Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980.

PURPOSE: The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years. PATIENTS AND METHODS: The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received. RESULTS: Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). CONCLUSION: Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.

Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and Lu/BCAM.

Patients with polycythemia vera (PV) have a JAK2 (a cytosolic tyrosine kinase) mutation and an increased risk of vascular thrombosis related to red blood cell (RBC) mass and platelet activation. We investigated functional RBC abnormalities that could be involved in thrombosis. RBC adhesion to human umbilical vein endothelial cells (HUVECs) was measured by a radiometric technique and in a flow system by video microscopy, and adhesion molecule expression was determined using specific antibodies (against CD36, CD49d, ICAM-4, Lu/BCAM, CD147, and CD47) and flow cytometry in a group of 38 patients with PV and a group of 36 healthy volunteers. Adhesion of PV RBCs was 3.7-fold higher than that of normal RBCs (P < .001). Adhesion was inhibited when PV RBCs were incubated with anti-Lutheran blood group/basal cell adhesion molecule (Lu/BCAM) or when HUVECs were treated with anti-laminin alpha(5) and to a lesser extent with anti-alpha(3) integrin. Lu/BCAM was constitutively phosphorylated in PV RBCs. Transfection of K562 cells with JAK2 617V>F resulted in increased expression and phosphorylation of Lu/BCAM. Phosphorylation of Lu/BCAM increases RBC adhesion. Our results indicate that JAK2 mutation might be linked to Lu/BCAM modification and increased RBC adhesiveness, which may be a factor favoring thrombosis in PV.

Leukocyte scintigraphy compared to intraoperative small bowel enteroscopy and laparotomy findings in Crohn's disease.

BACKGROUND: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings. METHODS: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data. RESULTS: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed. CONCLUSIONS: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.

Monoclonal immunoglobulin with antitransferrin activity: A rare cause of hypersideremia with increased transferrin saturation.

Two unusual but similar cases of very high serum iron, extremely high transferrin concentrations (5.4 to 6.5 g/L), and increased transferrin saturation are reported. No anemia or microcytosis was observed. The ferritin concentration remained within the normal range, and no iron overload was observed. In one case, the in vivo half-life of 59Fe-labeled transferrin was shown to be prolonged (206 minutes versus 75 minutes for controls). In both patients, a monoclonal IgG was observed in the serum. The association between serum transferrin and monoclonal IgG was demonstrated by Western blot analysis and affinity chromatography. We suggest that the transferrin bound to the monoclonal IgG molecule has a prolonged half-life in the circulation, leading to high transferrin concentrations, and that the increased serum iron values prevent the onset of anemia. The antitransferrin activity of monoclonal antibody should be added to the list of situations accounting for elevated serum iron with elevated transferrin saturation.

Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia.

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a.

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.

[Polycythemia vera]. / Maladie de Vaquez.

Polycythemia vera (PV) is a chronic myeloproliferative disorder due to a haematopoietic stem cell's clonal proliferation. PV is also characterized by independency or hyper sensibility of haematopoietic progenitors to several cytokine as erythropoietin. This acquired disorder is often associated with thrombocytosis, leukocytosis and splenomegaly. Generally, diagnosis remains easy, based on basic clinical and biological abnormalities. Sometimes, positive diagnosis required more sophisticated tests as assay of endogenous erythroid colony, erythropoietin blood level and bone marrow biopsy. Usually natural history of disease remains long with a good quality of life. In some cases complications occur: mainly thrombosis and late myeloid metaplasia with myelofibrosis and acute leukemia. Therapeutic approachs remain complex and difficult to optimize based up on age and disease severity. Treatment searchs for reducing hyper viscosity complications and for avoiding therapeutic induced leukemia.

[Understanding positon emission tomography (PET) with [18F]-FDG in clinical oncology. Informations dedicated to patients and relatives]. / Comprendre la tomographie par émission de positons au [ 18F]-FDG en cancérologie. Information à l'usage des personnes malades et de leurs proches.

