Leukocyte Count Defines Patients on Risk for Thrombotic Complications with Well Controlled Essential Thrombocythemia- Data from a Patient- Registry

Abstract There is compelling evidence that white blood cell (WBC) counts impact the risk of thrombosis in patients with myeloproliferative neoplasms (MPN) (Barbui Blood 2013). Moreover, recent publications disclosed significant differences regarding certain disease characteristics and the course of disease in WHO 2008 (Tefferi Blood 2007) classified essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (PMF) (Kvasnicka Am J Hematol 2008; Barbui JCO 2011; Buxhofer-Ausch Am J Hematol 2012). Hence, patients cohorts classified prior to WHO 2008 may likely consist of a mix of patients with ET and prefibrotic PMF. We aimed to reproduce the influence of WBC counts on the thrombotic risk in patients under real-life conditions. Therefore we assessed data of 825 Austrian patients from a patient registry for anagrelide in ET that was initiated 2001 in Austria due to an official authorities demand and is now being maintained in several Central European countries. Efficacy of treatment was assessed by investigating the course of platelet counts and event free survival relating to the first minor or major thrombotic event. WBC counts from the first available time points were correlated with the first thrombotic event. The cut off for the WBC subgroup analysis was set at 8,5 G/l. Statistical analysis was performed using the open-source R statistical software package, version 3.0.2. Non-parametric two-sided 95% confidence intervals for medians were calculated. Survival probabilities were assessed by applying the Kaplan-Meier method. For the comparison of time to event between the leukocyte- specific subgroups the log-rank test was used. Median Follow up of the study cohort is 3,07 years. Platelet count at start of anagrelide was median 777 G/l (95% CI 757-803). After 12, 24 and 36 months patients presented with median platelet counts of 473, 457 and 438 G/l, respectively. Median WBC count at start of therapy was 9 G/l (95% CI 8,7-9,3) and after 12, 24 and 36 months 8,5 G/l, 9,2 G/l and 8,7G/l, respectively. Incidence of thrombotic events per 100 patient- years was 5,14 for all events and 1,65 for major events only. 102 patients experienced at least one minor or major thrombotic event (major events n=36). Median time to the first minor or major thrombotic event was 1,27 years. Probability of event free survival at 1 year is 94,4% and at 3 years 87,6%. Patients with a baseline WBC count of higher than 8,5 G/l exhibit a significantly shorter probability of event free survival than patients below the cut off (p= 0,007 for all thrombotic events; p= 0,026 for major events only). This data proof the efficacy of anagrelide in lowering platelet counts and reducing significantly the risk of thrombotic events in patients with ET. The significantly shorter event free survival of patients with a WBC count above 8,5 G/l confirms earlier studies for the first time in a real-life setting. This result emphasizes the separation of true ET from prefibrotic PMF by using the WHO 2008 classification. Moreover, further investigations are needed to assess, whether a correlation of certain platelet and leukocyte counts modifies the risk of thrombotic events in MPN. Disclosures Schloegl: AOP Orphan Pharmaceuticals AG: Research Funding.

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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.

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Long-Term Experience with Anagrelide (Thromboreductin®) In the Treatment of Essential Thrombocythemia: Data from an International Registry

Blood ◽

10.1182/blood.v116.21.5064.5064 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5064-5064

Author(s):

Michael Steurer ◽

Heinz Gisslinger ◽

Miroslav Penka ◽

Siegfried Sormann ◽

Jiri Schwarz ◽

...

Keyword(s):

