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Purpose To apply the German Hodgkin Study Group (GHSG) risk model in patients with recurrent/refractory Hodgkin lymphoma receiving involved-field radiotherapy after autologous stem cell transplantation. Material and methods The study consisted in the retrospective analysis of 30 consecutive patients with recurrent/refractory Hodgkin lymphoma who received involved-field radiotherapy after autologous stem cell transplantation. Our policy was of adding involved-field radiotherapy for patients with positive PET scan before autologous stem cell transplantation (23 out of 30 patients, 77%), and/or irradiating sites of bulky disease at relapse (11 out of 30 patients, 37%). Patients were stratified into four risk groups according to the presence of the five clinical risk factors identified by the GHSG; (1) stage IV disease; (2) time to relapse ≤ 3 months; (3) ECOG-PS ≥ 1; (4) bulk ≥ 5 cm; and (5) inadequate response to salvage chemotherapy. Results The median interval from autologous stem cell transplantation to involved-field radiotherapy was 3 months (range, 1–7 months), and the median involved-field radiotherapy dose was 35 Gy (range, 12–40 Gy). At a median follow-up of 35 months (range, 1–132 months), the 2-year progression-free survival in the entire series was 60%. When examining the four different GHSG risk groups, the progression-free survival rate at 2 years was 86%, 83%, 50%, and 36% for patients with score = 0, score = 1, score = 2, and score = 3 to 5, respectively (P = 0,01). Among the 12 patients having at least three risk factors who underwent thoracic involved-field radiotherapy, three (25%) developed pneumonitis. Conclusion The adoption of the GHSG risk model at the time of recurrence/progression is a useful prognostic tool to select patients with Hodgkin lymphoma for consolidative involved-field radiotherapy after autologous stem cell transplantation.

The hypomethylating agent Decitabine (DAC) is a valuable treatment option in acute myeloid leukemia (AML), particularly in elderly patients (pts) not suitable for intensive chemotherapy (CHT). However, limited data are available about efficacy and safety of DAC in clinical practice.We retrospectively reviewed data of 104 AML pts treated with DAC in eight Italian Hematological Centers from 2015 to 2017. The objective of this study was to evaluate the efficacy and safety of DAC in older AML pts outside of clinical trial. Seventy-five (75%) pts received DAC as first line treatment (Cohort 1) and 29 pts as salvage therapy (Cohort 2). All pts received a DAC schedule of 20 mg/sqm IV for 5-days, every 28 days. The median age was 72.5 years (74 in cohort 1 and 66 in cohort 2) and 16% of pts had an ECOG performance status2 at the start of DAC treatment (with non-significant difference in the two cohorts). The cumulative illness rating scale (CIRS) was6 in 27% of pts. Forty-five pts (43%) had secondary AML. Bone marrow blast count was30% in 64% of patients (67/104). In the relapsed cohort 17/29 (59%) patients were treated with DAC after conventional CHT, 5/29 (17%) after allo-SCT and 7/29 (24%) after azacitidine therapy.A total of 469 DAC cycles were given to the 104 pts with a median of 3 cycles (range 1-21) and 45/104 (43%) pts received4 cycles. The Overall Response Rate (ORR = Complete Remission-CR plus Partial Remission-PR) was 33%, significantly higher in Cohort 1 (42%) compared to Cohort 2 (14%) (p = 0.009). The median duration of response was 6 months (range 1-20). In Cohort 1 the best response (CR or PR) was obtained between 3th and 6th cycle. In multivariate Cox regression analysis, achievement of CR or PR (HR = 0.78; p = 0.0004), CIRS 6 (HR = 0.9; p = 0.04) and complex karyotype (HR = 0.8; p = 0.03) were significant predictors of better overall survival (OS). Median OS from the start of DAC therapy was 11 months for the whole population with a significant OS advantage in Cohort 1 (median OS 12.7 mths vs 6.3 mths; p = 0.003); median OS was significantly longer in responders compared to non-responders (22.6 mths vs 5.7 mths; p 0.0001). At the last follow-up, 56 patients (54%) are still alive and 48 (46%) are dead (71% due to disease progression). The most common toxicities were myelosuppression and documented infectious complications that occurred mainly during the first 4 cycles.These data confirm the efficacy (ORR 33%) and the acceptable safety profile of DAC in the real life management of AML in elderly pts unsuitable for intensive CHT, with a significant better performance in first line therapy (ORR 42%, median OS 12.7 mths). The efficacy of DAC, both in first line and as salvage therapy, may probably be improved with combined treatment strategies and/or with different DAC schedules that could increase its anti-leukemic effect.

