Cytoreductive Therapeutic Approach in the Essential Thrombocythemia (ET) Patients of the Registro Italiano Trombocitemia (RIT): Preliminary Data

Abstract Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p<0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p<0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p<0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p<0.001) and for HU (from 64 to 69 yrs, p<0.001) while it decreased for IFN (from 49 to 46 yrs, p<0.05). Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.

Download Full-text

Patients with Unexplained Thrombosis Require a Prompt Investigation to Search a Chronic Myeloproliferative Neoplasm (MPN), Even If Platelet Count Is <600x109/L. Analysis on 129 Patients from Registro Italiano Trombocitemie (RIT)

Blood ◽

10.1182/blood.v126.23.5181.5181 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5181-5181

Author(s):

Giulia Benevolo ◽

Alessandra Iurlo ◽

Gabriele Gugliotta ◽

Alessia Tieghi ◽

Gianluca Gaidano ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Advisory Committees ◽

Thrombotic Risk ◽

Cytoreductive Treatment ◽

Wbc Count

Abstract Background In patients with Ph-negative MPN, a prior thrombosis (PrTh) occurs in around 1/5 of cases, with variable platelet (PLT) count and variable distance from diagnosis. Objective To investigate the influence of PLT count at PrTh on diagnostic and therapeutic approach in MPN patients. Material and methods We evaluated 129 MPN patients from RIT, reclassified according to WHO 2008 criteria as ET (n70), initial-primary myelofibrosis (n29), early-PV (n10), and unclassifiable-MPN (n20). Results Patients, 60 males and 69 females, showed following PrTh: 91(71%) major arterial (37 AMI, 4 angina, 24 stroke, and 26 TIA); 12(9%) minor arterial; 22(17%) major venous (8 DVT, 7 splanchnic, 4 cerebral sinus, 3 pulmonary embolism); and 4(3%) minor venous events. PrTh occurred at a median distance of 4.1 months (range 0.1-118) from MPN diagnosis. This distance was >24 months in 21(16%) patients. At occurrence of PrTh, median age was 58 years. PLT count (x109/L) had a median value of 661 (range 150-2200), and was ≤450, 451-600, 601-700, 701-1000, and >1000 in 15(12%), 35(27%), 26(20%), 43(33%), and 10(8%) patients, respectively. Median white blood cell (WBC) count was 9.0 x 109/L and median hematocrit (HCT) value was 46% in males, and 41% in females. Median time (months) from PrTh to diagnosis of MPN was higher (p0.004) in patients with lower PLT count (x 109/L): ≤450 (50.2), 451-600 (11.7), 601-700 (2.7), 701-1000 (1.8), and >1000 (1.4). After occurrence of PrTh, all patients received conventional anti-thrombotic treatment, but in 7(5.4%) patients 9 recurrent thrombosis were reported before MPN diagnosis (11/100 pt-years). At MPN diagnosis, clonality was documented in 101(78%) patients (JAK2 V617F mutation in 96 cases, 74%). The age was >60 years in 61(47%) patients. PLT count (x109/L) had a median value of 720 (166-2440), and was ≤450 (n 7, 5%), 451-600 (n 21, 16%), 601-700 (n 28, 22%), 701-1000 (n 58, 45%), >1000 (n15, 12%). WBC count (109/L) had a median value of 8.9, and was >10 in 40 (31%) cases. Median HCT level (%) was 45.6 in males and 42.1 in females. Cardiovascular risk factors (CVRF), comorbidities and symptoms were documented in 103(80%), 97(75%), and 57(44%) cases, respectively. Thrombotic risk (IPSET-Th) was high in 97.5%, and intermediate in 2.5% of cases. All 129 patients received anti-thrombotic drugs (low dose aspirin in 95% of cases) and, immediately after the diagnosis, they started a cytoreductive treatment (hydroxycarbamide 89%, anagrelide 8%, interferon-alpha 3%). Patients with a PLT count (x109/L) at PrTh ≤600(n 50), as compared with those with a PLT count >600(n 79), showed a longer median time to the MPN diagnosis (16.7 vs 2.0 months, p<0.001). No significant difference was found in the rate of: arterial PrTh (80% vs 79.7%, p0.97); recurrence of thrombosis before the diagnosis (8% vs 4%, p0.69); JAK2 V617F mutation (80% vs 71%, p0.29); age >60 years (52% vs 44%, p0.39); CVRF (82%vs79%, p0.63); WBC >10 x109/L (23% vs 39%, p0.07); HCT high level [>47% in males, >44% in females](28% vs 36%, p0.37), and high thrombotic risk [IPSET-Th] (96%vs99%, p0.56). During follow-up (median 7.9 years) they showed a higher incidence of thrombosis recurrence (30%vs15%, p0.04; 4.5 vs 1.7/100 pt-y, p<0.01) Conclusion Time to MPN diagnosis was significantly longer in patients with PLT count (x109/L) at PrTh ≤600 vs >600, and this time to diagnosis was characterized by a not negligible thrombosis recurrence. Moreover, during follow-up they showed a higher incidence of thrombosis recurrence. This analysis strongly suggests that a PLT count <600 or even <450 x109/L, in patients with unexplained thrombosis, deserves the search of a probable MPN, in order to promptly start cytoreductive treatment in addition to a conventional anti-thrombotic therapy. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Clinical and Biological Features in Patients with Ph-Negative Chronic Myeloproliferative Neoplasm Showing Different Molecular Pattern. Comparative Study in 596 Patients of the Registro Italiano Trombocitemie (RIT)

