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Myeloproliferative neoplasms - Clinical B1556 RECURRENT CEP85L-PDGFRB FUSION IN A PATIENT WITH A TRANSLO- CATION T(5;6) AND AN IMATINIB-RESPONSIVE MYELOPROLIFERATIVE NEOPLASM WITH EOSINOPHILIA N Winkelmann 1 , 2* , C Hidalgo-Curtis 1 , 3 , K Waghorn 1 , 3 , J Score 1 , 3 , H Dickin- son 4 , A Jack 5 , S Ali 6 , N Cross 1 , 3 1 Leukaemia Research Group , Wessex Regional Genetics Laboratory, Salis- bury, United Kingdom, 2 Klinik für Innere Medizin II , Universitätsklinikum Jena, Jena, Germany, 3 Faculty of Medicine, University of Southampton, Southamp- ton, 4 Cytogenetics Unit, St. James´s University Hospital, 5 Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, 6 Hull Royal Infirmary, Hull Royal Infirmary, Hull, United Kingdom Background: Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies and solid tumors. In BCR-ABL1-negative myeloproliferative neoplasms (MPNs) several different tyrosine kinase fusion events have been described, most com- monly involving the genes encoding the platelet-derived growth factor recep- tor alpha (PDGFRA) or beta (PDGFRB). Since the introduction of small mole- cule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Here, we present the case of a 45 year old male with persistent unexplained eosinophilia. A bone marrow aspirate and biopsy showed increased cellularity with myeloid expansion and marked eosinophilia without signs of monoclonal- ity. Cytogenetic analysis on a bone marrow aspirate revealed a 46,XY,t(5;6)(q3?3;q2?2). Aims: In this patient our objective was to investigate the underlying fusion gene of his translocation t(5;6) and if possible use it as a molecular marker during treatment. Methods: Break apart FISH using previously described in house probes demonstrated that PDGFRB at 5q33 was disrupted but ETV6-PDGFRB, the most common fusion involving this gene, was not detected by RT-PCR.Stan- dard Gold Taq Polymerase based PCRs were performed on cDNA and gDNA extracted from peripheral blood leukocytes. Sanger Sequencing was performed on cDNA and gDNA in forward and reverse. Peripheral blood samples were received from this patient at 7 different time points before and after treatment. Results: At the time of initial analysis no similar translocation had been report- ed and therefore the diagnostic investigations suggested the likely presence of a novel fusion involving PDGFRB and an unknown partner gene on chromo- some 6. Initial attempts at RACE-PCR were unsuccessful and hampered by lim- ited availability of suitable pre-treatment material. Subsequently, a novel C6orf204-PDGFRB (now known as CEP85L-PDGFRB) fusion was reported in a patient with T-cell acute lymphoblastic leukemia (T-ALL). Thus, we hypothe- sized that our patient may harbour the same or similar genetic defect. For the RT-PCR, a product was amplified from the patient with the t(5;6) but not con- trols which upon sequencing revealed an in frame cDNA fusion between exon 11 of CEP85L and exon 12 of PDGFRB. For gDNA, Sequencing showed the genomic fusion was between intron 12 of CEP85L and exonic sequence of PDGFRB exon 11 (Figure 1).Five months after the start of imatinib treatment neither the genomic nor the mRNA fusion was detectable by nested PCR or RT- PCR. CEP85L-PDGFRB remained undetectable in all subsequent samples with a follow up of over 3 years. Imatinib was continued without interruption dur- ing this time The sensitivity of the PCR assay to detect the CEP85L-PDGFRB- fusion gene was 10 -4 . Summary / Conclusion: Here, we report a recurrent CEP85L-PDGFRB fusion in a patient with eosinophilia and an MPN. The fusion was confirmed by spe- cific amplification of the genomic breakpoints and reverse transcription poly- merase chain reaction (PCR).The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB mRNA or genomic DNA, confirming a long term molecular remission on ima- tinib. In our view, the detection of the exact gene fusion is clinically relevant for effective long term management of these neoplasms as it enables specific fol- low up by sensitive molecular analysis. B1557 CLINICAL SIGNIFICANCE OF IMMATURE PLATELET FRACTION IN BCR- ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS N Vazzana 1* , R Spadano 1 , S Di Zacomo 2 , G Rolandi 3 , A Dragani 1 1 Department of Hematology, Centre for Hemophilia and Rare Blood Disorders, 2 Department of Transfusion Medicine, Molecular Biology Unit, 3 Department of Transfusion Medicine, Coagulation Unit, Pescara, Italy Background: Platelet activation plays a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPN)-associated throm- bosis. Evidence is mounting to support a potential usefulness of immature platelet fraction (IPF) measurement for vascular risk stratification in various thrombotic disorders. Aims: The aim of this study was to characterize the clinical and laboratory determinants of IPF in patients with BCR-ABL1-negative MPN. In addition, we investigated the association between IPF and previous thrombosis. Methods: One-hundred thirty-five patients have been studied. Sixty-one patients (45.2%) had ET, 25 (18.5%) PV, and 21 (15.6%) MPN-U. Among the 28 (20.7%) patients with myelofibrosis, 25 patients had PMF, while 3 patients had post-TE or post–PV myelofibrosis. Forty-eight patients had a history of previous thrombotic event, including arterial thrombosis (n = 31), venous throm- bosis (n = 14), or both (n = 3) events. Complete blood counts, including the measurement of IPF were performed in whole blood by the fully automated hematology analyzer XE-2100 (Sysmex). Results: In patients on cytoreductive therapy but not in untreated patients, IPF% was significantly higher in those with previous thrombosis than in non- thrombotic patients [2.4 (1.7-3.4) vs. 3.3 (2.4-5.1) %, P=0.011]. Similarly, in patients aged ≥ 60 years but not in younger patients, IPF% was significantly higher in those with previous thrombosis than in nonthrombotic patients [2.6 (1.8 -3.7) vs. 3.6 (2.4 - 5.2)]. In the entire population, a significant inverse correla- tion has been observed between platelet count and IPF% (Rho = - 0.23, P=0.008). In addition, in non-PV patients, IPF% was not significantly different between JAK2 V617F positive vs. negative patients. Multivariate logistic regres- sion showed that only male gender (odds ratio, 3.3; 95% CI, 1.4 to 8.0; P=0.007) and the upper tertile of IPF% (odds ratio, 3.7; 95% CI, 1.2 to 10.7; P=0.018) are independently associated with a history of previous thrombosis, after adjust- ing for age, hematocrit, white blood cell count, platelet count, cardiovascular risk factors, underlining diagnosis, JAK2 mutational status and cytoreductive ther- apy. Summary / Conclusion: We found that increased platelet turnover, as reflect- ed by high IPF%, is associated with a history of thrombotic events in patients with MPN. In addition, our data support the hypothesis that current antithrom- botic therapy might not specifically address this mechanism of thrombogene- sis. New prospective studies are warranted to evaluate the usefulness of incor- porating IPF% in risk stratification models to better identify patients at increased risk for thrombotic complications and/or treatment failure. B1558 DISEASE CHARACTERISTICS AND PERIPHERAL BLOOD CD34+ CELLS IN IDIOPATHIC MYELOFIBROSIS S Improta 1 , M Villa 1* , A Gagliardi 1 , C Tommasino 2 , G Fossati 2 , L Mastrullo 1 1 U.O.C. Ematologia, 2 U.O.C. Patologia Clinica, P.O. San Gennaro ASL Napoli 1 Centro, Napoli, Italy Background: Idiopathic Myelofibrosis (IMF) is chronic myeloproliferative neo- plasm characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interac- tion between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34+ cells between the bone marrow (BM) and the PB. Aims: IMF is associated with downregulation of CXCR4 by CD34+ cells due to epigenetic events. Altered gene expression was corroborated by the detec- tion of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IMF CD34+ cells. Moreover, endothelial precursor cells (CD34+/CD133+) are increased in the blood of a subset of patients with IMF, and peripheral endothelial cells bear the same molecular markers as hematopoietic cells, suggesting a primary role of pathological endothelial cells in this disease. Methods: We evaluated, by flow cytometry, the number of CD34 positive cells in peripheral blood and the expression of CXCR4, CD9, CD117 and CD133 on these cells. In our institution we are following 31 patients affected by IMF, according to WHO criteria (M: 18, F: 13; median age: 57 years, range: 48-68 haematologica | 2013; 98(s1) | 619 Stockholm, Sweden, June 13 – 16, 2013