Background: Cytotoxic regimens used in induction treatments for acute myeloid leukemia (AML) almost always include standard or high-dose cytarabine (Ara-C). During or soon after induction therapy, leukemic patients frequently develop gastroenteric complications, characterized by abdominal pain and diarrhea. The association ofthese symptoms with f and melena is typical ofnecrotizing enterocolitis (NE), a life-threathening condition that can be documented by ultrasound abdominal scan. Patients and methods: We analyzed retrospectively the clinical course of169 adult patients with AML treated by standard dose Ara-C-containing induction regimens, either by continuous venous infusion (group 1) or subcutaneous injection (group 2). Ultrasonography was employed as early diagnostic tool in a majority ofpatients with gastroenteric complications. Bowel wall thickening was accurately measured and used to confirm the diagnosis of necrotizing enterocolitis. Results: In the first group of 115 patients (median age, 51 years), gastroenteric complications were observed in 55 patients (48%), and 10 patients (9%) received diagnosis ofNE, which was fatal in four. Patients with NE had a median age older than that of patients without gastroenteric symptoms, and a more prolonged neutropenia. In the second group of54 patients (median age, 60 years), gastroenteric events were observed in 14 patients (26%), and no case of NE was recorded. Conclusions: This retrospective analysis shows that NE is a serious complication occurring mainly in patients treated by Ara-C administered as continuous i.v. infusion. The Hematology Journal (2003) 4, 346–350. doi:10.1038/sj.thj.6200304

Life expectancy has impressively increased over the past century and the US population over 65 years is rapidly growing, especially those over 80 years. In fact, persons older than 80 years have increased by more than 250% between the years 1960 and 2000, and it is expected that the population aged >75 years will triple by the year 2030. With the increase of the geriatric population, there is a need for the development and validation of treatment strategies for NHL for these patients. Therapy in elderly patients needs special attention because older patients usually suffered of several co-morbidities and their management represents a challenge for physicians. In fact, older patients treated for lymphoma may not tolerate the high-dose therapies used in younger patients and have increased risk of therapy-related toxicity as a result of age-related physiological changes and frequent co-morbidities. The widespread use of a comprehensive geriatric assessment tool might overcome the difficulty to run prospective clinical trial in elderly patients with lymphoma.

Several studies suggested that staging bone marrow biopsy (BMB) could be omitted in patients with classical Hodgkin's lymphoma (cHL) when a positron emission tomography/computed tomography (PET/CT) is performed at baseline.To address the concordance between BMB and PET/CT in the detection of bone marrow involvement (BMI) and the BMB role in determining the Ann Arbor stage, we retrospectively collected data on 1244 consecutive patients with cHL diagnosed from January 2007 to December 2013. One thousand eighty-five patients who had undergone both BMB and PET/CT were analyzed, comparing the Ann Arbor stage assessed with PET/CT only to that resulting from PET/CT combined with BMB.One hundred sixty-nine patients (16%) showed at least one focal skeletal lesion (FSL) at PET/CT evaluation. Only 55 patients had a positive BMB (5.1%); 34 of them presented at least one FSL at PET/CT. To the contrary, 895 out of 1030 patients with a negative BMB did not show any FSL (86.9%). Positive and negative predictive values of PET/CT for BMI were 20 and 98%, respectively; sensitivity and specificity were 62 and 87%, respectively. Fifty-four out of 55 patients with a positive BMB could have been evaluated as an advanced stage just after PET/CT; only one patient (0.1%) would have been differently treated without BMB.Our data showed a very high negative predictive value of PET/CT for BMI and a negligible influence of BMB on treatment planning, strengthening the recent indications that BMB could be safely omitted in cHL patients staged with PET/CT.

A letter to the editor is presented related to the case where GATA1 is overexpressed in patients with essential thrombocythemia and polycythemia vera, but not in patients with primary myelofibrosis or chronic myelogenous leukemia.