Blood ◽

10.1182/blood.v126.23.4071.4071 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4071-4071

Author(s):

Luigi Gugliotta ◽

Alessandra Iurlo ◽

Gabriele Gugliotta ◽

Alessia Tieghi ◽

Giorgina Specchia ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Thrombotic Risk ◽

Biological Features ◽

Molecular Pattern ◽

Significant Difference ◽

Cytoreductive Treatment ◽

Wbc Count

Abstract Background. In patients with Ph-negative chronic myeloproliferative neoplasm (MPN) the molecular pattern, beside other characteristics at diagnosis, has been related to the disease prognosis. Aim. To compare clinical and biological features at diagnosis and during the follow-up in gender/age-matched MPN patients showing different molecular pattern. Material and methods. The Registro Italiano Trombocitemie (RIT) is a web-based registry that includes thrombocythemic MPN patients diagnosed according to PVSG or WHO criteria, registered after 2005, and then prospectically followed. The JAK2 V617F mutation (JAK2+) was reported in 941 (58.4%) out of 1610 tested patients. On the basis of subsequent tests, performed in part of the JAK2 WT (JAK2-) subjects, 103 patients were JAK2-/CALR+ (CALR+), 14 patients were JAK2-/CALR-/MPL+ (MPL+), and 46 were JAK2-/CALR-/MPL- (3NEG). The 103 CALR+ patients were compared with 309 (103 x 3) JAK2+ patients matched for gender, age, and revised diagnosis (WHO 2008 criteria). A similar comparison was done between 46 3NEG patients and other 138 (46 x 3) JAK2+ matched patients. Results. CALR+ and matched JAK2+ patients had, as expected, the same gender distribution (males 41%), the same median age (51 years), and no significant difference (p 0.42) in the WHO diagnosis distribution. CALR+ patients, as compared with JAK2+ patients, showed at diagnosis: higher median platelet (PLT) count (839 vs 718 x109/L, p<0.001); lower median white blood cell (WBC) count (7.3 vs 8.9 x109/L, p<0.001); lower median hemoglobin (Hb, 14.2 vs 14.8 g/dL in males, p 0.01; 12.9 vs 14.0 g/dL in females, p<0.001); lower median hematocrit (HCT, 42.4 vs 45.0 %, p 0.002 in males; 38.7 vs 42.2 in females, p<0.001); lower rate of low (<5) serum erythropoietin (0 vs 32%, p 0.003); lower rate of prior thrombosis (PrTh, 5/103, 4.9% vs 60/309, 19.4%, p<0.001), observed for both arterial and venous PrTh; lower rate of high/intermediate thrombotic risk (IPSET, 37% vs 55%, p 0.003). CARL+ and JAK2+ patients had the same rate of antiplatelet and cytoreductive treatment (96% vs 96%, and 86% vs 84%, respectively). During the follow-up the incidence of thrombotic and hemorrhagic events was not significantly different (1.3 vs 1.1/100 pt-years, and 1.0 vs 0.6/100 pt-years, respectively). Moreover, no significant difference was observed in the incidence of evolution to overt primary myelofibrosis (PMF, 0.76 vs 0.61/100 pt-years), polycythemia vera (PV, 0 vs 0.24/100 pt-years), and AL/MDS (0.08 vs 0.10/100 pt-years). Finally, the same overall survival was found after 5, 10. 15, and 20 years (99, 97, 94, 93%, respectively). 3NEG patients, as compared with JAK2+ matched patients, showed at diagnosis: lower median WBC count (7.9 vs 10.9 x 109/L, p 0.03); lower Hb and/or HCT level (p 0.006); lower rate of splenomegaly (7% vs 28%, p 0.003); lower rate of symptoms (35% vs 51%, p 0.049). No significant difference was found in: median PLT count (700 vs 720 x 109/L, p 0.61); PrTh (7% vs 16%, p 0.11); prior hemorrhage (4.7% vs 7.5%, p 0.52); high/intermediate thrombotic risk (IPSET, 36 vs 48%, p 0.37). Moreover, no significant difference was observed during the follow-up in: antiplatelet and cytoreductive treatment; thrombosis and hemorrhage rate; PMF, PV, and AL/MDS evolution; overall survival. Conclusion. CALR+ patients, as compared with JAK2+ matched patients, although showed a lower thrombotic risk (lower WBC and HCT levels, lower PrTh rate), received the same antiplatelet and cytoreductive treatment, had the same incidence of adverse events during the follow-up (vascular complications and disease evolution/transformation), and had the same overall survival. 3NEG patients, as compared with JAK2+ matched patients, showed results similar to those observed by comparing CALR+ and JAK2+ matched patients. To better define the role of the precise definition of molecular pattern in Ph-MPN patients, new prospective controlled studies seem necessary. Disclosures De Stefano: Janssen Cilag: Research Funding; Roche: Research Funding; Novartis: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Shire: Speakers Bureau. Passamonti:Novartis: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

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 ◽

Essential Thrombocythemia ◽

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.

Download Full-text

The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia

Blood ◽

10.1182/blood.v100.2.714 ◽

2002 ◽

Vol 100 (2) ◽

pp. 714-717 ◽

Cited By ~ 28

Author(s):

Luciana Teofili ◽

Francesco Pierconti ◽

Annalaura Di Febo ◽

Nicola Maggiano ◽

Nicola Vianelli ◽

...

Keyword(s):