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EHA17B1556 RECURRENT CEP85L-PDGFRB FUSION IN A PATIENT WITH A TRANSLO- CATION T(5;6) AND AN IMATINIB-RESPONSIVE MYELOPROLIFERATIVE NEOPLASM WITH EOSINOPHILIA N Winkelmann1,2*, C Hidalgo-Curtis1,3, K Waghorn1,3, J Score1,3, H Dickin- son4, A Jack5, S Ali6, N Cross1,3 1Leukaemia Research Group , Wessex Regional Genetics Laboratory, Salis- bury, United Kingdom, 2Klinik für Innere Medizin II , Universitätsklinikum Jena, Jena, Germany, 3Faculty of Medicine, University of Southampton, Southamp- ton, 4Cytogenetics Unit, St. James´s University Hospital, 5Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, 6Hull Royal Infirmary, Hull Royal Infirmary, Hull, United Kingdom
Background: Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies and solid tumors. In BCR-ABL1-negative myeloproliferative neoplasms (MPNs) several different tyrosine kinase fusion events have been described, most com- monly involving the genes encoding the platelet-derived growth factor recep- tor alpha (PDGFRA) or beta (PDGFRB). Since the introduction of small mole- cule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Here, we present the case of a 45 year old male with persistent unexplained eosinophilia. A bone marrow aspirate and biopsy showed increased cellularity with myeloid expansion and marked eosinophilia without signs of monoclonal- ity. Cytogenetic analysis on a bone marrow aspirate revealed a 46,XY,t(5;6)(q3?3;q2?2). Aims: In this patient our objective was to investigate the underlying fusion gene of his translocation t(5;6) and if possible use it as a molecular marker during treatment. Methods: Break apart FISH using previously described in house probes demonstrated that PDGFRB at 5q33 was disrupted but ETV6-PDGFRB, the most common fusion involving this gene, was not detected by RT-PCR.Stan- dard Gold Taq Polymerase based PCRs were performed on cDNA and gDNA extracted from peripheral blood leukocytes. Sanger Sequencing was performed on cDNA and gDNA in forward and reverse. Peripheral blood samples were received from this patient at 7 different time points before and after treatment.
Results:At the time of initial analysis no similar translocation had been report- ed and therefore the diagnostic investigations suggested the likely presence of a novel fusion involving PDGFRB and an unknown partner gene on chromo- some 6. Initial attempts at RACE-PCR were unsuccessful and hampered by lim- ited availability of suitable pre-treatment material. Subsequently, a novel C6orf204-PDGFRB (now known as CEP85L-PDGFRB) fusion was reported in a patient with T-cell acute lymphoblastic leukemia (T-ALL). Thus, we hypothe- sized that our patient may harbour the same or similar genetic defect. For the RT-PCR, a product was amplified from the patient with the t(5;6) but not con- trols which upon sequencing revealed an in frame cDNA fusion between exon 11 of CEP85L and exon 12 of PDGFRB. For gDNA, Sequencing showed the genomic fusion was between intron 12 of CEP85L and exonic sequence of PDGFRB exon 11 (Figure 1).Five months after the start of imatinib treatment neither the genomic nor the mRNA fusion was detectable by nested PCR or RT- PCR. CEP85L-PDGFRB remained undetectable in all subsequent samples with a follow up of over 3 years. Imatinib was continued without interruption dur- ing this time The sensitivity of the PCR assay to detect the CEP85L-PDGFRB- fusion gene was 10-4 . Summary / Conclusion: Here, we report a recurrent CEP85L-PDGFRB fusion in a patient with eosinophilia and an MPN. The fusion was confirmed by spe-
cific amplification of the genomic breakpoints and reverse transcription poly- merase chain reaction (PCR).The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB mRNA or genomic DNA, confirming a long term molecular remission on ima- tinib. In our view, the detection of the exact gene fusion is clinically relevant for effective long term management of these neoplasms as it enables specific fol- low up by sensitive molecular analysis.
