MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell'Adulto.

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell'Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia.

Thirty-one patients with either advanced AML (18) or blastic CML (13) were treated with an intensive timed sequential combination of VP-16 (100 mg/m2/day i.v., days 1-3 and 8-10), intermediate-dose Ara-C (500 mg/m2 i.v. over 1 h q 12 h, days 1-3 and 8-10) and carboplatin (150 mg/m2/day i.v. continuous infusion, days 1-3 and 8-10). CR rates were 9/18 (50%) for patients with AML and 9/13 (69%) for those with blastic CML, for an overall CR rate of 58%. Among patients with AML, CR rates for specific subgroups were: primary resistant disease 2/6; resistant relapse 1/5; second relapse 6/7. Ten patients were refractory to VAC and three (10%) died of complications during marrow hypoplasia. Median overall survival was 7 months, and median DFS of the 18 responders 4 months. The major toxicity was myelosuppression and infection. The VAC regimen has significant activity and acceptable toxicity in myelogenous leukemias. The very high response rate observed in blastic CML warrants further testing of carboplatin-based regimens in this poor-risk form of leukemia.

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia.

A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results.

5-Aza-2'-deoxycytidine (Decitabine) is a new cytosine analog with potent antileukemic activity and able to induce in vitro gene activation and cellular differentiation by a mechanism probably involving DNA hypomethylation. The aim of this pilot study was to evaluate the efficacy and the toxicity of Decitabine, used as single induction agent, in the treatment of poor prognosis acute myeloid leukemia (AML) patients, and to explore its mechanism of action. A total of 12 patients were treated with Decitabine at 90-120 mg/m2 as a four hour intravenous infusion, three times daily for three consecutive days every four to six weeks. A minimum of two courses were required for response evaluation and to consider a patient as therapeutic failure. A total of 10/12 patients were fully evaluable for response; three patients achieved a complete remission (CR) and one a partial remission (PR). Extra-hematological toxicity was generally mild. As for the mechanism of action, both a differentiation induction effect and a cytotoxic mechanism have been observed. In particular, CRs and PRs were probably obtained through the induction of leukemia cell differentiation as shown by the kinetic of remission and immunotyping studies. The preliminary results of this ongoing study suggest that Decitabine may have a prominent role in the treatment of those AML patients with poor general conditions and/or advanced age.

The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTC-GIMEMA AML-10 trial.

Variable numbers of CD34+ cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10(6) CD34+ cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34+ cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield (<1 x 10(6) CD34+/kg; n = 50), intermediate yield (1-6.9 x 10(6) CD34+ cells/kg; n = 128) and high yield (> or = 7 x 10(6) CD34+ cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34+ yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P < 0.0001). Multivariate Cox's proportional hazards model showed that the CD34+ yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.

Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols.

In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.

Outcome of patients with acute myeloid leukemia who failed to respond to a single course of first-line induction therapy: a GIMEMA study of 218 unselected consecutive patients. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto.

The outcome of a cohort of 218 consecutive patients who failed to respond to a single course of standard daunorubicin plus ARAC (three + seven) induction regimen has been retrospectively evaluated to assess the characteristics of this group of AML patients and the effectiveness of second-line induction programs. Seventy-four of the 218 patients (33.9%) attained complete remission with salvage chemotherapies. The multivariate analysis of pretherapy characteristics of the patients showed that peroxidase positivity and age were the most important factors in determining whether or not the patient would have a favorable response to second-line induction regimen. In addition, comparison of marrow characteristics at diagnosis with those of marrow after the first-line therapy (marrow leukemic index, MLI) provided the greatest differences between second-line CR and resistant patients. Finally, peroxidase positivity and MLI predicted for remission duration and overall survival. Allogeneic BMT, however, appeared the most important factor for survival and event-free survival of remitting patients. These results are of importance when considering that better defined prognostic factors provide an objective rationale for selecting appropriate strategies for the treatment of patients who do not respond to a single course of induction regimen.

Acute megakaryoblastic leukemia: experience of GIMEMA trials.

The objective of the study was to evaluate the incidence, characteristics, treatment and outcome of acute megakaryoblastic leukemia (AMeL) in patients enrolled in GIMEMA trials. Between 1982 and 1999, 3603 new consecutive cases of AML aged over 15 years were admitted to GIMEMA trials. Of them, 24 were AMeL. The incidence of AMeL among AML patients enrolled in GIMEMA trials was 0.6% (24/3603). Diagnosis was based on morphological criteria. Out of 11 cytogenetic studies performed two presented chromosome 3 abnormalities. Twelve patients (50%) reached a CR, five (21%) died in induction and seven (27%) were unresponsive. The median duration of CR was 35 weeks (range 10-441). Seven patients underwent transplantation procedures (1 BMT, 4 aBMT, 2 aPBSCT). Four patients died in CR due to chemotherapy-related complications. Comparing the CR rate between AMeL and the other cases of AML enrolled in GIMEMA trials, no differences were observed. These results were mirrored for different age groups. The median survival was 40 weeks. At present, after a follow-up of a minimum of 2 years, only two patients are alive in CR, all the others having died. A 5-year Kaplan-Meier curve shows a disease-free survival of 17% and an actuarial overall survival of 10%. AMeL is a rare form of AML. The CR duration and the overall survival in this group of patients are very poor, even if similar to those observed in other AML. Furthermore, a high number of deaths in CR were observed. On the basis of these data, a specific therapeutic approach, possibly with innovative treatments, should be evaluated.