Bone Marrow ◽

Expression Pattern ◽

Essential Thrombocythemia ◽

Staining Intensity ◽

Thrombotic Risk ◽

Significant Percentage ◽

Increased Risk ◽

Significant Difference ◽

Thrombotic Complications ◽

Strong Staining

Abstract Using immunohistochemistry, we investigated the expression of c-mpl in bone marrow megakaryocytes of 88 patients with essential thrombocythemia (ET), 6 patients with secondary thrombocytosis (ST), and 20 patients with lymphoma (controls). Considering both the pattern of expression and the staining intensity, we identified a uniform and a heterogeneous pattern of c-mplexpression. The uniform pattern was found in all the controls, all the patients with ST, and 28 of the patients with ET, with a strong staining intensity observed in most megakaryocytes (> 80%). In contrast, c-mpl expression was heterogeneous in 60 patients with ET, 18 of whom (30%) presented with thrombosis at diagnosis, a significant difference from patients with a uniform c-mpl pattern (2 of 28; 7%; P = .026). In particular, the overrepresentation of thrombotic complications in patients with a heterogeneous c-mpl expression pattern was found mainly among patients with a significant percentage (10% to 40%) of weakly stained or c-mpl–negative megakaryocytes (heterogeneous-weak pattern; 13 of 30; 43%;P = .002). Accordingly, this pattern was associated with a 6.1-fold increased risk of thrombosis compared with that of patients with a uniform c-mpl pattern. In conclusion, the presence of a heterogeneous pattern of c-mpl distribution in bone marrow megakaryocytes could be a useful diagnostic criterion in the differential diagnosis of thrombocytosis. Furthermore, detection of a significant percentage of weakly stained or c-mpl–negative megakaryocytes can identify patients with a higher risk of thrombosis.

Download Full-text

Novel Insights Regarding Pediatric Essential Thrombocythemia

Blood ◽

10.1182/blood-2019-123865 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4191-4191

Author(s):

Assaf Arie Barg ◽

Gili Kenet ◽

Tami Livnat ◽

Gal Goldstein ◽

Joanne Yacobovich ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Data ◽

Essential Thrombocythemia ◽

Research Funding ◽

Complete Blood Count ◽

Myeloproliferative Neoplasm ◽

Bone Marrow Biopsies ◽

Acquired Von Willebrand Syndrome ◽

Von Willebrand

Background: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm. As it is extremely rare in children, data regarding its clinical course are scarce and pediatric treatment guidelines are lacking. Aim: To evaluate diagnosis, treatment and clinical outcome in a group of pediatric ET patients. Methods: Medical files of all pediatric patients (age 0-18 years) diagnosed with ET between January 2010 and February 2019 in three tertiary hospitals were reviewed. Study was approved by all institutional ethics committees. Diagnosis was established according to the WHO criteria of ET. All patients had undergone bone marrow biopsy (BMB) and molecular evaluation for JAK2V617F. Patients with wild type JAK2V617F were also tested for JAK2 exon 12 mutation, calreticulin (CALR) mutations and thrombopoietin receptor (MPL) mutation. Complete blood count parameters at first evaluation and follow up were collected. Lag in