Clinical Trials ◽

Essential Thrombocythemia ◽

Real Life ◽

Orphan Drugs ◽

Patient Registry ◽

Bleeding Events ◽

Platelet Counts ◽

Life Conditions ◽

Term Data

Abstract Abstract 5064 Background: In 2001 Thromboreductin® was registered in Austria as the first EU country for the treatment of Essential Thrombocythemia (ET). Due to the low incidence of ET authorities demanded to establish a patient registry to evaluate safety and efficacy of anagrelide in the long-term treatment of ET. Following market authorization in several EU countries the patient registry is now being maintained in 10 Central European countries. Whereas most clinical trials have only a relatively short follow-up, a patient registry is able to provide long-term data. Patients and Methods: This multinational, multi-center post-marketing observational registry is conducted to assess long-term efficacy and safety of anagrelide in patients with ET under “real-life” conditions. The clinical information is entered into the registry by the treating physicians. Besides relevant clinical data such as risk factors, past thrombotic as well as bleeding events, disease symptoms classified as “major” and “minor” events and previous ET therapies including anticoagulation, laboratory values including renal and liver function parameters as well as blood counts are monitored regularly. Results: This evaluation of the Thromboreductin® Patient Registry database includes 1572 ET patients (median age: 59 years), 1059 (67%) were women and 513 (33%) were male patients; 62% of patients were pretreated with cytoreductive agents, 38% were treatment naïve. The median observation period was 1.9 years (range: 7 days – 10 years), with 168 patients (11%) being followed for at least 5 years. Treatment with anagrelide lowered the platelet count from a median of 742 × 109 /l (95%CI 717/757) to a median of 415 × 109 /l (95%CI, 397/435). Eighty-four percent of patients achieved platelet counts < 450 × 109 /l, no differences between pretreated (85%) and treatment-naïve /82%) patients were observed. During the 3464 patient years (PY) included in this evaluation a total of 338 ET-related events (including both thrombotic and bleeding events) were reported of which 102 (2,9% per PY) were considered as “major”. Of the 220 patients with a history of ET-related events, 178 patients (81%) have so far remained event-free under anagrelide therapy. Adverse effects were lower than those previously reported in clinical trials with headache, palpitations and diarrhea being the most frequent side effects (all < 3%) leading to treatment discontinuation in 43 patients (2,7%). No new toxicities have been observed. Conclusion: We consider anagrelide to be safe and effective in terms of lowering platelet counts and reducing disease-related events in unselected ET patients treated outside clinical trials under “real-life” conditions. Based on our favourable long-term data we suggest that anagrelide may be considered a first-line agent in the management of ET. Disclosures: Steurer: AOP Orphan Drugs: Honoraria. Petrides:AOP Orphan Drugs: Consultancy.

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Influence of Platelet and White Blood Cell Counts until Major Thrombosis: Analysis from a Patient Registry in Essential Thrombocythemia

Blood ◽

10.1182/blood.v126.23.2814.2814 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2814-2814

Author(s):

Veronika Buxhofer-Ausch ◽

Michael Steurer ◽

Siegfried Sormann ◽

Ernst Schloegel ◽

Wolfgang Schimetta ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Research Funding ◽