B1557 CLINICAL SIGNIFICANCE OF IMMATURE PLATELET FRACTION IN BCR- ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS N Vazzana1*, R Spadano1, S Di Zacomo2, G Rolandi3, A Dragani1 1Department of Hematology, Centre for Hemophilia and Rare Blood Disorders, 2Department of Transfusion Medicine, Molecular Biology Unit, 3Department of Transfusion Medicine, Coagulation Unit, Pescara, Italy
Background: Platelet activation plays a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPN)-associated throm- bosis. Evidence is mounting to support a potential usefulness of immature platelet fraction (IPF) measurement for vascular risk stratification in various thrombotic disorders. Aims: The aim of this study was to characterize the clinical and laboratory determinants of IPF in patients with BCR-ABL1-negative MPN. In addition, we investigated the association between IPF and previous thrombosis. Methods: One-hundred thirty-five patients have been studied. Sixty-one patients (45.2%) had ET, 25 (18.5%) PV, and 21 (15.6%) MPN-U. Among the 28 (20.7%) patients with myelofibrosis, 25 patients had PMF, while 3 patients had post-TE or post–PV myelofibrosis. Forty-eight patients had a history of previous thrombotic event, including arterial thrombosis (n = 31), venous throm- bosis (n = 14), or both (n = 3) events. Complete blood counts, including the measurement of IPF were performed in whole blood by the fully automated hematology analyzer XE-2100 (Sysmex). Results: In patients on cytoreductive therapy but not in untreated patients, IPF% was significantly higher in those with previous thrombosis than in non- thrombotic patients [2.4 (1.7-3.4) vs. 3.3 (2.4-5.1) %, P=0.011]. Similarly, in patients aged ≥ 60 years but not in younger patients, IPF% was significantly higher in those with previous thrombosis than in nonthrombotic patients [2.6 (1.8 -3.7) vs. 3.6 (2.4 - 5.2)]. In the entire population, a significant inverse correla- tion has been observed between platelet count and IPF% (Rho = - 0.23, P=0.008). In addition, in non-PV patients, IPF% was not significantly different between JAK2 V617F positive vs. negative patients. Multivariate logistic regres- sion showed that only male gender (odds ratio, 3.3; 95% CI, 1.4 to 8.0; P=0.007) and the upper tertile of IPF% (odds ratio, 3.7; 95% CI, 1.2 to 10.7; P=0.018) are independently associated with a history of previous thrombosis, after adjust- ing for age, hematocrit, white blood cell count, platelet count, cardiovascular risk factors, underlining diagnosis, JAK2 mutational status and cytoreductive ther- apy. Summary / Conclusion:We found that increased platelet turnover, as reflect- ed by high IPF%, is associated with a history of thrombotic events in patients with MPN. In addition, our data support the hypothesis that current antithrom- botic therapy might not specifically address this mechanism of thrombogene- sis. New prospective studies are warranted to evaluate the usefulness of incor- porating IPF% in risk stratification models to better identify patients at increased risk for thrombotic complications and/or treatment failure.
B1558 DISEASE CHARACTERISTICS AND PERIPHERAL BLOOD CD34+ CELLS IN IDIOPATHIC MYELOFIBROSIS S Improta1, M Villa1*, A Gagliardi1, C Tommasino2, G Fossati2, L Mastrullo1 1U.O.C. Ematologia, 2U.O.C. Patologia Clinica, P.O. San Gennaro ASL Napoli 1 Centro, Napoli, Italy
Background: Idiopathic Myelofibrosis (IMF) is chronic myeloproliferative neo- plasm characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interac- tion between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34+ cells between the bone marrow (BM) and the PB. Aims: IMF is associated with downregulation of CXCR4 by CD34+ cells due to epigenetic events. Altered gene expression was corroborated by the detec- tion of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IMF CD34+ cells. Moreover, endothelial precursor cells (CD34+/CD133+) are increased in the blood of a subset of patients with IMF, and peripheral endothelial cells bear the same molecular markers as hematopoietic cells, suggesting a primary role of pathological endothelial cells in this disease. Methods:We evaluated, by flow cytometry, the number of CD34 positive cells in peripheral blood and the expression of CXCR4, CD9, CD117 and CD133 on these cells. In our institution we are following 31 patients affected by IMF, according to WHO criteria (M: 18, F: 13; median age: 57 years, range: 48-68
haematologica | 2013; 98(s1) | 619
Stockholm, Sweden, June 13 – 16, 2013