121 Background: The advent of highly active antiretroviral therapy (HAART) allowed to extend autologous stem cell transplantation (ASCT) to HIV-positive patients affected by lymphoma. In the literature, data are lacking on long-term events developed by this population. Methods: Herein we are reporting the preliminary analysis of long-term data of 43 pts out of 61 pts, affected by high-risk or relapsed lymphoma and treated by ASCT in different European countries. These 61 pts reached a complete response after ASCT and received HAART concomitantly to chemotherapy. We considered the following events after ASCT: lymphoma relapses, second cancers, opportunistic infections (OIs) and cardiovascular events. Results: Thirteen pts experienced OIs, after 0.36 years from ASCT (IQR: 0.12 -2.91). Twelve pts had a secondary malignancy and 6 pts had a lymphoma relapse, at a median time of 4.90 years (IQR: 2.56 – 9.90) and 2.88 years (IQR: 0.57 – 4.27) from ASCT, respectively. Six pts developed a cardiovascular event at 6.29 years (IQR: 4.84 – 9.32) from ASCT. Eight pts died: 3 of lymphoma relapse, 3 of second malignancy, 1 of acute myocardial infarction and 1 of car accident. With a median of 9.18 years of follow-up, (IQR: 5.99-12.43) the OS, PFS and EFS of the entire sample of pts were 82%, 75% and 35% at 10 years, respectively. Conclusions: Thirty-five out of 43 pts are still alive and in long-term complete remission after ASCT. These data confirm the long-term dramatic efficacy of ASCT. We support surveillance of OIs early after ASCT and of second cancers, lymphoma relapses and cardiovascular events from ASCT. Secondary malignancies developed by our pts are non-AIDS-defining cancers and a majority are linked to a viral pathogenesis or lifestyle behaviours (i.e. smoking). Secondary cancers and lymphoma relapses are the main causes of death in this population. Cardiovascular events may represent a cause of death but also a major reason of disability.

The reverse seroconversion to hepatitis B virus infection has been sporadically described in onco-haematological patients receiving cytotoxic therapy or allogeneic bone marrow transplantation and can be associated with the development of acute icteric hepatitis. We present a male HBsAg-negative, anti-HBc-positive patient with Hairy Cell Leukemia who developed acute B hepatitis more than 1 year after the last course of 2-CdA and 6 months after splenectomy, while the patient was receiving therapy with alphaIFNr. The acute B hepatitis promptly responded to lamivudine therapy followed by viral clearance.

We recently published a study aiming to verify the frequency of amyloid deposits in the bone marrow of patients with multiple myeloma (MM) who did not present any signs or symptoms of systemic amyloidosis, applying the Congo red technique on bone marrow smears obtained by aspiration from the posterior iliac spine. The results suggested that nearly 40% of patients affected by MM may have amyloid deposits in their bone marrow. Subsequently, this finding has not been confirmed by another study performed with histological specimens of bone marrow in a similar clinical setting. To explain this discrepancy, we performed a comparative study on the bone marrows of 36 patients affected by MM, evaluated by both cytological and histological techniques. The results of this study confirm the high frequency of amyloid deposits in the bone marrow of patients affected by MM when the analysis is made on cytological smears, and indicate that the presence of amyloid on marrow smears is confirmed by core biopsies simultaneously performed in only 25% of cases. Should further studies confirm our findings, cytological assessment could be considered a sensitive technique to detect bone marrow amyloid deposits.

Abstract 1973 Background. Hematological and extra-hematological adverse events associated to Hydroxyurea (HU) treatment in patients with chronic myeloproliferative neoplasms (MPN) are object of particular interest in the Ph-negative MPN since they can significantly limit the HU use. Objective. To evaluate the extra-hematological adverse events associated to HU treayment in a large cohort of Essential Thrombocythemia (ET) patients. Material and Methods. One thousand and seventy-five out of the 2005 ET patients registered in the RIT were treated with HU and are the object of this report. The patients, 641 females (59.6%) and 434 males (40.4%), diagnosed according to the PVSG or WHO criteria in 54 hematological centers of the RIT, started treatment with HU as first (92%) or second (8%) line, at median age of 65 years.The mean duration of HU treatment was 3.3 years. The HU treatment was withdrawn in 221 (20.5%) patients after a mean of 3.0 years.The administered dose of HU was 0.25–3.0 g/day (median 1), and a mean cumulative dose was 1113 g. The extra-hematological adverse events (EHAEs) observed during the HU treatment were distinguished in HU related AEs (HU-EHAEs), ET related AEs (ET-EHAEs) and HU or ET unrelated AEs (U-EHAEs).Results. During the HU treatment (3587 pt-y) 378 EHAEs were reported in 207 (19.3%) patients, being the HU-EHAEs 244 (6.8/100 pt-y) in 170 (15.8%) patients. In detail, the HU-EHAEs were: dermatological in 108 (48.3%) cases (38 hyperpigmentation, 26 leg ulcers, 22 maculo-papular rash, 10 lichenoid eruptions, 5 skin cancer, 4 alopecia); gastro-intestinal in 80 (32.8%) cases (37 nausea/vomiting, 30 diarrhea, 13 gastro-intestinal intolerance); systemic in 35 (14.3%) cases (28 fever, 7 fatigue); neurological in 19 (7.8%) cases (headache); miscellanea in 2 (0.8%) cases. Conclusion. This preliminary analysis in 1075 ET patients of the Registro Italiano Trombocitemia (RIT) treated with HU shows that the extra-hematological adverse events referred to the HU (HU-EHAEs) occurred with not negligible rate (6.8/100 pt-y) and need to be object of attention in the management of ET patients. Disclosures: No relevant conflicts of interest to declare.