Who Classification ◽

Thrombotic Event ◽

Youden Index ◽

Thrombotic Risk ◽

Cox Regression Analysis ◽

Platelet Counts ◽

Cell Counts ◽

The Impact

Abstract Retrospective studies could not proof a correlation of elevated platelet counts at diagnosis with thrombotic events. However, randomized and prospective clinical studies on platelet lowering therapies justify recommendations for the normalization of platelet counts as an appropriate endpoint for treatment in high-risk essential thrombocythemia (ET). Furthermore, there is increasing evidence that leukocytosis is an important risk factor for arterial thrombosis, especially in WHO classified ET. Leukocytosis is even more pronounced in prefibrotic primary myelofibrosis (PMF) compared to WHO classified ET. Patient cohorts that were diagnosed prior to the WHO classification likely consist of a mixture of ET and prefibrotic PMF. Some authors suppose interplay between white blood cells (WBC) and platelets in patients with myeloproliferative diseases. The current study considers the Austrian cohort of a European registry, which was established to document the efficacy of the platelet-lowering therapeutic anagrelide in myeloproliferative neoplasms. Out of 845 patients, only those with a confirmed diagnosis of ET according to the PVSG classification until 2001 or according to the WHO classification thereafter were included in the analysis. Median follow up of the 620 included patients is 3.1 years (range 1.21-5.73 years), corresponding to 2428 patient years. 418 patients (67%) were females and the median age at study entry was 62 years (range 51-72 years). Thirty four patients (5.5%) experienced at least one major arterial or venous event until data analysis corresponding to 1.40 events per 100 patient years. The influence of platelet and WBC counts on thrombotic risk was assessed by correlating the first major thrombotic event with the median of all blood counts recorded during the course of the disease until an event or until end of observation. The median platelet counts until the first event occurred and until end of observation (in patients without an event) were 595.8 G/l (range 495.0-743.0 G/l) and 500.0 G/l (range 410.5-619.5 G/l), respectively, and thus were substantially different (p= 0.008). The median WBC counts until the first event occurred and until end of observation (in patients without an event) were statistically not different but might indicate a trend with 9.60 G/l (range 8.70-10.95 G/l) and 8.42 G/l (range 7.05-10.70 G/l), respectively (p=0.084). By using the calculated (Youden index) cut offs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of platelets (p= 0.008) as well as WBC counts (p= 0.011) above the cut offs until the time to a major event. Interestingly, in this analysis, the influence of higher platelet counts on major thrombotic events was more pronounced than that of higher WBC counts. The frequency of major events per 100 patient years was highest when both platelet and WBC counts ranged above the calculated cut offs and was substantially different from the frequency when both, platelet and WBC counts ranged below the cut offs (3.05 vs. 1.4, p<0.001). In conclusion, our data add evidence to the impact of elevated platelet as well as elevated WBC counts on the time until a thrombotic event and on the frequency of thrombosis in ET. Moreover, we suspect a particular interaction between platelets and WBC which might not only be the result of simple addition of risk but might rather be based on biological interplay. We speculate that this interaction depends on particular cell counts of platelets and WBC which will need to be defined. Disclosures Buxhofer-Ausch: AOP Orphan: Research Funding. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

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Is It Better to Treat Adolescents with Acute Lymphoblastic Leukemia as Old Children or as Young Adults?

Blood ◽

10.1182/blood.v112.11.3968.3968 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3968-3968 ◽

Cited By ~ 1

Author(s):

Marta Alves ◽

Liane Daudt ◽

Karina L. M. Mazzucco ◽

Adriano Taniguchi ◽

Tiago Nava ◽

...

Keyword(s):

Overall Survival ◽

Young Adults ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Poor Risk ◽

Wbc Count

Abstract PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. PATIENTS AND METHODS: From January 1997 to December 2007, 34 and 11 adolescents (10 to 20 years of age) were treated according to German pediatric BFM 90 and 95 and adult BFM 84 protocols, respectively. Age, B/T lineage, WBC count, complete remission, cytogenetics, and response to steroids were analyzed. Age, B/T lineage and WBC count were similar. Poor risk-cytogenetics (t (9;22),t(4;11) and hypodiploidy less than 45 chromosomes were present only in BFM 90 and 95 group. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving overall survival (OS) and event-free survival (EFS). RESULTS: OS in 10 years and EFS was, respectively, 68.6% and 68.7% for the pediatric protocol and 31.4% and 21.6% for the adult protocol. CONCLUSION: This study’s findings were similar to others in USA, UK, France, Italy and Holland that clearly demonstrate that current pediatric regimens are more effective for adolescents and may contribute to indicate that adolescents should be included in intensive pediatric protocols. Keywords: leukemia, survival, adolescent.

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

Blood ◽

10.1182/blood.v112.11.5248.5248 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5248-5248

Author(s):

Luigi Gugliotta ◽

Alessia Tieghi ◽

Anna Candoni ◽

Monia Lunghi ◽

Gianluca Gaidano ◽

...

Keyword(s):

Bone Marrow ◽

Essential Thrombocythemia ◽

Therapeutic Approach ◽

Jak2 V617f ◽

Bone Marrow Biopsies ◽

Thrombotic Risk ◽

Significant Difference ◽

Cytoreductive Treatment ◽

Wbc Count

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.