years). Results: In all patients, at diagnosis, we found a high count of CD34+ cells in PB (greater than 15x106/l; median:2,4x106/l, range:1,8-3,2x106/l) compared with normal controls and other Philadelphia-negative chronic myeloproliferative neoplasms. In all cases CD34+ cells were negative for CXCR4 while express- ing high intensity CD9. About 40% of CD34+ cells expressed CD133, while 20% expressed CD117 at low intensity. In no case was detected coexpression of CD133 and CD117, suggesting a simultaneous presence of two distinct hematopoietic progenitors, endothelial progenitors and myeloid progenitors. We monitored every 6 months the phenotypic pattern of CD34+ cells, and after 36-48 months we observed an increase of myeloid precursors (CD34+/CD117+: 45,7%) compared with a reduction of endothelial precursors (CD34+/CD133+: 15,3%) in patients who showed clinical and laboratory signs of disease progression. Summary / Conclusion: By comparing these findings with other clinical data, our results seem to confirm that, according to the natural history of disease from an initial stage towards a fibrotic phase (pancytopenia and/or splenomegaly), there was a change in PB CD34+ cells. Immunophenotypic profile of PB CD34+ cells is associated in IMF with patients’ clinical characteristics and may have potential prognostic application.
B1559 THROMBOTIC CEREBRAL EVENTS IN ESSENTIAL THROMBOCYTHEMIA C Cecchetti1*, A Aroldi1, M Riva1, E Pogliani1, E Elli1 1Hematology division, San Gerardo Hospital, Monza, Italy, Monza, Italy
Background: Patients with Essential Thrombocythemia (ET) are frequently asymptomatic and many remain so. Symptomatic patients tend to present with thrombotic manifestations in distinct locations. The thromboses are more com- monly arterial than venous. The thrombotic cerebral events (TCE) are rare, also if ET patients may present a wide spectrum of neurologic symptoms (NS) at onset or during the course of the disease, secondary to microvascular involve- ment Aims: We retrospectively described CTE occurred in 310 patients affected by ET referred in our centre from 1990 to 2012 in order to identify clinical and bio- logical features associated to these complications Methods: We analysed the incidence of TCE; in particular we evaluated the prevalence of JAK2V617F mutation in this setting and the possible role of JAK2 mutation in the management of CTE Results: 33/310 patients (10.6%) presented TCE. The average age of TCE patients was 71 years, with prevalence of female sex (21 vs. 12 patients). Only 4 patients were high risk for 2 o more cardiovascular factors (hypertension, dia- betes, obesity, dyslipidemia, smoking, thrombophilia). 54,5% of patients devel- oped CTE before diagnosis of myeloproliferative neoplasm (MPN), with a medi- an time of 16 months of latent phase of myeloproliferative disease prior to con- firmed diagnosis of ET. Of the 22 TCE preceding diagnosis, 18 were arterial events (8 transient ischemic attack, 9 strokes), only 2 events were venous (2 ocular thrombosis). 7 patients (21,2%) developed CTE as presentation of dis- ease. All these patients received anti-platelets treatment starting from throm- botic event. At time of diagnosis, cytoreductive therapy, mainly with hydrox- yurea, was started. Therefore, 11 patients (33,3%) developed TCE after diag- nosis of ET, despite of anti-platelet and cytoreduction, with 15% of patients (5/33) with recurrent neurological thrombosis. The blood count at diagnosis and at time of TCE was similar, in particular no leucocytosis or extreme thom- bocythemia were present. The median value of hematocrit, white blood cell count and platelets at time of CTE were 41%, 7.720/mm3 and 650.000/mm3, respectively. JAK2V617F mutation was evaluated in 30/33 patients, with sig- nificant prevalence of JAK2 positive versus negative patients (83,3% vs. 16,7%). All patients with recurrent CTE were JAK2 mutated. Overall, 91% of patients (30/33) are alive, with an average follow-up of 57,6 months Summary / Conclusion: we observed that 10,6% of ET patients presented CTE, with high prevalence (75,7%) of cerebral events as first presentation at time of diagnosis or as first sign of latent disease, for CTE antecedent to diag- nosis. The majority of cerebral events were arterial. Mostly of patientswere females and presented higher prevalence of JAK2V617F mutation. This may lead to the fact that, in selected cases of CTE, where there is evidence of lab- oratory signs suggestive of MPN, the detection of the JAK2V617F mutation pro- vides an early diagnosis of MPN. Moreover, a subgroup of patients (33,3%) developed CTE also after ET diagnosis and during antiplatelet and cytoreduc- tive treatment, with high risk of thrombotic CTE recurrence (15%). This seems to suggest that in this selected setting, an enhancement of thrombotic prophy- laxis could be proposed, for example with association of cytoreduction and anti-coagulant oral therapy, in presence of JAK2 mutation or other significant cardiovascular factors or thrombophilia predisposition