High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

Is aggressive chemotherapy the best choice for patients with acute nonlymphocytic leukemia after myelodysplastic syndromes?

Myelodysplastic syndromes (MDS) evolve in overt acute nonlymphocytic leukemia (ANLL) in about 40% of patients: the treatment of ANLL-MDS is not yet well clarified. To identify the role for aggressive and conservative approaches in ANLL-MDS, we evaluated retrospectively 78 patients in a 7-year period. Thirty-one patients (16 males and 15 females, median age 57.5 years, median MDS duration 5.5 months) were eligible for aggressive chemotherapy; 17 patients (54.8%) achieved complete remission (CR), 10 (32.3%) were resistant and 4 (12.9%) died during induction from infective complications. All patients that achieved CR relapsed, with a median CR duration of 6 months (range 2-28 months); median survival of the whole group was 8.5 months, while median survival of responders was 9 months. No prognostic factor revealed a statistical significance in the outcome, due to the small number of patients in each subgroup. Forty-seven patients (27 male and 20 female, median age 71.8 years, median MDS duration 10.1 months) were not eligible for aggressive chemotherapy; 16 patients (34.2%) received supportive care only, 31 patients (65.8%) needed conservative chemotherapy for disease progression. Median survival of the conservatively treated group was 5.5 months, without statistical difference from the aggressively treated group; 10/47 conservatively treated patients (21%) survived for longer than 12 months. In conclusion, aggressive chemotherapy may play a role only in a selected population of ANLL-MDS patients, while further studies could be helpful to identify the optimal conservative approach.

Safety and efficacy of bronchovascular reconstruction after induction chemotherapy for lung cancer.

OBJECTIVE: The aim of this study was to ascertain the safety and efficacy of bronchial sleeve resection and reconstruction of the pulmonary artery in patients who had undergone induction chemotherapy for lung cancer. METHODS: Between January 1991 and July 1996, we operated on 68 patients who had received three cycles of cisplatin-based induction chemotherapy. In 27 of these cases, we performed a lobectomy (n = 25) or bilobectomy (n = 2) associated with reconstruction of the bronchus, the pulmonary artery, or both. In only five additional patients, pneumonectomy had to be carried out. Before chemotherapy, 14 patients were in stage IIIA and 13 were in stage IIIB. All patients in stage IIIB had T4 disease; no N3 cases were included. At thoracotomy, one patient had no evidence of tumor, six were in stage I, 13 were in stage II, six were in stage IIIA, and one was in stage IIIB. Sixteen patients had epidermoid carcinoma and 11 had adenocarcinoma. RESULTS: Sixteen patients underwent bronchial sleeve resection; 11 had various types of pulmonary artery reconstruction, associated with the bronchial sleeve in eight cases. In 26 patients, resection was radical with histologically negative margins. Neither bronchial complications nor deaths occurred. One patient had empyema and two had wound infections. Mean chest tube duration was 6 days. After a postoperative follow-up of 4 to 69 months (mean 25 months), 14 patients are alive and free of disease, one is alive with disease, and 12 have died. There were no local recurrences. The 1- and 4-year survival rates are 78% and 39%, respectively. CONCLUSIONS: Although it is technically demanding, lobectomy associated with bronchovascular reconstruction is feasible, with good immediate and long-term results, after induction chemotherapy.

Multimodality treatment of thymoma: a prospective study.

BACKGROUND: Thymomas are a heterogeneous group of tumors. Treatment of invasive lesions is not well standardized. The aim of this study is to propose a clinicopathologically based protocol for multimodality therapy. METHODS: Between 1965 and 1988, we operated on 83 patients with thymoma who did not receive standardized adjuvant therapy. In 1989, on the basis of the retrospective analysis of the data, we started a multimodality therapy protocol and used it for 65 patients. Twelve patients had medullary thymoma (11 stage I and 1 stage II), 13 had mixed type (6 stage I and 7 stage II), and 40 had cortical thymoma (4 stage I, 11 stage II, 12 stage III, and 13 stage IV). We considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy plus radiotherapy was always administered. Group III (n = 25), malignant thymoma, comprised stage III and IV cortical thymomas and stage III mixed thymomas; resectable stage III lesions were removed, and highly invasive stage III and stage IV lesions underwent biopsy, neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients. RESULTS: The 8-year survival rate for patients in stages I, II, III, and IV was 95%, 100%, 92%, and 68%, respectively. Patients with medullary thymoma had a 92% 8-year survival rate; those with mixed type, 100%; and those with cortical thymoma, 85%. Group I had an 8-year survival rate of 94%; group II, 100%; and group III, 76%. Survival was compared with that of patients operated on before 1989: differences were not significant for group I; survival improved in group II (100% versus 81%; p = not significant); and group III showed significant improvement (76% versus 43%; p < 0.049). CONCLUSIONS: Multimodality treatment with neoadjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy may improve the results of radical resection and the survival of patients with invasive and malignant thymoma.