diagnosis, defined as the period between the time at which thrombocytosis was first noticed until diagnosis of ET was documented. Patients were evaluated for acquired von Willebrand syndrome (AVWS) by testing for von Willebrand antigen level and activity. Clinical data included any adverse events particularly those related to thrombosis or bleeding. Initial treatment strategies and any need for therapy modifications were recorded. Results: Twelve children (5 males and 7 females) followed for a median time of 27.5 months (range 4-108 months) were included. Table 1 displays their demographic and clinical data. Family history of thrombocytosis was negative in all patients. Median age at which thrombocytosis was first noted was 8 years (range 1-14.5 years). In 5/12 patients thrombocytosis was detected as an incidental finding. In 7/12 patients CBC was performed due to symptoms including headache, visual disturbances, seizure and acroparesthesia (table 1). Patients who suffered from neurological symptoms had undergone cranial MRI; all were interpreted as normal. The mean lag period between the time in which thrombocytosis was first noted until diagnosis of ET was 36 months (range: 0.1-120 months). Molecular diagnosis yielded 5/12 patients who were positive for JAK2V617F, one patient with a JAK2 exon 12 mutation and 2/12 patients with mutations involving CALR (one with type 1 and one with type 2 mutation). No subjects with CMPL mutation were detected. Four children tested negative for all mutations. Bone marrow biopsies were compatible with ET and no chromosomal aberrations were identified in our cohort. Evaluation for AVWS was performed in nine of the panties. It was diagnosed in 67% of assessed patients. Median VWF:Rco/VWF:Ag 0.18 (range: 0.01-0.76). At diagnosis treatment with Aspirin was initiated in 4/12 patients. Cytoreductive therapy with Hydroxyurea was added at diagnosis in 2/4 patients, both symptomatic at presentation. One Patient underwent plateletpheresis at presentation due to severe headache and extreme thrombocytosis. In 3/8 untreated patients, therapy was added during follow up, with either Aspirin (n=1, due to increased severity of headaches and raising platelet count) or Hydroxyurea (n=2, following TIA). During follow up period neither leukemia nor myelofibrosis evolved in our cohort. One patient developed a provoked DVT, secondary to a femoral CVL. Three patients experienced TIA during study period. Two females experienced excessive bleeding (heavy menstrual bleedings and bleeding due to a raptured corpus luteum), both diagnosed with AVWS. Conclusions: Our study suggests that pediatric hematologists should increase awareness to ET as delayed diagnosis is common. Among children with ET, AVWS may be more prevalent as compared to adults and may increase the risk of bleeding. Further collaborative multicenter studies are required for robust data collection and may facilitate future ET treatment in children. Table 1 Disclosures Kenet: Alnylam: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Opko Biologics: Consultancy, Honoraria, Research Funding; BPL: Research Funding. Steinberg Shemer:Emendo bio: Consultancy. Revel-Vilk:Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding.