B1560 CHARACTERIZATION OF DIFFERENT REGIMENS FOR INTRODUCING SECOND-LINE ANAGRELIDE: RESULTS FROM A MULTICENTER STUDY OF 177 PATIENTS IN FRANCE J Rey1*, J Viallard2, K Keddad3, J Smith4, P Wilde4, J Kiladjian5 1Onco-Hematology, Paoli-Calmettes, Marseille, 2Service de Médecine Interne,
Hôpital Haut-Lévêque, Bordeaux, 3Shire, Boulogne-Billancourt, France, 4Shire Pharmaceuticals Ltd, Basingstoke, United Kingdom, 5Centre d’Investigation Clinique, Hôpital Saint Louis et Université Paris7, Paris, France
Background:Anagrelide (ANA) is indicated in the EU for at-risk patients (pts) with essential thrombocythemia (ET) and at least one of: >60 years; platelet count >1000x109/L; history of thrombo-hemorrhagic events; in whom prior ther- apy (PT) is not sufficiently effective or well tolerated. The Summary of Product Characteristics (SPC) recommends starting ANA at 1.0mg/day, in two divided doses and maintaining this dose for ≥1 week. Then the dose may be individu- ally titrated to achieve the lowest effective dose required to reduce and/or main- tain platelet count <600x109/L, ideally at 150–400x109/L. The dose increment must not exceed 0.5mg/day per week and 2.5mg is the maximum single dose. There is no recommendation on how to transition from PT to ANA. Aims: This observational study (NCT01192347) aimed to identify switch modal- ities used when introducing ANA and determine their influence on 6-month (mo) outcomes (including efficacy, tolerability and maintenance on ANA at 6 mo) in 44 clinical sites across France. Methods: Pts were enrolled within 1 mo of switching to ANA; up to 1 mo of ret- rospective data were collected. As this was a non-interventional study, dosing schedule and follow-up visits were at the investigator’s discretion. Pts were fol- lowed up for 6 mos. All relevant data were collected and recorded from pt records at the end of the follow-up. Results: In total, 177 pts were enrolled (safety set n=175), the majority were female (62%) and aged >60 years (76%). Median age was 70 years. Median baseline platelet count was 553x109/L. Intolerance to therapy (65%) and inef- ficacy (41%) were the most frequent reasons for treatment switch (factors not mutually exclusive). ANA starting doses ranged from 0.3–1.5mg/day. The SPCrecommended starting dose was used most frequently (53%). However a notable proportion of pts started on 0.5mg/day (41%). The median ANA dose at study end was 1.5mg/day (range 0.3–4.0mg/day). The method of ANA intro- duction was consistent with the SPC in 76% of pts. Almost all pts switched to ANA from hydroxycarbamide (93%). Most pts discontinued PT before ANA was introduced (66%; Group A). 22% discontinued PT after introduction of ANA (Group B; 17% within the first mo [Subgroup B1] and 5% in the subsequent 5 mos [Subgroup B2]). A further 9% had not discontinued PT by the end of the follow-up (Group C) and 5 pts (3%) were determined to have no PT. At the end of the follow-up, 85% of pts were still continuing on ANA, Groups: A (82%), B1 (93%), B2 (100%), C (81%). 71% of pts achieved platelet responses, Groups: A (67%), B1 (83%), B2 (100%), C (56%); 42% full response (<400x109/L) and 29% partial response (400–600x109/L or a reduction of ≥200x109/L). The medi- an final platelet count was 412x109/L and the absolute median change from baseline was -94.5x109/L. 75% of pts who received ANA in line with the SPC achieved platelet response vs 54% of those not consistent with the SPC. 46% pts reported adverse drug reactions (ADRs) all described in the SPC. The most frequent were palpitations (13%), headache (11%), diarrhea 6% and asthenia 6%. 17% pts discontinued ANA due to ADRs (mainly palpitations or headache). Summary / Conclusion: 85% of pts remained on ANA at the end of the 6-mo follow-up. ANA was introduced using the SPCrecommended dosing sched- ule in 76% of pts and 71% achieved platelet responses. Overall, ANA was well tolerated and the most frequent adverse events were in line with the SPC. Introducing ANA according to the SPC and subsequently withdrawing PT was associated with the highest platelet response rates. For the France Observatoire Xagrid (FOX) investigators.