Background: Indolent non follicular B-Cell Lymphomas (INFL) are a heterogeneous group of lymphomas and include small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphomas (LPL) and marginal zone lymphomas of splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) subtypes. In 2010 the NF10 study was started by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of this group of lymphomas. We provide a preliminary report describing registered cases with an emphasis on initial therapy. Methods: The registration of consecutive adult patients with newly diagnosed INFL and no exclusion criteria is ongoing at a dedicated website via secure HTTP protocols. For the purposes of the study in addition to the conventional INFL subtype, the category of disseminated MZL and CD5- low grade lymphoma were also considered. So far the study has been activated in 65 centers in Europe and South America. Results: Between July 2010 and July 2015, 665 cases have been registered. The current report is based on 395 cases that have been validated. Forty-seven (12%) cases were registered as SLL, 76 (19%) as LPL, 59 (15%) as CD5-low grade and 213 (54%) as MZL, including 73 (18%) SMZL, 18 (5%) NMZL, 81 (21%) ENMZL or 41 (10%) disseminated subtypes. Median age was 67 years (range 29-94), 53% of patients were males; Ann Arbor stage was III-IV in 79%; 14% had B symptoms, 7% had ECOG performance status > 1, lactate dehydrogenase and b2-microglobulin were elevated in 70% and 54% of cases, respectively. Six percent of cases were HCV positive (HCV+ rate was 7.5% among MZL cases). Regarding HBV infection, 21% of patients were HBcAb-positive and 3% of patients were HBsAg-positive. Immediate systemic therapy was planned in 50% of patients. SMZL, SLL and CD5-low grade were the subtypes with the lower rates of immediate therapy (44%, 46% and 24% respectively) whereas ENMZL were addressed to systemic therapy in 67% of cases. When systemic therapy was prescribed rituximab (R) was used in 88%. In 81% of patients R was combined to cytotoxic therapy including alkylating agents in 40%, CHOP-like in 18%, bendamustine in 17% and fludarabine in 6%. ENMZL and CD5-low grade had the highest rates of R-alkylating use (61% and 64%); SMZL and MZL were frequently treated with R-CHOP like regimens (35% and 40%). Young age at diagnosis (less than 60 years) and increased b2-microglobulin were more frequently associated with patients requiring immediate systemic therapy. With 22 months of median follow up, 2-year progression free survival and overall survival (OS) were 88% (95CI: 83-92) and 95% (95CI: 91-97) respectively; the initial choice of deferring immediate therapy did not impact on OS. Conclusions: We provide a complete report on the initial approach to patients with INFL showing that immediate therapy is required in half of the cases with a heterogeneous approach among INFL subtypes. The majority of patients requiring therapy was treated with the combination of R and alkylating agents. The NF10 study confirms that a web-based world-wide cooperation allows the collection of a relevant and complete data set, providing a platform for future prognostic and pathobiological studies in order to identify novel and more efficient therapeutic targets. Disclosures Luminari: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Mundipharma: Other: Speakers Honoraria; Celgene: Other: Speakers Honoraria. Gaidano:Celgene: Research Funding; Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards.

Purpose The sensitivity of lymph node excisional biopsy requires validation. Power Doppler ultrasound (US) helps predict the malignant status of lymphadenopathies. We used power Doppler US to select for biopsy the lymph node most suspected of malignancy. Patients and Methods One hundred fifty-two patients having lymphadenopathies with clinical suspicion of lymphoma were divided into two well-matched groups and randomly assigned to undergo either standard or power Doppler US-directed lymph node excisional biopsy. Results Histology showed a malignancy in 64% of patients in the standard group (lymphoma, 49 patients; carcinoma, two patients) and in 87% of patients in the US-assisted group (lymphoma, 62 patients; carcinoma, one patient). There were significantly fewer biopsy-related complications in the assisted group than in the standard group. During the follow-up of the patients with lymph nodes reported as being reactive, 14 of 29 patients in the standard group were rebiopsied and were found to have lymphoma (13 patients) or carcinoma at the subsequent lymph node histology, whereas none of the patients in the assisted group (nine patients) required a second biopsy. Thus, biopsy provided false-negative results for malignancy in 21% of patients affected by lymphoma in the standard group and never in the assisted group (P < .01). Conclusion Power Doppler US is an accurate tool for screening lymphadenopathies to be removed by excisional biopsy in patients with suspected lymphoma.

