Enrico Maria Pogliani

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the italian registry

PURPOSE To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND METHODS Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death. RESULTS Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkins lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each). CONCLUSIONS The present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Context Optimal duration of anticoagulation after pulmonary embolism is uncertain, but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors. Contribution After 3 months of successful anticoagulation, 326 patients were randomly assigned to stop therapy immediately or extend therapy to 6 months or 1 year. Regardless of duration of anticoagulation, 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy. Implications Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued. Patients at high risk for recurrence may require indefinite anticoagulation. The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment (1, 2). On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued, different durations of oral anticoagulation are currently recommended in different patient categories. A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors (3-5). Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis (1, 2, 5-7). Only a limited proportion of patients included in these studies presented with pulmonary embolism. Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease. However, patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis (8, 9). We performed a multicenter randomized trial to evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism. The primary outcome of the study was symptomatic, objectively confirmed recurrence of venous thromboembolism. Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic, objectively confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of oral anticoagulant therapy without having a recurrence or bleeding. The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objectively diagnosed deep venous thrombosis. Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors. Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer, known thrombophilia, or any transient risk factor for venous thromboembolism. Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture, recent surgery or childbirth, or prolonged immobilization (that is, lasting >7 days), or occurring during the use of oral contraceptives or pregnancy. Patients with pulmonary embolism associated with permanent risk factors (known cancer or known thrombophilia) were excluded from the study. Systematic screening for occult cancer or thrombophilia was not performed before enrollment. Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than 2 years, those who could not return for the follow-up visits, and those who declined to participate. The institutional review boards of the participating hospitals approved the study; all patients gave informed consent. Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism (WODIT-PE) was a multicenter randomized, open trial with independent, blinded assessment of the outcome events. The study was designed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism. Patients who had completed 3 months of warfarin or acenocumarol therapy were randomly assigned to discontinue anticoagulation or to continue it for 3 additional months (pulmonary embolism associated with transient risk factors) or 9 additional months (idiopathic pulmonary embolism). Randomization was performed centrally in permuted blocks of six. The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the study centers, all in Italy. Outcome Measures The primary outcome of the study was the recurrence of symptomatic, objectively confirmed venous thromboembolism after the initial 3 months of anticoagulation. The secondary outcome was the cumulative incidence of adverse outcome events (recurrence of venous thromboembolism, death, or major bleeding). The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan. Sudden, otherwise unexplained death was also considered a recurrence of pulmonary embolism. The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography. In patients with deep venous thrombosis at baseline, the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography (proximal veins) or venography in the contralateral leg or, in the ipsilateral leg, an extension of an intraluminal filling defect on venography; a newly noncompressible venous segment; or an increase of 4 mm or more in the diameter of the thrombus (proximal veins) on ultrasonography (10). Bleeding was defined as major if it was clinically overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells, if it was retroperitoneal or intracranial, if it warranted the permanent discontinuation of therapy with the study drug, or if it required rehospitalization. Deaths were classified as the result of pulmonary embolism, bleeding, or another identifiable cause or as unexplained. All suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths were reviewed centrally by an independent, external adjudication committee whose members were unaware of the treatment group assignments. Follow-up Patients were instructed to return for follow-up visits at 3, 6, and 12 months after randomization and every 6 months thereafter until the completion of the study. Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed. For all patients who died during the follow-up period, the date and cause of death were documented. We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death. Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic, objectively confirmed recurrence of venous thromboembolism in the two treatment groups. The analysis was performed on an intention-to-treat basis. It was assumed that the rate of recurrence of venous thromboembolism would be 12% in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation. We also assumed that the prolongation of oral anticoagulant therapy would produce a 50% reduction in the risk for recurrence. Given these assumptions, we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80% and a type I error rate of 5%. To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen, one prespecified interim analysis of efficacy and safety was planned after we randomly assigned 50% of planned patients. The following criteria for stopping the trial were defined a priori: an overall rate of recurrence of thromboembolic events lower than 7.5%, an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy (P < 0.001 by a one-sided test), a risk for recurrence in the continued therapy group that was less than 25% lower than that in the group assigned to discontinue therapy, or a rate of major bleeding higher than 5% in the continued therapy group. The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method (11). Rates of recurrence in the two groups were compared with the use of the log-rank test (12). Results Patients Patients were recruited between January 1997 and December 2000 when, after 326 patients were included, the results of the interim analysis showed a difference of less than 25% in the risk for recurrent venous thromboembolism between the two treatment groups. At the time of