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Comparing Induction and Consolidation with or without Cytarabine In the Treatment of Acute Promyelocytic Leukaemia In Hong Kong Chinese

Blood ◽

10.1182/blood.v116.21.4366.4366 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4366-4366

Author(s):

Man Fai Law ◽

Sze-Fai Yip ◽

Hay Nun Chan ◽

Yiu Ming Yeung ◽

Wai Choi

Keyword(s):

Overall Survival ◽

Hong Kong ◽

Relapse Rate ◽

Acute Promyelocytic Leukaemia ◽

Hong Kong Chinese ◽

Promyelocytic Leukaemia ◽

Newly Diagnosed ◽

Event Free Survival ◽

Free Survival ◽

Wbc Count

Abstract Abstract 4366 Previous studies suggested that cytarabine was not required in the treatment of newly diagnosed acute promyelocytic leukaemia (APL). They suggested that omitting cytarabine in the treatment of APL could reduce treatment toxicity without increasing relapses and affecting survival. No previous study assessed the effect of cytarabine in the treatment of Chinese APL patients. We compared the outcome of APL patients with or without cytarabine in induction and consolidation therapy in Hong Kong Chinese in a local hospital. Method It was a retrospective study of newly diagnosed APL patients from Jan 1996 to Dec 2009. They were divided into two groups. One group was given ATRA (All-trans-retinoic acid) 45mg/m2/day combined with daunorubicin 60mg/m2/day for 3 days plus cytarabine 200mg/m2/day for 7 days as induction therapy. It was followed by two courses of consolidation with daunorubicin and cytarabine and then 2-year maintenance with low dose chemotherapy and intermittent ATRA. Another group was given the same treatment without cytarabine. The remission rate, relapse rate, overall survival and event-free survival were compared in the two groups of patients. Results Eighteen patients with median age of 41 (range 24–62) received cytarabine. 22% of them had initial WBC count >10,000/uL. Eight patients with median age of 42 (range 16–57) received no cytarabine. 25% of them had WBC count >10,000/uL. The complete remission rates were 100% in both groups. The two-year relapse rate was 5.5% (1/18) for cytarabine group and 62% (5/8) for no cytarabine group (p=0.004, Fisher's exact test). The two-year event-free survival was 82% for cytarabine group and 37% for no cytarabine group (p=0.0017). The two-year overall survival was 89% for cytarabine group and 75% for no cytarabine group (p=0.18). The adverse effects profile was similar in both groups. Conclusion The results support a role of cytarabine in addition to ATRA and daunorubicin in the treatment of newly diagnosed APL. The relapse rate was much lower in patients receiving cytarabine. The two-year event-free survival and two-year overall survival were also significantly better in the cytarabine group. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Evaluation of 205 Patients with Essential Thrombocythemia: Clinical Outcome, Efficacy and Safety with Respect to Different Therapies.

Blood ◽

10.1182/blood.v106.11.4941.4941 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4941-4941

Author(s):

Nicola Vianelli ◽

Antonio deVivo ◽

Mauro Fiacchini ◽

Alessandro Lucchesi ◽

Benedetta Giannini ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Normal Population ◽