Objectives In the past essential thrombocythemia was considered a disease of the elderly. At present, the number of young people suffering from this disease is growing, with a slightly higher frequency in females. We investigated the effects of interferon alfa therapy in these patients. Study design We describe 9 pregnancies in 4 women affected by essential thrombocythemia. Results Four pregnancies were carried out without interferon alfa therapy, and resulted in 2 intrauterine deaths, 1 spontaneous abortion, and 1 neonatal death. Interferon alfa was given during another 5 pregnancies; among them, 2 ended in preterm deliveries with normal infants, and 3 in full-term deliveries. The literature is reviewed. Conclusion Our cases and published series suggest that fetal outcome is improved by therapy, and that interferon alfa may be the best therapeutic option.

Trilineage extramedullary myeloid tumor (EMT) is an uncommon medical condition mostly diagnosed in patients affected by acute or chronic myeloid leukemia or, more rarely, by a myelodysplastic syndrome, among which the most frequent is refractory anemia with excess of blasts in transformation (RAEB-t). The prognostic significance of EMT is still unclear, although the appearance of trilineage EMT is often considered to affect the outcome adversely. A 70-year-old lady with previous history of intestinal resection for colonic adenocarcinoma in 1995 and subsequently treated with 5-fuorouracyl developed a refractory anemia with excess of blasts (RAEB) in 1998. During the follow-up, a progression to RAEB-t was recorded. During chemotherapy for this condition, slight enlargement of left supraclavicular and right submandibular nodes was noticed. Fine-needle biopsy was performed with ancillary studies. A diagnosis of trilineage extramedullary myeloid tumor was reached. The patient was treated with low doses of chemotherapy with a good response lasting 12 months. The peculiar cytologic picture of this condition when corroborated by ancillary studies (immunocytochemistry and flow cytometry) is diagnostic of this rare condition. Furthermore, the extramedullary myeloid tumor in this case did not significantly affect the response to the chemotherapy of RAEB-t.

Spleen size was assessed in 73 patients with thrombocytosis and in 15 healthy subjects, comparing palpation with ultrasonography (US) measurement of longitudinal diameter and volume. Intraobserver and interobserver variability for volume on US, checked in 12 patients, was very low. Correlation between spleen volume measured by US and that measured by computed tomography was excellent. Splenomegaly was detected by palpation in 25% of patients, by US assessment of longitudinal diameter in 33%, and by US assessment of volume in 52%. After diagnostic work-up, 54 patients had a diagnosis of essential thrombocythemia (ET), 4 of idiopathic myelofibrosis (IMF), and 15 of secondary thrombocytosis (ST). Spleen volume in patients with ST was in the normal range (138 ± 47 mL) and was significantly lower than that in patients with ET or IMF (370 ± 210 mL;P

Introduction: R-CHOP is the gold standard for the treatment of elderly patients with DLBCL. However, unfit and frail patients frequently do not qualify for CHOP-based chemotherapy. Alternatives are an urgent medical need. Bendamustine plus rituximab (BR) has been established as a standard treatment of indolent lymphomas and preliminary data have shown a promising activity in DLBCL, both in the relapsing and upfront setting. Methods: Within the Fondazione Italiana Linfomi (FIL), we started a phase II study (R-BENDA frail study, EUDRACT2011-001421-24) in elderly patients (>70 years) with a newly diagnosed DLBCL not suitable for R-CHOP-based chemotherapy. All patients were evaluated according to ADL, IADL and CIRS-G and were considered FRAIL if the following criteria were meet: in patients aged 70-80 ADL8 grade 2 comorbidities; in patients older than 80 years ADL>5 or IADL>6 or 5-8 grade 2 comorbidities. Patients received bendamustine at a dose of 90 mg/m2 daily on days 1 and 2 of each 28-day cycle along with rituximab on day 1 for up to 6 cycles. Results: From February 2012 to February 2014, 49 patients were enrolled in 24 Italian centers. The majority (57%) were male and 57% had stage III-IV with 41% elevated LDH. The median age was 82. Overall, 83% of the planned cycles were delivered without dose reduction or delay; grade 3/4 neutropenia was reported in 25% of cycles followed by anemia 21%, and thrombocytopenia 20%. One case of febrile neutropenia was observed. Grade 3-4 non-hematological toxicity was mild and reported in 6% of cycles including 3 episodes of cardiovascular events and 7 other cases of different toxicities (one creatinine increase, one fatigue, one bleeding, one peripheral neurotoxicity, one hyponatriemia, one hyperglycemia and one liver toxicity). Two deaths during treatment have been observed (cardiac failure and sudden death). At the interim analysis (23 patients) the overall response rate was 56% with a complete response rate of 39%. Conclusions: Combination therapy with BR demonstrates low toxicity profile in this high risk population. The promising results on activity can encourage clinicians to considered BR for the treatment of FRAIL elderly patients with DLBCL not eligible for R-CHOP. Disclosures No relevant conflicts of interest to declare.

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 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.

Background: in the Essential Thrombocythemia (ET) patients considered at high risk for thrombosis, a treatment with low-dose aspirin is usually performed and a cytoreductive therapy is recommended. Hydroxyurea (HU), Interferon alpha (IFN) and Anagrelide (ANA) are largely used, but their side effects/toxicity or inefficacy are not rarely cause of drug withdrawal. Since HU, IFN, and ANA have different activity and toxicity patterns, the combined use of two drugs at lower dose may result very useful to overcome the limits of a single drug at conventional or high dose. Aim: to evaluate the ET patients enrolled into the RIT who received a combined cytoreductive therapy, with particular interest for feasibility, efficacy and toxicity. Patients: fifty-six ET patients, 18 males and 38 females, diagnosed in the years 1998–2008 according to the PVSG or WHO criteria, are object of this study. The patients at diagnosis had a median platelet count of 792 × 109/L (600–2009), with disease related symptoms in 18 cases (32%) and previous thrombotic or haemorrhagic events in 6 (12 %) and 1 (2%) cases, respectively. Results: the patients received as first cytoreductive drug HU (n 32, 57%) at a median dose of 1 g/day (0.5–3.0), or ANA (n 13, 23%) a median dose of 1.5 mg/day (0.5–4.0), or IFN (n 11, 20%) at a median dose of 9 MU/week (3–9). The 32 patients receiving HU started a combined therapy HU+ANA as a consequence of hematological toxicity (n 23), fever (n 4), cutaneous ulcers (n 2), inefficacy (n1), other causes (n 2); the 13 patients receiving ANA started a combined therapy ANA + HU (n10) or ANA + IFN (n 3) as consequence of cardiovascular side effects (n 10), anemia (n 2), or GI side effects (n 1); the 11 patients receiving IFN started a combined therapy IFN+ANA as consequence of unaccepted side effects. All patients who started the combined therapy had reduced the dosage of the initial drug. The median follow-up of the patients on combined therapy was 11 months (1–75). A hematological response (platelet count 4 × 109/L and Hb >12.5 g/dl, was registered in 21 of 42 (50%) patients on HU + ANA and in 11 of 14 (79 %) patients on IFN + ANA. Diseaserelated or drug-related symptoms (headache, dizziness, palpitation, abdominal pain) were registered in 7 of 56 (12 %) patients; no thrombotic or hemorrhagic complications occurred. Conclusion: in these ET patients the combined therapy HU + ANA or IFN + ANA was well tolerated and able to control the symptoms and to obtain a satisfactory hematological response (particularly with IFN + ANA). These promising results could be due to the low dosage and to synergic effect of the combined drugs, but controlled studies are needed to prospectively evaluate the role of the combined therapy in ET patients.