Download Full-text

Essential Thrombocythemia: A Comparison of Overall and Thrombosis Free Survival in Two Discrete Periods of the First Decade of 2000. a Retrospective Analysis

Blood ◽

10.1182/blood.v128.22.5469.5469 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5469-5469

Author(s):

Marco Montanaro ◽

Ambra Di Veroli ◽

Marianna De Muro ◽

Cristina Santoro ◽

Massimo Breccia ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Alkylating Agents ◽

New Drugs ◽

Free Survival ◽

Group I ◽

Significant Difference ◽

Chi Squared ◽

Patients At Risk ◽

Wbc Count

Abstract To evaluate the prognosis of patients with Essential Thrombocythemia (ET) in the first decade of the century we assessed retrospectively the thrombosis free survival (TFS) and the overall survival (OS) of the patients diagnosed from 01/01/2000 to 31/12/2009 and collected in the database of our group. The diagnosis of ET was performed with PVSG, WHO 2001 or WHO 2008 criteria, according to the period of the first observation. The whole population of 757 patients was then divided in two groups: the first (group I) with the diagnosis performed between 01/01/2000 to 31/12/2005 (334 patients) with a median follow-up of 111,9 months, the second (group II) diagnosed between 01/01/2006 to 31/12/2009 (385 patients) with a median follow-up of 58,2 months. The main clinical features of the two groups of patients are reported in the Table 1. No difference was observed between the two groups as to age, gender, platelet and WBC count, Hb level, Cardio-Vascular Risk Factors (CVRF), spleen enlargement and occurrence of previous thrombotic events. The frequency of the JAK-2 V617F mutation resulted significantly different (49.1% vs 68.4%) but in the group I the search of the mutation was never performed at the diagnosis. The TFS and OS were calculated from the date of diagnosis to the date of any appropriate event or to the date of last follow-up with Kaplan-Meier product limit method; the comparison of proportions and median values was computed with the Chi-squared and the Mann-Withney tests, as indicated. No significant difference emerged neither for TFS (p= 0,09, HR 1,42, 95% C.I. 0.89-2.30) nor for OS (p= 0,15, HR 1,34, 95% C.I. 0,87-2,06). We also considered the type of treatment used in the two groups to assess the potential link between the therapy and TFS or OS. No difference emerged between the two groups as to anti-aggregating treatment (mainly ASA), equally utilized in both groups [287/369, 77,8%, and 330/383, 78,3%, respectively (p = 0,95)]. As for the cyto-reductive therapy, Hydroxyurea was used in 74.8% vs 67.9% (p= 0.60) and alkylating agents in 1.9% vs 2.1% (p= 0.85), whereas Anagrelide was used in 10,6% vs 3,9% (p= 0,001) and Interferon in 9,5% vs 5,2% (p= 0,037), respectively. This more frequent use of Anagrelide and Interferon in the first group (2000-2005) did not modify TFS and OS of the patients. In conclusion, no improvement was observed in the prognosis of ET patients in the recent years: thus, new efforts to identify patients at risk and the introduction of new drugs as JAK-2 inhibitors are warranted to improve the prognosis of these patients. Table Table. Disclosures Breccia: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria. Lo Coco:Pfizer: Consultancy; Baxalta: Consultancy; Novartis: Consultancy; Lundbeck: Honoraria, Speakers Bureau; Teva: Consultancy, Honoraria, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Download Full-text

