical characteristics (i.e cardiovascular risk factors [CVRF] and International Prognostic Score for Thrombosis in Essential Thrombocythemia [IPSET] score) except for the median platelet count: LAB 636 x109/L [436- 2500] vs HAB 687 x109/L[440-1980L], p=0.035). CVE after diagnosis of ET were more frequent in patients with HAB (41/137, 30%) than in patients with LAB (5/48, 10%), p=0.007. Only one LAB patient with CVE had JAK2 allele burden >5%. Treatments received by both groups were not significantly different. None of the patients from both groups progressed to AML, whereas 1/48 vs. 6/137 of patients evolved to MF. Median follow-up of patients with LAB and HAB was 3.4 years [0.1-17.7] and 4.3 years [0.1-27.8], respectively (Table 1). Conclusions In these series of ET patients from the GEMFIN group, patients with LAB had significantly lower median platelet count at diagnosis and less CVE after diagnosis than patients with HAB, although CVRF and IPSET scores and treatment approach were similar. The clinical behavior of LAB patients may resemble that of individuals with CHIP. The therapeutic algorithm of ET patients with LAB may be somehow different than that of patients with HAB and therefore, might be revised. Disclosures Bellosillo: Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biocartis: Honoraria; Merck-Serono: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman â€"La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; ThermoFisher: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; BMS: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Pérez:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The Clinical Phenotype of Patients with Essential Thrombocythemia Harboring MPL 515W>L/K Mutation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 678-678 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Elisabetta Antonioli ◽  
Alessandro Pancrazzi ◽  
Paola Guglielmelli ◽  
Simonetta Di Lollo ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Mutant Allele ◽  
Clinical Phenotype ◽  
Primary Myelofibrosis ◽  
Allele Burden ◽  
Long Term Stability ◽  
Blood Smears ◽  
Significant Difference ◽  
Systemic Symptoms

Abstract A 515W>L/K mutation in MPL (MPLmut) has been described in 5–10% of patients (pts) with myelofibrosis (Pikman Y, PloS Med 2006), possibly associated with JAK2617V>F allele. Among 217 subjects with primary myelofibrosis, the 18 MPLmut pts presented a more severe anemic phenotype than MPL wild-type (MPLWT) pts (Guglielmelli P, BJH 2007). MPL 515W>L mutation has been reported also in 4 pts with essential thrombocythemia (ET) (1%) (Pardanani A, Blood 2006). We have collected 13 MPLmut pts in an unselected series of 273 ET pts according to WHO criteria (4.7% of total) to evaluate whether MPL mutation associated with unique clinical characteristics and eventually whether MPLmut ET pts should be re-classified as having WHO pre-fibrotic myelofibrosis. A novel quantitative real-time PCR assay for 515W>L and 515W>K allele in granulocyte DNA has been designed; detection limit was 0.01% for W>L allele and 0.1% for W>K allele. Six pts were 515W>L and seven were 515W>K; 1 pt with W>L and 4 pts with W>K allele had only mutant allele. Mean mutant allele burden was 44(+/−25)% and 59(+/−21)% for W>L and W>K, respectively. Seven MPLmut pts (53%) also harbored JAK2617V>F allele, as compared to 164/260 of MPLWT (63%); they were 2/6 pts with 515W>L and 5/7 with 515W>K. Mean 617V>F allele burden was significantly lower in MPLmut (11+/− 9%) than MPLWT pts (24+/− 17%; P=0.03). There was no difference in age or gender, but median disease duration was longer in MPLmut pts (110 vs 57 months, P=0.001). At diagnosis, platelet count was significantly higher in MPLmut pts (1,113+/− 438x109/L vs 864+/− 302x109/L; P=0.02), while hemoglobin, serum ferritin, LDH level, and leukocyte count were not statistically different. Frequency of pts presenting endogenous erythroid colonies or PRV-1 over-expression was similar among MPLmut (37% and 44%, respectively) or MPLWT pts (48% and 43%). There was no difference in splenomegaly, systemic symptoms, major thrombosis (30% vs 21%) or hemorrhages (8% vs 6%) between MPLmut and MPLWT pts. However, pts with microvessel disease were significantly more frequent among MPLmut (77% vs 34%, P=0.002). Bone marrow (BM) biopsy at diagnosis of MPLmut pts was reviewed in a blinded fashion among 30 random biopsies from MPLWT ET pts. There was no significant difference in total cellularity, erythoid or myeloid lineage beteween MPLWT and MPLmut pts. Megakaryocyte hyperplasia was prominent in MPLmut pts, with Mks being either scattered or in loose clusters similarly to MPLWT pts. However, in addition to typical large Mks, MPLmut pts displayed a discrete number of small-size vWF and/or CD61-pos Mks. BM fibrosis quantification (revised EUMNET criteria) revealed grade 0–1 fibrosis in all but one MPLmut pts, who presented grade 1–2. Finally, there was no evidence of leukoerythroblastosis in blood smears. One pt died after 11 yrs of major thrombosis, none evolved to myelofibrosis. Overall, these data indicate that prevalence of MPL mutation in ET may be higher (5%) than previously reported, but the mutation per se does not associate with a unique clinical phenotype, a part for a higher platelet count and greater occurrence of microvessel symptoms. Increased number of small-size Mks was observed in BM biopsy, but the whole hystologic pattern, as well as long-term stability of disease, did not support alternative diagnosis of pre-fibrotic myelofibrosis.