Epidemiological, diagnostic, prognostic and therapeutical data were retrospectively obtained by the Italian Registry in over 2000 Essential Thrombocythemia (ET) patients who mainly were diagnosed according to the PVSG criteria and were treated with potentially leukemogenic drugs. The Registro Italiano Trombocitemie (RIT), that is a GIMEMA project, has been activated in order to registry italian ET patients, to improve the diagnosis appropriateness (WHO criteria), to promote the acquisition of biological data, to evaluate the compliance to the therapeutical guidelines of the Italian Society of Hematology (SIE), to monitor in particular the ET patients receiving Interferons alpha and Anagrelide, to evaluate cases of pregnancy, pediatric age and familiarity, to define the prognostic value of the biological factors as JAK2 mutation, clonality, etc, to create a network for activation of new clinical and biological studies. The RIT, co-ordinated by the Hematology Unit of Reggio Emilia, is a web based registry that beside a public area comprehends a database of italian ET patients. The data, with respect of the privacy rules, are object of validation and analysis by various RIT expert subcommittees. Eighty hematological Institutions adhered to the RIT and 801 patients have been registered since June 2005. The ET diagnosis was done according to the PVSG (90%) and WHO (10%) criteria. The patients, 492 females and 309 males, had age 70 yr (30%), and the median age was 59 years. At diagnosis the platelet count was >1000 ×109/L in 29% of cases (mean 932). Few patients had prior thrombosis (4%; major 2%) and prior hemorrhage (2.6%). Patients at high risk of thrombosis were 55% on considering age >60 yr and/or previous thrombosis and/or PLT count >1500 ×109/L, and 65% on considering the PLT count cut-off of 1000 ×109/L. The patients shown general thrombotic risk factors (70%), disease related symptoms (40%) and splenomegaly (25%). By applying the WHO diagnostic criteria, the picture of true ET was found in 27% of cases. Sixty pregnancies have been reported. Aspirin was administered in 72% of patients and cytoreduction was performed in 62% of them, with use of Hydroxyurea (65%), Anagrelide (10%), Interferons alpha (10%), Pipobroman (4%), Busulfan (2%). A separate analysis for patients treated with Anagrelide and Iterferons alpha is in progress. To improve the diagnostic approach, the RIT has promoted the bone marrow biopsy revision (WHO criteria) and the acquisition of the new biological parameters.

Anagrelide treatment is considered potentially responsible of cardiovascular toxicity and side effects. For this reason, we have retrospectively evaluated 130 patients (pts) with Essential Thrombocythemia (ET) treated with Anagrelide in 10 Italian Hematological Centres belonging to the GIMEMA Group. The pts, 55 males and 75 females, had at diagnosis a mean age of 43 years (range 13–82) and a mean platelet (PLT) count of 1086x10(e)9/L. The Anagrelide treatment was started after a mean of 47 months from diagnosis(range 0–196). A previous treatment with cytoreductive drugs (mainly HU and IFN) and antiplatelet agents (mainly ASA), was performed in 65% and 98% of cases, respectively. The mean Anagrelide dose was 1 mg/day at start and 1.7 mg/day in the maintenance phase (mean PLT count below 500x10(e)9/L). Twenty-five patients (19%) discontinued the treatment after a mean of 27 months (range 1–85) for the following reasons: compliance loss (n8), no satisfactory response (n7), palpitations and tachycardia (n6), other side effects (n4), anemia (n1), renal toxicity (n1), thromboembolism (n1). During the follow-up (median 28 months) 4 thrombotic complications (1.15/100 pt-yrs) and 2 minor hemorrhages (0.57/100 pt-yrs) were registered. Moreover, 15 pts showed non lethal cardiovascular events: angina (n6), cardiomiopathy (n4), arrhythmia (n3), AMI (n2). An instrumental cardiovascular evaluation with Echocardiography (ECHO) and ECG was performed at Anagrelide start in 58 pts: the Ejection Fraction (EF) was abnormal in only one pt (EF 47%). The instrumental monitoring was done in 28 pts every 6–12 months. Four out of these 28 pts showed a decrease of the EF below the level of 50% (43%,45%,47%, and 49%), and only 1 pt discontinued Anagrelide for this reason (see table). The clinical and instrumental cardiovascular evaluation in ET patients receiving Anagrelide is becaming of routinary application and an observational prospective study of the Registro Italiano Trombocitemia (RIT) is now in progress. | CASES | AGE | EF % BASELINE | EF % 1ST YEAR | EF% 2ND YEAR | |:---------------------------------------------------------- | --- | ------------- | ------------- | ------------ | | *Anagrelide discontinuation because tachycardia and EF