Molecular and Clinical Features of the Myeloproliferative Neoplasm Associated with JAK2 Exon 12 Mutations: a European Multicenter Study.

Blood ◽

10.1182/blood.v114.22.3904.3904 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3904-3904 ◽

Cited By ~ 2

Author(s):

Francesco Passamonti ◽

Susanne Schnittger ◽

François Girodon ◽

Jean-Jacques Kiladjian ◽

Mary Frances McMullin ◽

...

Keyword(s):

Polycythemia Vera ◽

Clinical Features ◽

Conflicts Of Interest ◽

Collaborative Study ◽

Myeloproliferative Neoplasm ◽

Jak2 V617f ◽

Female Ratio ◽

Significant Difference ◽

Wbc Count

Abstract Abstract 3904 Poster Board III-840 While about 95% of patients with polycythemia vera carry the unique V617F mutation in JAK2 exon 14, several mutations in exon 12 have been described in the minority of JAK2 (V617F)-negative subjects. The initial study [N Engl J Med 2007 Feb 1;356(5):459-68] led to the conclusion that JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis. Very recent studies suggest that the 'GGCC' haplotype of JAK2 confers susceptibility to the somatic acquisition of both JAK2 (V617F) and exon 12 mutations [Nat Genet 2009 Apr;41(4):450-4, Leukemia 2009 May 14, Epub ahead of print]. Indeed, we reported pedigrees with familial polycythemia vera in which there were both JAK2 (V617F)-positive and JAK2 exon 12 mutation-positive siblings [Blood 2008 Feb 1;111(3):1686-9]. The myeloproliferative neoplasm associated with JAK2 exon 12 mutations is a rare disorder, and only small groups of patients have been reported so far by various investigators. We therefore started a collaborative study in Europe with the aim of collecting about 100 patients with this condition in order to define the molecular and clinical features of this myeloproliferative neoplasm. An ad hoc database was developed for data collection and management. As of August 1, 2009, 77 patients with the required clinical and hematologic data at diagnosis have been recruited (median follow-up 3.2 years, range 0-27 years), while complete follow-up information was available for 57 of these patients. Various approaches were employed for the detection of JAK2 exon 12 mutations, including genomic DNA sequencing, allele-specific PCR assays, and high resolution melting. Overall, 16 different exon 12 mutations were identified. The most frequent mutation were N542-E543del (26 patients), K539L (12 patients), R541-E543delinsK (6 patients), and F537-K539delinsL (6 patients); the remaining mutations occurred less frequently. With respect to the clinical phenotype at presentation, the Kruskal-Wallis test did not reveal any significant difference between the above most frequent mutations. Median age at diagnosis was 53 years (range 15-92), and the male/female ratio was 43/34. Mean hemoglobin level was 19.3 ± 2.2 g/dL, mean WBC count 8.5 ± 3.2 × 109/L, and mean PLT count 334 ± 197 × 109/L. Overall, 48 out of 77 (62%) patients presented with isolated erythrocytosis, 12 (16%) with erythrocytosis and leukocytosis (WBC count > 10 × 109/L), 8 (10%) with erythrocytosis and thrombocytosis (PLT count > 400 × 109/L), and 8 (10%) displayed a full myeloproliferative pattern (erythrocytosis, leukocytosis and thrombocytosis). Serum erythropoietin level was below the lower normal limit in 46 out of 58 (79%) patients. Twenty-one of 25 (84%) patients had endogenous erythroid colonies. During follow-up, two patients had deep venous thrombosis, two progressed to post-polycythemia vera myelofibrosis (diagnosed according to the IWG-MRT criteria) and two developed a myelodysplastic syndrome. In conclusion, the available data indicate that the myeloproliferative neoplasm associated with JAK2 exon 12 mutations is mainly associated with isolated erythrocytosis at clinical onset, but also suggest that the subsequent clinical course may be similar to that of JAK2 (V617F)-positive polycythemia vera, at least in a portion of patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