B1561 RISK OF LIMPHOPROLIFERATIVE NEOPLASMS IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS S Cancio1*, G Soler1, J Miguel Torregrosa1, E Caparrós1, M Osma1, F Ortuño1, G Luengo-Gil1, V Vicente1, F Ferrer-Marín1 1Hematology and Clinical Oncology, Hospital Universitario Morales Meseguer, Murcia, Spain
Background: Over the last years, two large cohorts of patients have reported that chronic myeloproliferative neoplasms (cMPN) patients have a significant- ly higher risk of developing lymphoproliferative neoplasm (LPN) compared with the general population [1,14% (22/1915) and1,34% (11/820), respectively (Rumi, Haematologica 2011; Vannucchi, Cancer Epidemiol Biomarkers Prev 2009)]. In most cases, diagnosis of LPN was subsequent to the MPN one (91%), and only in 3 cases (9%) the diagnosis of LPN was synchronic or pre- vious to the MPN one. If any genetic susceptibility exists, a random order of onset of the myeloid or lymphoid neoplasm should be expected. Authors of these series attribute the low number of cMPN patients with a previous or con- current LPN due to a more aggressive behavior of lymphoid neoplasms, so these patients would die before cMPN develops. The molecular mechanisms underline the predisposition of cMPN patients to develop a LPN is not known. Aims: The aim of our study was to evaluate the frequency and time of onset of LPN in patients with cMPN in our health area, and to investigate if specific genetic marker for predisposition to cMPN may also contribute to the risk of developing LPN. Methods: All consecutive patients with newly diagnosed of cMPN in our unit between 2000 and 2011 were included in this study. Among 155 cMPN cases,
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18th Congress of the European Hematology Association
92 (60%) were diagnosed of essential thrombocitemia (ET), 37 (24%) of polycitemia vera (PV), 24 (15.5%) of myelofibrosis and 1 (0,5%) of systemic mastocytosis (SM) by using WHO criteria. In addition to carry out JAK2V617F, c-KIT (D816V) mutation analysis for the SM case, we performed mutational screening of hotspots: CBL (exons 8 and 9), ASXL1 (exon 12), N/K-RAS (exons 1 and 2), IDH1/2 (exon 4), TP53 (exons 4-10) and complete coding regions for RUNX1 and TET2. Mutation analysis was made by conventional Sanger sequencing. Results: Of the 155 patients included, 4 (2.6%) developed a LPN: in one of them, LPN onset was 2 years before PV whereas in the other 3 patients (2 TE and 1 SM), diagnosis of both neoplasms was simultaneous. All four cases were men over 60 years. Distribution of LPN cases was as following: 2 cases of CLL, both 0-A stage; 1 case of T-LGLL (TCR gamma/delta+), and 1 case of B- cutaneous non-Hodgkin lymphoma. This last patient was the only one who required treatment (CHOP-R and radiotherapy), whereas the rest of the patients remain in therapeutic abstention. In 2 of 3 patients with classic MPN, JAK2V617G mutation was detected, whereas the patient with SM presented the c-KIT mutation (D816V). We were not able to detect any additional mutation genes we had evaluated in patients with both myeloid and lymphoid neoplasms. Summary / Conclusion: Accordingly to previous studies, the risk of develop- ing a LPN in patients with cMPN is greater in men than women and no corre- lation with mutational status of JAK2 seems to underlie. By contrast, we did not find a higher incidence of LPN between patients with cMPN…