Alkylating Agents ◽

Thrombotic Event ◽

Age At Diagnosis ◽

Thrombotic Risk ◽

Blastic Transformation ◽

Solid Malignancy ◽

Hemorrhagic Events

Abstract Essential Thrombocythemia (ET) is a myeloproliferative disorder associated with persistent thrombocytosis. The main clinical features are recurrent thrombotic and/or hemorrhagic events, involving both the arterial and venous systems. Data concerning the role of platelet-lowering agents to prevent thrombotic and hemorrhagic events are not conclusive, despite the risk associated to the use of some of them as hydroxyurea (HU) or alkylating agents like busulfan (BU), to induce a leukemic transformation or solid malignancy. We report here our experience, on 205 (M 78, F 127) consecutive ET patients (pts) referred to our Institute between January 1977 and December 2003, with a median follow-up of 76 months (4–318). Median age at diagnosis was 66 (15–91) years; median platelet (PLT) number was 780 (465–3700) x109/L. One hundred and ninety-five pts (95%) were considered at high risk for thrombosis. One hundred and eighty of them (92.3%) were treated with platelet-lowering agents: HU (82 pts), BU (39 pts), HU+BU (37 pts), IFNa (6 pts), HU+IFNa (10 pts), BU+IFNa (2 pts) or HU+BU+IFNa (4 pts). In 30/180 (16.7%) and 124/180 (68.9%) pts the treatments were able to maintain the PLT number <400x109/L (Complete remission) and 400–600x109/L (Partial remission), respectively, for at least 2/3 of their follow-up. Only three pts withdrawn HU or BU for toxicity. A total of 192 (93.6%) pts received antiplatelet agents (121 Aspirin, 34 Ticlopidine, 37 others) for a median period of 53(1–318) months; in 42 pts this therapy was withdrawn, in most cases after gaining control of the platelet count (PLT <600x109/L). During follow-up we registered 33 thrombotic events in 21 (10.2%) pts, and 22 hemorrhagic events in 20 (9.8%) pts, while dizziness, headache and other symptoms due to microvascular disturbance were present in 88 pts. Patients who received both HU and BU consecutively developed a significantly higher number of thrombotic events, compared to pts who received a single drug (p=0.004); this could be explained by the difficult control of the disease in this subgroup of pts. Previous thrombotic event, age and platelet number at diagnosis, thrombocytosis control during follow-up and presence of one or more common cardiovascular risk factors were evaluated in order to establish any correlation with thrombotic risk. Only the first two factors resulted significant. Blastic tranformations, myelofibrosis evolution and solid malignancy occurred in 2(1.0%), 4(1.9%) and 8(3.9%) pts, respectively. The two pts who showed blastic transformation were treated with a particularly high total dose of HU (3039500mg) if compared to the median dose administered (462000mg) or with the sequential association of HU and BU. No strict correlation was observed between the 8 pts who developed a solid malignancy and the therapy administered. The overall survival expressed by the Kaplan-Meier curve was approximately 85% at 12 years after diagnosis, that is similar to the life expectancy of normal population. In conclusion, in our experience HU and BU resulted effective with neglegible toxicity in controlling thrombocytosis in ET pts. Only previous thrombosis and older age at diagnosis significantly increase the risk of thrombotic event during follow-up. The ET blastic transformation seems to be related to the HU+BU association or to a higher total HU dose administered.

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A NUP98-NSD1 Fusion Gene Can Be Detected in a Small Subset of Adult AML Patients with Normal Karyotype

Blood ◽

10.1182/blood.v118.21.2531.2531 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2531-2531

Author(s):

Annette Fasan ◽

Claudia Haferlach ◽

Tamara Alpermann ◽

Wolfgang Kern ◽

Torsten Haferlach ◽

...

Keyword(s):

Fusion Gene ◽

Normal Karyotype ◽

Fusion Transcript ◽

Chromosomal Band ◽

Event Free Survival ◽

Employment Equity ◽

Aberrant Expression ◽

Free Survival ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2531 Introduction: Fusion genes can be detected in approximately 30–35% of all AML cases and usually are the result of a cytogenetically detectable chromosomal rearrangement. Very recently, a novel fusion gene has been described in AML with normal karyotype (Hollink et al, Blood, 2011). This cryptic fusion involves nucleophosmin 98kD (NUP98) in chromosomal band 11p15 and the non homeobox gene NSD1 in chromosomal band 5q35. NUP98-NSD1 has been described in this single study with a frequency of 16.1% in pediatric and 2.3% in adult AML patients with distinct characteristics (e.g. mutual exclusivity with NPM1) and dismal prognosis. Aim: The aim of this study was to further evaluate NUP98-NSD1 rearrangements in adult AML with normal karyotype (NK) for frequency, association with other mutations and impact on outcome. Patients and Methods: Screening for NUP98-NSD1 fusion gene was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) in a total cohort of 148 de novo AML patients with NK and NPM1 wildtype status. The NUP98-NSD1 positive cases were verified by direct Sanger Sequencing of the PCR products. The cohort was composed of 84 males and 64 females. Median age was 55.4 years (range: 15.7 to 85.8 years). Further mutation analysis was available in subcohorts: FLT3-ITD (n=32 mut/117 screened), CEBPA (n=22 mut/124 screened), MLL-PTD (n=32 mut/117 screened) and RUNX1 (n=26 mut/83 screened). Results: In total, in 8/148 (5.4%) patients a NUP98-NDS1 fusion transcript was detected. NUP98-NDS1-positive cases had significantly higher platelet counts (median 221 vs 87 × 10e9/L; p=0.001). Patients with NUP98-NDS1 were younger than the NUP98-NDS1-negative patients (median: 43.5 years vs 55.4 years, p=0.067). Sex (5 male vs. 3 female), white blood cell count and hemoglobin levels at diagnosis were not different compared to NUP98-NDS1-negative cases. Cytomorphology revealed AML with minimal differential differentiation (n=4), with maturation (n=1), and myelomonocytic AML (n=3). In 3 NUP98-NDS1-positive cases immunophenotyping data was available and all 3 cases aberrantly expressed CD7. NUP98-NDS1-positive cases have a higher frequency of FLT3-ITD compared to NUP98-NDS1-negative cases (5/8, 62.5% vs. 27/140, 19.3%; p=0.015) and were mutually exclusive of CEBPA and RUNX1 mutations. With respect to survival the NUP98-NDS1-positive cases had a worse event free survival compared to NUP98-NDS1-negative cases (median 5.1 months vs. 25.2 months; p=0.054). Conclusions: A NUP98-NSD1 fusion transcript was detected in 5.4% of normal karyotype adult AML patients without NPM1 mutation. NUP98-NSD1-positive cases are characterized by younger age, high coincidence of FLT3-ITD, aberrant expression of CD7, relatively high platelet counts, and a short event free survival. Thus NUP98-NSD1 translocations seem to define a new subgroup of NK-AML. Importantly, in this prognostically adverse and so far cytogenetically undetectable group close and sensitive PCR based monitoring for minimal residual disease is available. Thus, this data suggests to perform PCR based screening for NUP98-NSD1 in AML with normal karyotype that lack NPM1 and CEBPA mutations. Disclosures: Fasan: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet Count At the Time of the Event: Data From the Czech Registry of Patients Treated with Anagrelide,

Blood ◽

10.1182/blood.v118.21.3857.3857 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3857-3857

Author(s):

Jiri Schwarz ◽

Miroslav Penka ◽

Petra Ovesna ◽

Olga Cerna ◽

Yvona Brychtova ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Jak2 V617f ◽

Protein C Deficiency ◽

Thrombotic Risk ◽

Female Ratio ◽

Platelet Counts ◽

Cell Counts ◽

Registry Entry

Abstract Abstract 3857 Background: Recent studies of prognostic parameters in Ph- myeloproliferative neoplasms with thrombocythemia (MPN-t) indicate that WBC counts at diagnosis, rather than platelet (Plt) counts, determine the risk of thrombosis. We have studied these and other risk parameters in our patient cohort. Patients: 843 prospectively assigned patients from the Czech segment of the International registry of patients treated with anagrelide (ANG; Thromboreductin®) were studied. The male: female ratio was 2:3, the median age was 51 (0–96) years. The majority of patients (68.1%) was pretreated by other cytoreducing drugs. According to PVSG criteria, the diagnoses were the following: essential thrombocythemia – 569, primary myelofibrosis – 155, polycythemia vera – 92, or other – 27 patients. Data from the time of diagnosis, from the time of registry entry (at the start of ANG therapy) and from the time of the thrombotic event were evaluated. The median follow-up since registry entry was 33 (0–117) months and the follow-up comprised 2505 patient-years. All patients were treated with ANG and in 80% of follow-up reports, acetylsalicylic acid (ASA) was mentioned to be given in parallel. In 18% of entries (from registration and follow-up), administration of another cytoreducing drug (mainly hydroxyurea or interferon) in combination with ANG was noted. Results: Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers of arterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapy dramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively. At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2 V617F mutation (P=0.001), hereditary or acquired thrombophilia (P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thrombotic event (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk (P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively with microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial events, whereas others (f.V “Leiden” mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected preferentially with venous events. However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate any significance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuous in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time of the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory event received ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries). Conclusions: The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate of venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may receive more cytoreducing and/or antiaggregation therapy. Disclosures: Schwarz: AOP Pharmaceuticals: Consultancy.

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Event-Free Survival According to Age in Patients with Chronic Myeloid Leukemia Receiving Imatinib Frontline: The Younger, the Later, the Worse?