V617F JAK2 Mutation and Bone Marrow Fibrosis Define Subgroups Of Patients With Polycythemia Vera and Essential Thrombocythemia With Shared Clinicobiological Profiles

Blood ◽

10.1182/blood.v122.21.5268.5268 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5268-5268

Author(s):

Panagiotis Baliakas ◽

Vassiliki Douka ◽

Michalis Iskas ◽

Tasoula Touloumenidou ◽

Angeliki Paleta ◽

...

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Jak2 V617f ◽

Age At Diagnosis ◽

Advanced Age ◽

Jak2 V617f Mutation ◽

Hydroxyurea Treatment ◽

V617f Mutation ◽

Wbc Count

Abstract The JAK2 V617F mutation is of high diagnostic value in the evaluation of myeloproliferative neoplasms (MPN) as it helps to document clonality; in addition, it may also predict for response to hydroxyurea treatment. According to recent studies, the presence of bone marrow (BM) fibrosis at diagnosis may be associated with the clinical evolution of MPNs, in particular development of secondary acute myeloid leukemia (AML) or transformation to myelofibrosis (MF), however the underlying mechanisms remain unknown. In this study we characterized in detail subgroups of patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) carrying the JAK2 V617F mutation (M-JAK2) or displaying BM fibrosis at diagnosis with the ultimate aim of identifying potential associations and/or overlapping phenotypes. The present single-institution patient cohort included 118 cases diagnosed according to WHO 2008 criteria. Patient characteristics were as follows: (i) Diagnosis: PV/ET, 37/82; (ii) Gender: male/female, 58/60; (iii) median age at diagnosis: 59.8 years (range, 25-90). M-JAK2 was detected in 86/118 (72.9%) cases [PV: 32/37 (86.5%) - ΕΤ: 54/82 (65%)]. BM fibrosis was observed in 28/112 (25%) cases [PV: 10/34 (29.4%), ΕΤ: 18/78 (23%)], grade I in 24/28 (85%) cases and grade II in 4 cases (all with ΕΤ). Thirteen patients without BM fibrosis at diagnosis underwent a second BM biopsy at a median time of 4.7 years (range, 1-10): BM fibrosis was observed in 5/13 (38.4%), 4 carrying M-JAK2, of whom only one had received anagrelide before the second BM biopsy. With a median follow up of 6 years (range 1-10), one of these five patients developed AML. There was no statistically significant association between M-JAK2 and BM fibrosis at diagnosis, neither in the entire cohort, nor in each MPN (ET or PV) separately. In PV: (i) M-JAK2 was significantly (p<0.05) associated with advanced age at diagnosis, increased hemoglobin levels (Hb) and white blood cell (WBC) count at diagnosis; (ii) the presence of BM fibrosis demonstrated a strong trend for correlation with increased platelet counts at diagnosis (p=0.08). In ΕΤ: (i) M-JAK2 was significantly (p<0.05) associated with advanced age at diagnosis, splenomegaly, increased WBC count and Hb levels at diagnosis, and increased incidence of thrombotic events (12/54 versus 1/28); (ii) BM fibrosis was correlated with increased WBC and platelet count at diagnosis. Neither M-JAK2 nor BM fibrosis were correlated with increased incidence of hemorrhagic events, development of secondary AML or the presence of other concurrent malignancy. Furthermore, neither of these two parameters had any impact on overall survival, it has to be noted though that patients were not treated uniformly. In conclusion, the present analysis did not document a statistically significant correlation between M-JAK2 and BM fibrosis. Nonetheless, the clinicobiological similarities of patient subgroups defined by either of these parameters, as well as the increased incidence of BM fibrosis in sequential BM samples amongst M-JAK2 patients are suggestive of common pathogenetic mechanisms. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Extramedullary Hematopoiesis and Splenic Vein Thrombosis, a Unique Presentation Of Pre-Clinical Essential Thrombocythemia