scholarly journals Role of Non-Driver Mutations and JAK2V617F Allele Burden in Myelofibrotic and Acute Myeloid Transformation of Patients with Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1952-1952 ◽  
Author(s):  
Alicia Senín ◽  
Conchi Fernández ◽  
Beatriz Bellosillo ◽  
Laura Camacho ◽  
Raquel Longaron ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Essential Thrombocythemia ◽  
Chronic Phase ◽  
Progressive Increase ◽  
Driver Mutations ◽  
Evolutionary Pattern ◽  
Allele Burden ◽  
Jak2v617f Allele Burden ◽  
Acute Myeloid

Abstract Background: Non-driver mutations and JAK2V617F allele burden have been involved in progression to myelofibrosis (MF) or acute myeloid leukemia (AML) in patients with polycythemia vera (PV) and essential thrombocythemia (ET). It is unknown if both mechanisms play a different role in disease transformation and if they are useful in routine clinical practice. Methods: JAK2V617F allele burden was monitored in 208 patients (PV n=106, ET n=102) for a median of 6.5 years (range: 1-13). Quantification of JAK2V617F allele burden was assessed on the first available sample and every year thereafter. The evolutionary pattern of JAK2V617F allele burden was categorized as persistently low (<50%), persistently high (>50%), progressive increase (> 25% from baseline) or unexplained decrease (not therapy related). Next generation sequencing (NGS) analysis of 51 myeloid-related genes was performed in 100 patients with a median molecular follow-up of 10 years including all cases with transformation to AML or MF. Detected mutations by NGS in the last sample were studied in first paired sample obtained in the chronic phase (median time from diagnosis: 1.6 years). Time to myelofibrosis and time to AML were calculated according to the presence of non-driver mutations or the JAK2V617F evolutionary pattern. Multivariate analysis was performed by Cox regression. Results: With a median follow-up of 13 years (range: 1-30) 32 patients died whereas 24 and 12 patients progressed to MF and AML, respectively. Median age at diagnosis was 63 years (range: 20-94), 115 were women (55%) and 173 (83%) received cytoreduction. A persistently low JAK2V617F allele burden was observed in 62% of patients whereas the remainder presented a persistently high (25%), a progressive increase (11%) or a non-therapy-related decrease of JAK2V617F allele burden (2%). Non-driver mutations were detected in last sample in 48% of patients. Median number of mutations was 1 (range: 1-5). Mutational frequencies were: TET2 12%, DNMT3A 12%, TP53 9%, ASXL1 7%, RUNX1 4%, SF3B1 4%, SRSF2 4%, IDH1/2 4%, SH2B3 3 % and <2% for EZH2, ZRSR2, SETBP1, FLT3, NPM, BCOR, CBL, PTPN11, KAT6A, NF1, U2AF1, GNAS, PHF6, KTM2A, JAK2, BCORL1, NOTCH1, MPL and PRPF40B. Mutations were detected in first sample in 28% of patients (58% of those with mutations in last sample). Frequencies of mutations in first sample were: TET2 10%, DNMT3A 5%, TP53 5%, ASXL1 4%, SRSF2 4%, IDH1/2 3%, and < 2% for SF3B1, SH2B3, KMT2A and ZRSR2. The evolutionary pattern of JAK2V617F allele burden was not associated with the presence of mutations in first or last sample. Twelve patients progressed to AML (post-PV n=7, post-ET n=5), nine of them presented mutations in first sample. AML transformation at 15 years was 27% and 6.8% for patients with and without additional mutations in first sample, respectively (p=0.001). Mutated genes associated with a higher probability of AML transformation were DNMT3A (p<0.0001), SRSF2 (p<0.0001) and IDH (p<0.0001). Other variables associated with a higher probability of AML were age > 65 years (p=0.012) and exposure to busulfan (p=0.003). Evolutionary JAK2V617F pattern was not associated with the probability of AML (p=0.667). In multivariate analysis, an increased risk of AML transformation was observed for patients with additional mutations in the chronic phase (HR: 6.3; 95%CI 1.6-24.7, p=0.008) after adjusting for initial diagnosis, age and exposure to busulfan. Twenty-four MF transformations were documented (post-PV n= 18, post-ET n=6). Presence of additional mutations was not associated with the probability of MF (p=0.189). Patients with persistently high or a progressive increase of the JAK2V617Fallele burden showed a higher probability of MF transformation (24% versus 1.5% at 10 years, p<0.0001) that persisted in multivariate analysis after correction for age and initial diagnosis (HR 13.9, 95%CI: 2.9-65.6, p=0.001). Conclusion: Non-driver mutations are involved in the progression of PV and ET to AML but not to MF. NGS could be useful for identifying patients with PV or ET at risk of AML transformation. Acknowledgment:This work was supported by grants from the Instituto de Salud Carlos III, Spanish Health Ministry, FISPI13/00557, FISPI1300393, RD012/0036/0004, 2014 SGR567. Alicia Senín received a grant from Sociedad Española de Hematología y Hemoterapia. Disclosures No relevant conflicts of interest to declare.

Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 179-179 ◽  
Author(s):  
Gabriela M. Baerlocher ◽  
Elisabeth Oppliger Leibundgut ◽  
Christina Ayran ◽  
Martha Blaney ◽  
Bart Burington ◽  
...  
Keyword(s):  
Platelet Count ◽  
Maintenance Therapy ◽  
Progenitor Cells ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Jak2 V617f ◽  
Advisory Committees ◽  
Allele Burden ◽  
Prior Therapy

Abstract Abstract 179 Background: Myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), are driven by neoplastic progenitor cells. The JAK2 V617F mutation can be detected in approximately 50% of patients (pts) with ET, and the JAK2 V617F allele burden can be used to measure the treatment-induced molecular response (MR) over time. Telomerase is upregulated in neoplastic progenitor cells and sustains indefinite replication. Imetelstat is a first in class, potent, specific inhibitor of telomerase which selectively distributes to bone marrow and inhibits thrombopoiesis. In vitro studies demonstrate that imetelstat selectively inhibits spontaneous megakaryocytic colony-forming unit (CFU-Meg) growth from the blood of pts with ET but not from healthy individuals. Phase I studies have demonstrated that imetelstat inhibits telomerase activity in pts at doses of 7.5 mg/kg and above. Therefore, unlike conventional cytoreductive therapy and JAK2 kinase inhibitors, imetelstat may be uniquely able to selectively inhibit proliferation of neoplastic clonogenic cells in pts with ET and modify the biology and progression of the disease. Methods: A phase II study enrolled pts with ET who had failed or were intolerant to at least one prior therapy, or who refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly. After attainment of best platelet response in the induction phase, maintenance dosing with imetelstat was commenced with dosing based upon platelet count. Primary endpoint was best overall hematologic response (HR) with complete response (CR) defined as platelet count <400 × 103/μl maintained for at least 4 consecutive weeks in the absence of new thromboembolic events. A key secondary endpoint was rate of MR in patients with JAK2 V617F molecular mutations. JAK2 V617F allele burden was measured by allele-specific quantitative real-time PCR with a limit of detection of 0.1%. CFU-Meg growth pre- and post-treatment and tolerability were also assessed. Results: As of July 9, 2012, 13 pts were treated. Median age was 60 yrs (range 21–83) with a median of 2 prior treatments (range 1–3). Median years since initial diagnosis were 5.8 (range 0.3 to 24.9) and initial platelet count was 809 × 103/μl (range 601 to 1359 × 103/μl). Best overall HR was 100%, with 11 of 13 pts achieving a confirmed CR after a median of 6.1 weeks (range 5.1 to 14.1 wks). Twelve of 13 pts remain on maintenance therapy (median time on study 26.1 weeks) and despite transient elevations of platelets above best response, pts continue to be responsive to imetelstat. Four pts have reached 1 year of therapy and continue to be treated with ongoing HR. Dosing frequency on maintenance therapy was generally reduced with time. A substantial decrease in JAK2 V617F allele burden was demonstrated in all 5 JAK2 V617F-positive pts (mean allele burden reduction of 82%; range of 59–94%, see table below). Four pts who were eligible for MR assessment by LeukemiaNetcriteria (initial JAKV617F allele burden >10%) reached molecular partial responses (PR): one pt after 12 weeks, which has been maintained through 1 year, and 3 other pts at 24, 36 and 48 weeks of therapy. One additional pt with JAK2 V617F levels of 4.8% prior to therapy has also had a 75% reduction after 12 weeks of treatment. A reduction in the spontaneous growth of CFU-Meg was also observed in the 2 pts tested, with 93% and 96% reduction from baseline, respectively. Long-term administration of imetelstat was generally well tolerated. Common adverse events reported on therapy were mild to moderate gastrointestinal toxicities, reductions in neutrophil counts, and fatigue. Conclusions: Imetelstat rapidly induces and maintains hematologic responses in pts with ET who have failed or are intolerant to conventional therapies. Importantly, substantial MR is observed in all JAK2 V617F-positive pts and inhibition of the neoplastic clonogenic growth ex-vivo is demonstrated. The reduction in JAK2 V617F allele burden and cytokine-independent growth of CFU-Meg suggests that imetelstat has a relatively selective inhibitory effect on the growth of the neoplastic clone(s) which drive ET and has the potential to modify the underlying biology of MPNs. Additional data will be presented from this ongoing study. Disclosures: Baerlocher: Geron Corporation: Research Funding. Oppliger Leibundgut:Geron Corporation: Research Funding. Ayran:Geron Corporation: Employment. Blaney:Geron Corporation: Employment. Burington:Geron Corporation: Employment. Morfeld:Geron Corporation: Employment. Odenike:Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reddy:Geron Corporation: Employment. Roeth:Geron Corporation: Research Funding. Stuart:OncoMed Pharmaceuticals: Consultancy; Geron Corporation: Consultancy, Employment.