Bisantrene in relapsed and refractory acute myelogenous leukemia.

Because of the lack of standard treatment in refractory and relapsed acute myelogenous leukemia (AML) several new drugs have been employed alone to evaluate their efficacy in this peculiar category of patient. Bisantrene, a new anthracene bishydrazone derivative, has shown antileukemic effect in phase I and II clinical trials with acceptable extrahaematological toxicity. Seven patients (six males and one female, median age 41.8 years) received Bisantrene (250 mg/sqm/daily 1-7) as a single agent in relapsed or refractory leukemia. 5 out of 7 patients achieved complete remission, one attained partial remission and one was resistant. However, haematological toxicity was severe with prolonged myelosuppression. Hepatic toxicity was the main extrahaematological side effect and occurred in 3 of 7 patients, however all of them recovered within 40 days. No cardiovascular dysfunction occurred although all the patients had been heavily previously treated with anthracyclines. Our data confirm that Bisantrere is active in relapsed and refractory AML and suggest the need for larger clinical trials to better evaluate its efficacy.

Is recombinant human erythropoietin treatment in myelodysplastic syndromes worthwhile?

It has been recently demonstrated that erythropoietin increases the haemoglobin levels in anemia secondary to chronic renal failure. Moreover some recent experiences also suggested a possible role in the treatment of MDS. From April 1990 to April 1992, 23 patients (16 males and 7 females, median age 63.5 years) affected with low risk myelodysplastic syndrome (MDS) were treated with recombinant human erythropoietin (rHuEPO) to ameliorate Hb levels and transfusional requirement. All patients received high doses of rHuEPO (800 U/Kg weekly s.c. in 2-3 divided doses, for 3 months). A complete remission, defined as stable normalization of Hb level, was achieved in 1/23 patients. This patient had refractory anemia, by FAB criteria. A partial response, defined as stable increase of Hb levels > or = 1 g/dl and/or reduction of transfusional requirement > or = 50% lasting at least 3 months, was achieved in 7/23 patients. Patients with a partial response received rHuEPO at increased dosages (1200 U/Kg weekly s.c. 2-3 times): 1/7 achieved a complete response, 4/7 remained stable and 2/7 decreased to pre-therapy Hb value. These results suggest that rHuEPO may be a promising therapeutic tool for some MDS patients.

Reversal of encephalopathy during treatment with amphotericin-B.

A case of reversible encephalopathy during treatment with Amphotericin-B (AMB) is described. The comparison of the clinical course of AMB encephalopathy with total dose of AMB, cranial radiotherapy and MRI data available in previously reported cases, shows that this complication is characterized by a progressive, dose-dependent course, possibly influenced by cranial irradiation.

Is workflow technology suitable to represent and manage clinical trials?

The clinical trial has to be rigidly followed because it identifies a uniform clinical behaviour, which has to be adopted by the different physicians carrying out the test. The life cycle of the clinical trial is therefore based on a planning and definition phase, a next experimental phase connected with its diffusion to the involved centres and finally an evaluation phase of the results. An information system, which supports the users in the different phases of the clinical trial life cycle, has to take into account the different characteristics of each phase. The aim of this paper is to illustrate the role of WF technology as a component of an information system which supports the life cycle of a clinical trial also on the basis of the experience of the Italian Group for Haematological Disease of Adults (GIMEMA).

Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors.

BACKGROUND: An increased risk of thrombosis has been reported in primary immune thrombocytopenia (ITP) and with the use of thrombopoietin (TPO) receptor agonists, on the basis of population studies using administrative databases. OBJECTIVES: To evaluate if the incidence of venous and arterial thrombosis in patients with primary ITP is higher than a clinically significant cut-off set at of 3% and 6.4%. PATIENTS/METHODS: We undertook a retrospective multicenter investigation in a large cohort of patients requiring at least one treatment for ITP, enrolled from the major tertiary Italian centers treating ITP. A total of 986 patients were analyzed. RESULTS: During a 3888 patient-year follow-up, 43 first thrombotic events occurred: 28 arterial and 15 venous, resulting in a cumulative incidence of 3.2% for arterial (95% CI, 2.0-5.0) and 1.4% (95% CI, 0.8-2.5) for venous thrombosis at 5 years. The annualized rates for 100 patient-years were 1.14 (95% CI, 0.84-1.54), 0.39 (95% CI, 0.23-0.65) and 0.71 (95% CI, 0.49-1.04) for total, venous and arterial thrombosis. Splenectomy, performed in 136 patients (13.7%), increased thrombotic risk (HR = 3.5, 95% CI) compared with non-splenectomized patients. Age > 60 years, more than two risk factors for thrombosis at diagnosis and steroid use were independently associated with an increased risk of thrombosis. CONCLUSIONS: In this study, we demonstrate that the 5-year cumulative incidence of venous and arterial thrombosis in ITP is well below the predefined thresholds. Venous and arterial thromboembolism are not frequent complications in ITP, except in particular settings, such as in splenectomized and elderly patients.