Abstract 3836 Background. In essential thrombocythemia (ET) patients history of thrombosis and age over 60 y are validated risk factors for thrombosis; the thrombocytosis is a constitutive abnormality associated with both thrombotic and hemorrhagic risk; JAK2 V617F mutation, leukocytosis, and male gender are candidate thrombotic risk factors. Aims. To evaluate in ET patients clinical-biological characteristics at diagnosis and their relationship with thrombosis occurrence before and after diagnosis. Methods. A cohort of ET patients of the Registro Italiano Trombocitemia (RIT) was retrospectively analysed. This preliminary report in detail considers data on thrombosis history. Results. A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 55 y, median PLT count 783 × 109/L, median WBC count 8.8 × 109/L, median Hb 14.1 g/dL, bone marrow fibrosis (grade >0) in 33% of cases, history of thrombosis in 189 cases (19.3%). The patients at high risk (age over 60 y and/or history of thrombosis) were 511 (52 %). The thrombosis history in univariate analysis was significantly related to: age over 60 y (p 0.001), male gender (p 0.045), low thrombocytosis (PLT 8.8 x109/L, p 0.01), and JAK2 V617F mutation (p 0.006). No relationship was found with the bone marrow fibrosis. The 977 patients, when both PLT count and WBC count at diagnosis were considered, were subdivided in four groups: group 1: 202 pts with low thrombocytosis and leukocytosis; group 2: 270 pts with low thrombocytosis and no leukocytosis; group 3: 272 pts with high thrombocytosis and leukocytosis; group 4: 197 pts with high thrombocytosis and no leukocytosis. In those patients, the thrombosis history was: 26.7% in the group 1(both risk factors); 24.1% in the group 2 (PLT risk factor); 20.2% in the group 3 (WBC risk factor); 7.6% in the group 4 (no risk factors). The rate of thrombosis history in patients with one or two of these risk factors was significantly (p 0.001) higher than in patients with no risk factors. The thrombotic events during the follow up (4088 pt-y) are still object of analysis. Conclusion. In this cohort of ET patients the rate of thrombosis history in univariate analysis was related to age over 60 y. Moreover, a significant relationship was found with PLT count at diagnosis below the median value (783 x109/L), WBC count at diagnosis over the median value (8.8 x109/L), JAK2 V617F mutation, and male gender. Disclosures: No relevant conflicts of interest to declare.

Background The outcome of 129 pregnancies, in 97 women with ET diagnosed in seventeen Italian hematological centres from June 1998 to July 2007, were retrospectively analyzed by the RIT. Diagnosis was made according to criteria (PVSG or WHO) in use at the time of first observation. The median age was 27 years (range 17–45) at ET diagnosis and 32.5 years (range 21–45) at the beginning of the pregnancy. The diagnosis of ET was established in 87 patients before the first pregnancy (median interval 27 months, range 1–96), in 9 patients during a pregnancy and in one patient during an in vitro fertilization treatment. JAK2 (V617F) mutation was documented in 16 out of the 33 women studied till now. Platelet count ranged from 489 to 2,140 × 109/L (median 867) at diagnosis, and from 232 to 2,000 × 109/L (median 564) at delivery. Results: Only 120 out of the 129 pregnancies are valuable (six voluntary abortions and three ongoing pregnancies are not considered).The pregnancies outcome was: live birth in 90 cases (75%), spontaneous abortion in 26 cases (22%) (19 in the first trimester and 7 in the second trimester), still-birth in 4 cases (3%). Twelve (10%) premature births were reported, and two pregnancies ending in live birth were complicated by eclampsia or pre-eclampsia. The foetal growth was within normal limits in 76 out of the 78 full term births. The delivery was by caesarean section in 40% of cases. Thirty-six pregnancies (30%) occurred during cytoreductive treatment, but the outcome was not different than in the other ET patients (p 0.49). Aspirin treatment (mainly 100 mg/ day) was reported in 92 pregnancies (76.6%), associated in 18 cases to prophylactic LMWH during the last week before delivery and six weeks post-partum. The rate of successful pregnancy in the group receiving ASA was not different respect to the group not receiving ASA (p 0.62,). JAK2 mutation was not significantly (p 0.08) associated with a higher risk of foetal loss, but the analysis has to be completed since the study is still ongoing. The IFN treatment (as single agent or combined with ASA) was performed in 21 high-risk pregnancies. Nineteen of these pregnancies were valuable (1 ongoing and 1 elective abortion): 18 pregnancies (95%) ended in live births, and this outcome was significantly better than in patients not receiving IFN (p 0.04). Conclusion This retrospective study shows that in ET women: the IFN therapy seems able to protect against fetal loss; low-dose aspirin has not a statistically significant favourable impact on the pregnancy outcome; the unfavourable effect of JAK2 mutation could be confirmed after completion of the study. A prospective study has been recently activated by the RIT (GIMEMA project), with aim to improve the diagnostic and therapeutic approach of pregnant ET.