In response to the evolution of the information-seeking behaviour of patients and concerns from health professionals regarding cancer patient information, the French National Federation of Comprehensive Cancer Centres (FNCLCC) introduced, in 1998, an information and education program dedicated to patients and relatives, the SOR SAVOIR PATIENT program (SSP). The methodology of this program adheres to established quality criteria regarding the elaboration of patient information. Cancer patient information, developed in this program, is based on clinical practice guidelines produced by the FNCLCC and the twenty French regional cancer centres, the National League against Cancer, the French Hospital Federation, the National Oncology Federation of Regional and University Hospitals, the French Oncology Federation of General Hospitals, many learned societies, as well as an active participation of patients, former patients and caregivers. The guidelines, "Standards, Options: Recommendations" (SOR) are used as primary information sources. The handbook SOR SAVOIR PATIENT Understanding positron emission tomography (PET) with [18F]-FDG in clinical oncology, integrally published in this issue of the Bulletin du Cancer, is an adapted version of the clinical practice guidelines (CPG) Standards, Options and Recommendations for positron emission tomography (PET) with [18F]-FDG in clinical oncology. The main objectives of this article are to allow persons affected by cancer and their close relatives to better understand this medical imaging technique and its implementation. This document also offers health professionals a synthetic evidence-based patient information source that should help them communicate that information during the physician-patient encounter. Positron emission tomography (PET) is a scintigraphy technique using a radiotracer, [18F]-fluorodeoxyglucose (abbreviated [18F]-FDG), administered intravenously into the patient's arm. This tracer, similar to glucose (sugar), binds to cancer cells and temporarily emits radiations that can be recorded by a special camera in the PET scanner. PET scanning can be used to obtain complementary information at different stages of the disease, whether for assessing diagnosis, treatment evolution or follow-up. By 2007, in the framework of the government plan against cancer, about seventy-five PET scanners are expected to be installed in France. Twenty-four are currently in use; a similar number is under installation. At the end of this process, all French regions should have at least one PET imaging equipment. The SOR SAVOIR PATIENT guide: Understanding positron emission tomography (PET) with [18F]-FDG in clinical oncology and the integral report of CPG SOR 2003: Standards, Options and Recommendations for positron emission tomography (PET) with [18F]-FDG in clinical oncology can be downloaded from the FNCLCC website: http:\\www.fnclcc.fr.

[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome.

Assessment of early therapeutic response using metabolic imaging is potentially useful to determine prognosis in aggressive lymphoma. Between January 2000 and January 2004, 90 patients with newly diagnosed aggressive lymphoma (median age 53 years, 94% diffuse large B-cell) were prospectively explored with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) prior to induction chemotherapy, after 2 cycles ("early PET"), and after induction completion. Therapeutic response was evaluated using conventional diagnostic methods at 4 cycles. Induction treatment with an anthracycline-containing regimen was administered to all patients, associated with rituximab in 41%. According to the International Prognostic Index (IPI), 37 patients and 53 patients belonged to the lower- and higher-risk groups, respectively. At midinduction, "early PET" was considered negative in 54 patients and positive in 36. After completion of induction, 83% of PET-negative patients achieved complete remission compared with only 58% of PET-positive patients. Outcome differed significantly between PET-negative and PET-positive groups; the 2-year estimates of event-free survival reached 82% and 43%, respectively (P < .001), and the 2-year estimates of overall survival reached 90% and 61%, respectively (P = .006). Predictive value of "early PET" was observed in both the lower-risk and higher-risk groups, indicating prognostic independence from the IPI. Therefore, FDG-PET should be an early guide to first-line strategies in aggressive lymphoma.

Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells.

Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.

Risk of leukemic transformation in PV and ET patients.

Despite a prolonged survival of around 15 years linked to a prolonged complete remission induced by myelosuppression, myeloproliferative syndromes such as polycythemia vera (PV) and essential thrombosis (ET) remain at risk of lethal adverse affects such as thrombotic events and acute transformation. The major risk at diagnosis, in the absence of treatment, is essentially thrombosis. Different therapeutic trials have shown the necessity to maintain circulating blood cells (RBC and platelets counts) near normal levels to avoid thrombosis. Phlebotomies alone in PV lead in the long run to metaplasia and increased platelet counts and should only be kept for emergency cell count reduction. Myelosuppression is thus until recently the most widely accepted effective alternative. However, the effects of long term chronic administration of myelosuppresive agents needs to be analyzed and monitored as the biological changes which appear during the course of these diseases linked or not to the intrinsic clonal haematopoietic abnormality may lead to malignant transformation. Thus, alternative therapies need to be evaluated and predisposition factors taken in account.

[Impact of [18F]-FDG-PET on medical decision making in oncology: evaluation by the referring physicians during the opening year]. / Impact de la TEP au [18F]-FDB sur la décision médicale en cancérologie: évaluation par les prescripteurs durant la première année de fonctionnement.

The first study evaluating directly by the referring physician the clinical impact of [18F]-FDG-PET on modification of patient's management was performed only recently in California by means of a questionnaire. We have used the same methodology to evaluate this clinical impact during the opening year of our PET centre in France. A questionnaire was sent to the referring physician of each of the 476 patients who had at least one routine FDG-PET examination during the year 2000. Of 348 responses (response rate = 73%), the disease was upstaged in 26% of the cases and down-staged in 9%. Intermodality management changes (change from a scheduled therapeutic modality for a different one) were reported in 37% of the cases and intramodality changes in 9%. Those modification rates were respectively 38% and 7% in recurrence of colorectal cancer (153 patients), 47% and 7% in lung cancer (118 patients), 16% and 23% in lymphoma (43 patients), 25% and 6% in the staging of head and neck cancers (32 patients). When comparing with the corresponding studies performed in California, there were no significant differences between the rates of intermodality management changes. In contrast, intramodality management changes were less frequent in our survey, except for lymphoma. Globally, the clinical impact of FDG PET was similar with a higher response rate in our study (73% versus 35%); it was above the mean rate derived from a recent meta-analysis in more than 5,000 patients.