Blood ◽

10.1182/blood.v122.21.5257.5257 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5257-5257 ◽

Cited By ~ 1

Author(s):

Abdulraheem Yacoub ◽

Abigail Brockman

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Liver Biopsy ◽

Essential Thrombocythemia ◽

Extramedullary Hematopoiesis ◽

Common Finding ◽

Thrombotic Risk ◽

Vein Thrombosis ◽

Life Threatening

Abstract Essential thrombocythemia (ET) is of the BCR-ABL-Negative myeloproliferative neoplasms (MPN). The incidence of ET is approximately 2.5 in every 100,000 person per year. However, given the good prognosis, associated long life expectancy, and increasing detection in younger populations,ET is associated with a higher prevalence rate estimated to be 24 in every 100,000 person per year. ET is characterized by thrombocytosis, vasomotor symptoms, and a variable but increased risk of thrombosis and bleeding. Half of all ET patients will have a positive JAK2 and/or MPL mutation(s). Extramedullary hematopoiesis (EMH) is not a common finding in ET. Nonetheless, ET and other MPNs are associated with the mobilization of CD34+ cells into the peripheral blood. This process can ultimately lead to the seeding of extramedullary sites with primitive hematopoietic capacity, resulting in EMH within the spleen and liver, as well as a variety of other organs. Herein we describe a case that presented with life-threatening thrombosis and was found to have hepatic EMH several months prior to a clinical and pathologic diagnosis of ET. Case description A 22 year-old woman presented 10 days post Cesarean section with abdominal pain and hematemesis. Abdominal imaging showed hepatomegaly, splenomegaly, along with splenic and portal vein thrombosis. The patient underwent an emergency surgical splenectomy due to severe portal hypertension and endoscopic evidence of gastric variceal bleeding. A random liver biopsy was also performed intra-operatively. The splenectomy resulted in resolution of the GI bleeding and the varices normalized on follow up. Her platelet count was normal at the time of operation, but post-splenectomy her platelet count peaked at 1,217 K/ µL. Extensive testing did not unravel any identifiable inherited and/or acquired hypercoaguable factors. Subsequently anticoagulation therapy was recommended for 6 months. On pathology review, the spleen histology showed congestion, but otherwise no diagnostic abnormalities were noted. The liver biopsy showed evidence of EMH but did not identify any liver parenchymal disease. On subsequent follow up, the patient had persistent and marked thrombocytosis for over a year. A bone marrow biopsy was performed which showed a hypercellular bone marrow and megakaryocytic hyperplasia with a few large forms. There was no dysplasia or significant reticulin fibrosis. JAK2 mutation and BCR-ABL translocation were negative. Hydroxyurea and aspirin were started due to high risk of thrombosis. Discussion We report this unique case in which there was evidence of extramedullary hematopoiesis, along with pathologic and life threatening visceral thrombosis several months before the patient met criteria for diagnosis of ET. This supports the notion that neoplastic cells can mobilize and seed other organs early in the course of MPNs, including ET. Thrombotic risk in MPNs can also occur in the preclinical phase of MPNs as has been suggested in other reports. We also conclude that the demonstration of EMH in individuals with no preexisting hematologic neoplasm should warrant close follow up and assessment. Disclosures: No relevant conflicts of interest to declare.

Download Full-text