Blood ◽

10.1182/blood.v126.23.4038.4038 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4038-4038 ◽

Cited By ~ 1

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Ida Carmosino ◽

Federico Vozella ◽

Federico De Angelis ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Real Life ◽

Age At Diagnosis ◽

Molecular Response ◽

Event Free Survival ◽

Secondary Resistance ◽

Free Survival

Abstract Differences in baseline features and follow-up among patients with chronic myeloid leukemia (CML) according to age at diagnosis have been recently reported in cohorts from clinical controlled trials (Castagnetti F et al, 2015). To evaluate this issue in a real-life setting, we revised 207 consecutive CML patients treated at our Institution with imatinib frontline from 6/2002 to 6/2013, dividing them in young adults (>20 <45 years) (YA), middle-aged adults (≥45 <65 years) (MA) and elderly (≥65 years) (EL). The main features at baseline of the whole cohort and of the 3 age groups are reported in the Table. Table.ALLYAMAELpN° of patients207617274M/F108/8930/3140/3238/360.752Median WBC (x 109/l)IQR66.1 (32.7 - 119.0)109.8 (65.9 - 148.0)59.5 (31.3 - 126.6)40.1 (26.5 - 81.4)<0.001Median Hb (g/dl)(IQR)12.5 (11.0 - 13.5)11.7 (9.8 - 12.7)12.7 (11.0 - 14.2)12.8 (11.3 - 13.7)0.002Median PLT (x 109/l)IQR414 (275 - 616)445 (291 - 597)378 (262 - 546)457 (271 - 732)0.287Spleen enlargement (>5cm) N° (%)17 (8.3)11 (18.3)4 (5.6)2 (2.7)0.003Sokal score (N°)Low/Int/High89/93/2047/9/338/27/54/57/12<0.001Comorbidities ≥ 2, N° (%)77 (37.2)5 (8.1)26 (36.1)46 (62.1)<0.001 The rates of complete cytogenetic response (CCyR) were similar (86.4% in YA, 95.5% in MA and 91.0% in EL, p=0.227) while the rate of major molecular response was higher in the MA group (89.7% vs 63.8% in YA and 75.8% in EL, p=0.001). The number of events (permanent discontinuation due to toxicity, primary or secondary resistance, any death for CML related or unrelated causes) was lower in the MA group [8 (11.1%) vs 21 (34.4%) in YA and 28 (37.8%) in EL, p=0.001]: no difference was observed in the rate of evolution to blastic phase [3 (4.9%) in YA, 1 (1.4%) in MA and 2 (2.7%) in EL, p=0.478]. The number of deaths was higher in the EL group [12 (16.2%) vs 2 (3.2%) in YA and 0 in MA, p<0.001]: it is worth of note, however, that 11/12 deaths in the EL group were not related to CML progression. The 4-year event-free survival (EFS) for the whole cohort was 73.5% (95%CI 67.0 - 80.0): the 4-year EFS in the MA group [92.0% (95%CI 85.1 - 98.9)] was significantly higher than in YA group [67.3% (95%CI 55.1 - 79.5)] and in EL group [61.1% (95%CI 49.5 - 73.7)] (p=0.001). The 4-year overall survival (OS) for the whole cohort was 94.4% (95%CI 90.9 - 97.9): the 4-year OS in the EL group [72.4.% (95%CI 56.9 - 87.9)] was significantly lower than in YA group [96.3% (95%CI 91.2 - 100)] and in MA group (100%) (p<0.001). In conclusion, age at diagnosis influences significantly the course of CML patients treated with imatinib: the MA group has the best follow-up with an excellent OS and EFS, while the relatively lower OS and EFS in the EL group are clearly related to the incidence of unrelated deaths like in the general aged population. A possible explanation of the counterintuitive worse course of YA group is the delayed diagnosis in these patients (higher WBC counts, lower Hb levels, higher rate of spleen enlargement > 5 cm) compared to aged patients, who have often concomitant diseases and make routinely blood analyses: however, a more aggressive biology of CML in YA could not be excluded and warrants further investigations. Disclosures No relevant conflicts of interest to declare.

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