Clinical correlates of JAK2V617F allele burden in essential thrombocythemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7030-7030
Author(s):  
J. Kittur ◽  
R. A. Knudson ◽  
T. L. Lasho ◽  
C. M. Finke ◽  
N. Gangat ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Venous Thrombosis ◽  
Essential Thrombocythemia ◽  
Mutant Allele ◽  
Leukocyte Count ◽  
Hemoglobin Level ◽  
Thrombotic Complication ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

7030 Background: JAK2V617F occurs in approximately 50% of patients with essential thrombocythemia. Qualitative studies of mutation analysis have previously reported an association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count, and lower platelet count. A possible association with thrombotic complication has also been considered. Methods: Allele-specific, quantitative PCR analysis for JAK2V617F was performed on 176 patients with ET, using genomic DNA from archived bone marrow, which was collected within one year (n=72), between 1 and 5 years (n=64), or after 5 years (n=40) of diagnosis. Results: JAK2V617F was detected in 96 patients (55%), in whom mutant allele burden ranged from 1% to 100% (median 6.3%). Neither mutational frequency (p=0.37) nor mutant allele burden (p=0.62) was affected by the timing of bone marrow sample collection. Presence of JAK2V617F was significantly associated with higher hemoglobin level (p<0.0001), lower platelet count (p=0.001), higher leukocyte count (p=0.008), increased incidence of venous thrombosis occurring after diagnosis (p=0.02), and older age at diagnosis (p=0.03). All but age retained significance in multivariable analysis. In mutation-positive patients (n=96), JAK2V617F allele burden clustered between 1% and 22% in 94 cases, in whom it correlated directly and significantly with platelet and leukocyte counts, palpable splenomegaly at diagnosis, and venous thrombosis occurring after diagnosis. Conclusions: JAK2V617F allele burden imparts additional phenotypic effects in ET. No significant financial relationships to disclose.

Increased Thromboxane Biosynthesis in Essential Thrombocythemia

1995 ◽  
Vol 74 (05) ◽  
pp. 1225-1230 ◽  
Author(s):  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Raffaele Tartaglione ◽  
Sergio Cortelazzo ◽  
Tiziano Barbui ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Therapeutic Strategy ◽  
Low Dose ◽  
Thrombotic Risk ◽  
Dose Aspirin ◽  
Gender And Age ◽  
Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

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

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1409-1411 ◽  
Author(s):  
Peter J. Campbell ◽  
Cathy MacLean ◽  
Philip A. Beer ◽  
Georgina Buck ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasm ◽  
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.

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