Multicenter Independent Assessment of Outcomes in Chronic Myeloid Leukemia Patients Treated With Imatinib

BACKGROUND Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. PATIENTS AND METHODS Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided. RESULTS A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. CONCLUSIONS In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.

ABVD versus BEACOPP for Hodgkin's Lymphoma When High-Dose Salvage Is Planned

BACKGROUND BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkins lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS We randomly assigned 331 patients with previously untreated and unfavorable Hodgkins lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. RESULTS The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. CONCLUSIONS Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).

Recurrent SETBP1 Mutations in Atypical Chronic Myeloid Leukemia

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.

Crizotinib in Anaplastic Large-Cell Lymphoma

The anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been shown to induce a response in lung cancers in which ALK is mutated. Crizotinib is also effective in anaplastic large-cell lymphoma, the tumor in which ALK rearrangement was initially detected.

Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments

Polycythemia vera and essential thrombocythemia are typically complicated by thrombosis. According to this multicenter study recurrent thrombosis is observed in about one third of patients. Cytoreduction protects against recurrence of thrombosis. The contemporary use of oral anticoagulants or antiplatelet agents further reduce the incidence of re-thrombosis. Background Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence. Design and Methods We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed. Results Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19–2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02–12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38–0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15–0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22–0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13–0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16–0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents. Conclusions In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage

In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS-like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.

Chemotherapy-Phased Imatinib Pulses Improve Long-Term Outcome of Adult Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Northern Italy Leukemia Group Protocol 09/00

PURPOSE Short imatinib pulses were added to chemotherapy to improve the long-term survival of adult patients with Philadelphia chromosome (Ph) -positive acute lymphoblastic leukemia (ALL), to optimize complete remission (CR) and stem-cell transplantation (SCT) rates. PATIENTS AND METHODS Of 94 total patients (age range, 19 to 66 years), 35 represented the control cohort (ie, imatinib-negative [IM-negative] group), and 59 received imatinib 600 mg/d orally for 7 consecutive days (ie, imatinib-positive [IM-positive] group), starting from day 15 of chemotherapy course 1 and from 3 days before chemotherapy during courses 2 to 8. Patients in CR were eligible for allogeneic SCT or, alternatively, for high-dose therapy with autologous SCT followed by long-term maintenance with intermittent imatinib. RESULTS CR and SCT rates were greater in the IM-positive group (CR: 92% v 80.5%; P = .08; allogeneic SCT: 63% v 39%; P = .041). At a median observation time of 5 years (range, 0.6 to 9.2 years), 22 patients in the IM-positive group versus five patients in the IM-negative group were alive in first CR (P = .037). Patients in the IM-positive group had significantly greater overall and disease-free survival probabilities (overall: 0.38 v 0.23; P = .009; disease free: 0.39 v 0.25; P = .044) and a lower incidence of relapse (P = .005). SCT-related mortality was 28% (ie, 15 of 54 patients), and postgraft survival probability was 0.46 overall. CONCLUSION This imatinib-based protocol improved long-term outcome of adult patients with Ph-positive ALL. With SCT, post-transplantation mortality and relapse remain the major hindrance to additional therapeutic improvement. Additional intensification of imatinib therapy should warrant a better molecular response and clinical outcome, both in patients selected for SCT and in those unable to undergo this procedure.

Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome

The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkins lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkins disease (HD, n=32). Median follow-up was 33 months (range, 12–82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL