Comparative Analysis between [(18)F]Fludarabine-PET and [(18)F]FDG-PET in a Murine Model of Inflammation.

Lymphoma research has advanced thanks to introduction of [(18)F]fludarabine, a positron-emitting tool. This novel radiotracer has been shown to display a great specificity for lymphoid tissues. However, in a benign process such as inflammation, the uptake of this tracer has not been questioned. Indeed, in inflammatory zones, elevated glucose metabolism rate may result in false-positives with [(18)F]FDG-PET Imaging. In the present investigation, it has been argued that cells, involved in inflammation, might be less avid of [(18)F]fludarabine. To generate inflammation, Swiss mice were intramuscularly injected with 0.1 mL of turpentine oil into the right front paw. Imaging sessions with (18)F-labeled tracers named above were conducted on days 5 and 25 after inoculation. For each animal, volumes of interest (VOI), delineating the muscle of the inflamed (IP) and normal paws (NP), were determined on PET scans. For characterization of inflammation, muscle samples from IP and NP were stained with hematoxylin and eosin (H&E). In early (day 5) inflammation, [(18)F]FDG accumulation was 4.00 ± 1.65 times greater in the IP than in the contralateral NP; for [(18)F]fludarabine, this IP/NP ratio was 1.31 ± 0.28, resulting in a significant difference between radiotracer groups (p < 0.01). In late (day 25) inflammation, the IP/NP ratios were 2.07 ± 0.49 and 1.03 ± 0.07, for [(18)F]FDG and [(18)F]fludarabine, respectively (p < 0.001). [(18)F]Fludarabine showed significantly weaker uptake in inflammation when compared with [(18)F]FDG. This encouraging finding suggests that [(18)F]fludarabine-PET might well be a robust approach for distinguishing tumor from inflammatory tissue, avoiding false-positive PET results and thus enabling an accurate imaging of lymphoma.

Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study.

In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit.

Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation.

We present results of a phase 3 randomized trial of autografting in chronic lymphocytic leukemia versus observation for responding patients after first- or second-line treatment. The primary objective was to demonstrate that autografting improves the 5-year event-free survival (EFS) from 30% to 50%. There were 223 enrolled patients, 72% men and 28% women, 83% after first and 17% after second-line treatment. Binet stages were progressive A 13%, B 67%, C 20%; at randomization, 59% were in complete remission, and 41% in less than complete remission. Patients were randomized between autografting (n = 112) and observation (n = 111). Median EFS was 24.4 months (range, 16.7-32 months) in the observation group and 51.2 months (39.8-62.5 months) in the autografting group; the 5-year EFS was 24% and 42%, respectively (P < .001). Accordingly, the 5-year relapse incidence was 76% versus 54% (P < .001). Median time to relapse requiring therapy or death was 40 months (25-56 months) in the observation arm and 65 months (59-71 months) after autografting (P = .002). Cox modeling confirmed that autografting significantly improved EFS (hazard ratio 0.44, 95% confidence interval 0.30-0.65; P < .001). At 5 years, the probability of OS was 85.5% and 84.3% for autografting and observation, respectively (P = .77). In chronic lymphocytic leukemia, consolidating autografting reduces the risk of progression by more than 50% but has no effect on overall survival.

Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC.

Long-term responses have been reported after autologous stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL). We conducted a prospective, randomized trial of ASCT in previously untreated CLL patients. We enrolled 241 patients < 66 years of age with Binet stage B or C CLL. They received 3 courses of mini-CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone) and then 3 courses of fludarabine. Patients in complete response (CR) were then randomized to ASCT or observation, whereas the other patients were randomized to dexamethasone, high-dose aracytin, cisplatin (DHAP) salvage followed by either ASCT or 3 courses of fludarabine plus cyclophosphamide (FC). The primary end point was event-free survival (EFS). After up-front treatment, 105 patients entered CR and were randomized between ASCT (n = 52) and observation (n = 53); their respective 3-year EFS rates were 79.8% and 35.5%; the adjusted hazard ratio was 0.3 (95% CI: 0.1-0.7; P = .003). Ninety-four patients who did not enter CR were randomized between ASCT (n = 46) and FC (n = 48); their respective 3-year EFS rates were 48.9% and 44.4%, respectively; the adjusted hazard ratio was 1.7 (95% CI: 0.9-3.2; P = .13). No difference in overall survival was found between the 2 response subgroups. In young CLL patients in CR, ASCT consolidation markedly delayed disease progression. No difference was observed between ASCT and FC in patients requiring DHAP salvage.

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia.

BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.

PHD2 mutation and congenital erythrocytosis with paraganglioma.

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.

Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study.

Whether rituximab could effectively and safely avoid splenectomy for adults with chronic immune thrombocytopenic purpura (ITP) remains unresolved. A multicenter, prospective, open-label, single-arm, phase 2 trial was conducted to assess rituximab safety and efficacy in adult splenectomy candidates with chronic ITP. Sixty patients with chronic (>or= 6 months) ITP and platelet counts less than 30 x 10(9)/L received a weekly intravenous infusion of rituximab (375 mg/m(2)) for 4 weeks. All other ITP treatments were stopped. A good response was defined as a platelet count 50 x 10(9)/L or more, with at least a doubling of the initial value at 1 and 2 years after the first rituximab infusion. Patients who required another treatment during follow up were considered nonresponders. Sixteen patients experienced transient side effects that necessitated treatment discontinuation for only 1. Good 1-year responses were obtained in 40% of the patients (24/60 [95% confidence interval: 28%-52%]). At 2 years, 33.3% (20/60 patients) had good responses and 6.7% (4/60) had sustained platelet counts of 30 x 10(9)/L or more without treatment. Thirty-six (60%) patients failed to respond; 25 underwent splenectomy. Based on these results, rituximab was an apparently safe and effective splenectomy-avoiding option in some adults with chronic ITP. This trial is registered at http://clinicaltrials.gov as NCT00225875.

Occupational exposure to organic solvents and lymphoid neoplasms in men: results of a French case-control study.

OBJECTIVES: Investigating the role of occupational exposure to solvents in the occurrence of lymphoid neoplasms (LNs) in men. METHODS: The data were generated by a French hospital-based case-control study, conducted in six centres in 2000-2004. The cases were incident cases aged 18-75 years with a diagnosis of LN. During the same period, controls of the same age and gender as the cases were recruited in the same hospitals, mainly in the orthopaedic and rheumatological departments. Exposure to solvents was assessed using standardised occupational questionnaires and case-by-case expert assessment. Specific quantification of benzene exposure was attempted. The analyses included 491 male patients (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma, 104 of lymphoproliferative syndrome and 56 of multiple myeloma) and 456 male controls. Unconditional logistic regressions were used to estimate OR and 95% CI. RESULTS: Solvent exposure, all solvents considered together, was marginally associated with NHL (OR=1.4 (1.0 to 2.0) p=0.06), but not with other LNs. No association with the main chemical series of solvents was observed. There was no trend with the average intensity or frequency of exposure. Exposure to pure benzene was not significantly related to NHL (OR=3.4 (0.8 to 15.0)). The highest maximum intensities of benzene exposure were associated with diffuse large cell lymphoma (OR=2.1 (1.0 to 4.6)). CONCLUSION: The results of the present study provide estimates compatible with the hypothesis that exposures to pure benzene and high benzene intensities may play a role in some NHL. There was no evidence for a role of other organic solvents in the occurrence of LN.

Increased frequency of hematopoietic malignancies in relatives of patients with lymphoid neoplasms: a French case-control study.

Lymphoid neoplasms (LNs), including non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), lymphoproliferative syndrome (LPS) and multiple myeloma (MM), are among the most frequent cancers ( approximately 17,000 new cases per year in France), after those related to smoking. LNs were investigated using the data from the ENGELA study. ENGELA is a multicenter hospital-based case-control study that was carried out in France over the period September 2000-December 2004. In all, 822 cases (397 NHL, 149 LH, 168 SLP and 108 MM) and 752 controls were included and described 5,481 and 5,188 first-degree relatives, respectively. A positive association with a familial history of hematopoietic cancer was observed for LN (OR = 1.7 [1.0-2.8]) overall and for LPS (OR = 3.2 [1.4-6.8]). The associations with HL (OR = 10.4 [2.0-53.8]) and NHL (OR = 2.4 [1.0-5.9]) were stronger for men. The associations were also stronger when the disease had been diagnosed before the relatives were aged 45 years. The results mainly support the involvement of genetic factors and suggest that at least some of those factors may be sex-linked. However, the slight overrepresentation of affected spouses among the cases might also support the responsibility of environmental factors.

IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide.

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16-74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD(+). Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.

High efficacy with five days schedule of oral fludarabine phosphate and cyclophosphamide in patients with previously untreated chronic lymphocytic leukaemia.

A multicentre single-arm study testing the efficacy and toxicity of the oral combination of fludarabine and cyclophosphamide (FC) over 5 d in 75 patients with untreated B cell-chronic lymphocytic leukaemia. Oral FC demonstrated high efficacy with overall (OR) and complete response (CR) rates of 80% and 53%, respectively. Out of the 30 CR patients studied for Minimal Residual Disease (MRD) using 4-colour flow-cytometry and the 22 using Clonospecific polymerase chain reaction, 22 (66%) and 16 (68%), respectively, were MRD negative. Median survival and median treatment-free interval had not been reached at 7 years of follow-up. Median progression-free survival (PFS) was 5 years. Toxicity was acceptable, with 52% and 16% of National Cancer Institute grade 3/4 neutropenia and infections, respectively. Gastrointestinal toxicity was mild. Oral FC demonstrated a high efficacy and an acceptable safety profile and may be considered as the standard first line treatment in chronic lymphocytic leukaemia.

[Chronic lymphocytic leukemia]. / Leucémie lymphoïde chronique.

Chronic lymphocytic leukemia results from a proliferation/accumulation of monoclonal B lymphocytes. The diagnosis is easily made on blood cytology and immunophenotype. The complexity of mechanisms which govern the clonal evolution translate in a large pronostic diversity on long-term outcome, with a life expectancy ranging from a few years to more than 25 years in the most indolent forms. Prognostic appraisal is currently based on clinical and hematological presentation, whereas cytogenetics, immunoglobulin gene status, expression of proteins involved in cell proliferation such as ZAP70 or CD38 provide more precise but non routine indications. Although there is a lot of effective drugs against the clonal process, any of them are curative, and long term benefit of treatment tailored on individual prognostic features still deserves further studies. Therefore, current treatment recommendations aim at sustaining quality of life in elderly patients, whereas response quality and length are the main targets in younger ones.

18F-Fludarabine PET for Lymphoma Imaging: First-in-Humans Study on DLBCL and CLL Patients.

This was the first-in-humans clinical study of 18F-fludarabine, which is a radiopharmaceutical for PET imaging in lymphoma, for which many issues remain controversial with the standard radiotracer 18F-FDG. Methods:18F-fludarabine PET or PET/CT was performed on 10 patients: 5 with diffuse large B-cell lymphoma (DLBCL) and 5 with chronic lymphocytic leukemia. The tumor uptake, biodistribution, and radiation dosimetry of 18F-fludarabine were evaluated. Six successive partial-body PET scans were acquired for 250 min after an intravenous 4 MBq/kg bolus of 18F-fludarabine. SUVs were recorded for each involved lymph node territory and for several extranodal sites, with particular reference to the liver. To assess the time-related uptake profile of 18F-fludarabine, PET images were analyzed by delineating volumes of interest over the uptake sites on the optimal scan for visual observation and were projected onto all coregistered scans of the same subject. Physical examination, laboratory studies, and contrast-enhanced CT were performed on all patients. For the DLBCL group, 18F-FDG PET was also considered. Results: In DLBCL patients, increased 18F-fludarabine uptake was observed in sites considered abnormal by CT or 18F-FDG, with SUVs significantly higher in involved lesions than in physiologic nontarget sites. Nonetheless, the comparison of 18F-fludarabine and 18F-FDG PET showed discrepancies in 2 patients. In chronic lymphocytic leukemia patients, the uptake of 18F-fludarabine coincided with sites expected to be involved (including splenic invasion) according to conventional clinical and CT staging and was significant in hematopoietic bone marrow. No uptake was observed, whatever the disease group, in cardiac muscle or brain. The mean effective dose from a mean injected 18F-fludarabine activity of 305 ± 76 MBq was 3.07 ± 0.81 mSv. Conclusion:18F-fludarabine PET might well be a promising tool for lymphoproliferative diseases. The radiation dose of this radiopharmaceutical is below that of 18F-FDG. The specificity of this PET probe for lymphoid cells, its absence of accumulation in reactive tissues, and its feasibility for detection of bone marrow infiltration might play an innovative role in lymphoma imaging.

Occupation and lymphoid malignancies: results from a French case-control study.

OBJECTIVES: Investigating relationships between potential occupational risk factors and lymphoid malignancy (LM). METHODS: We conducted a multicenter hospital-based case-control study in France between 2000 and 2004, including 824 incident cases of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma, and "lymphoproliferative syndrome" and 752 frequency-matched controls. Data were collected through face-to-face standardized and detailed interviews. RESULTS: Farming was significantly associated with NHL (odds ratio [OR] = 1.4 [1.0 to 2.0]) and, although not significantly, with lymphoproliferative syndrome and multiple myeloma. ORs were higher for longest durations of exposure. Self-declared exposure to pesticides was significantly associated with NHL (OR = 1.8 [1.2 to 2.7]) and HL (OR = 2.2 [1.0 to 4.7]). Neither solvent-related jobs nor self-reported exposure to solvents were related to LM. Systematic screening based on job titles did not evidence any other association. CONCLUSIONS: The results support the hypothesis that farming plays a role in most types of LM.

Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study.

BACKGROUND AND OBJECTIVES: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM. DESIGN AND METHODS: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions. RESULTS: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05). INTERPRETATION AND CONCLUSIONS: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.

Prognostic value of early 18 fluorodeoxyglucose positron emission tomography and gallium-67 scintigraphy in aggressive lymphoma: a prospective comparative study.

The prognostic value of fluorodeoxyglucose positron emission tomography (FDG-PET) and gallium-67 scan (GS) performed early after chemotherapy was assessed in 40 patients with newly diagnosed aggressive lymphoma. FDG-PET and GS were performed before and after three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or two cycles of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone), with or without rituximab. Thirty-five patients had diffuse large B-cell lymphoma (DLBCL), two had mantle-cell lymphoma and three had T-cell lymphoma. Four patients relapsed despite early negative FDG-PET and GS including all three patients with T-cell lymphoma. Nine patients stayed in remission despite positive FDG-PET and/or GS of whom five showed moderate intensity residual bone uptake. Seven of these nine early false positives had a negative exam at the end of treatment. In patients with DLBCL, the 2-year event-free survival was 85% for negative versus 30% for positive FDG-PET patients (P = 0.003) whereas it was 78% for negative versus 33% for positive GS patients (P = 0.018). Sensitivity, specificity and diagnostic accuracy of FDG-PET and GS were not significantly different: 90% versus 70%, 76 versus 80% and 80 versus 77%, respectively. We conclude that both FDG-PET and GS are valuable tools to early predict outcome in patients with DLBCL.

Evaluation of the specificity of [(18)F]fludarabine PET/CT in a xenograft model of follicular lymphoma: comparison with [(18)F]FDG and impact of rituximab therapy.

BACKGROUND: [(18)F]Fludarabine is a novel positron emission tomography (PET) radiotracer for imaging lymphoma. The purpose of this preclinical study was to evaluate the robustness of [(18)F]fludarabine during rituximab therapy. In addition, a comparison was made between [(18)F]fludarabine and [(18)F]fluorodeoxyglucose ([(18)F]FDG) with regard to their concordance with histologically derived data. METHODS: CB17-SCID mice bearing human follicular DOHH-2 lymphoma were treated once weekly with rituximab (10 mg/kg) or physiological saline over 3 weeks. To obtain the tracer uptake in the metabolically active volume of the tumour (MAVT), a background-level threshold was applied to the volume of interest (VOI) defined on computed tomography (CT) image. The tumour uptake analysis was performed with MAVT-based segmentation for data analysis of sequential [(18)F]fludarabine PET/CT studies and with total tumour-based segmentation for comparison with histologically derived data. RESULTS: The correlation between the MAVT and [(18)F]fludarabine accumulation (%ID) in those viable tissues was equally significant for both vehicle- or rituximab-treated mice; for these latter, the presence of lymphoid tissues at the end of imaging sessions was confirmed histologically. A stronger correlation was demonstrated between quantitative values extracted from [(18)F]fludarabine-PET and histology (r (2) = 0.91, p < 0.001) when compared to [(18)F]FDG-PET (r (2) = 0.55, p = 0.03). CONCLUSIONS: [(18)F]Fludarabine uptake in the follicular lymphoma model compared favourably with [(18)F]FDG in terms of specificity for PET imaging and also remained robust for persistent viable tissues following rituximab therapy. [(18)F]Fludarabine PET/CT may be a promising approach to evaluate lymphoma, including their surveillance during therapy.

Role of fludarabine as monotherapy in the treatment of chronic lymphocytic leukemia.

Fludarabine is a synthetic adenine nucleoside analog that is indicated for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The recommended intravenous (i.v.) dosage regimen is 25 mg/m2 daily for 5 consecutive days, with treatment cycles repeated every 28 days. In treatment-naïve patients with Binet stage B and C CLL, i.v. fludarabine produces superior responses to established first-line chemotherapies. Fludarabine produces a higher overall remission rate (60-70%) and longer progression-free survival (median approximately 20-30 months) than standard therapy with chlorambucil+/-prednisone and CAP (cyclophosphamide/doxorubicin/prednisone), and a comparable overall remission rate to CHOP (cyclophosphamide/vincristine/prednisone/doxorubicin). Fludarabine demonstrates high efficacy in both intermediate-risk (Rai stage I or II) and high-risk (Rai stage III or IV) patients. Furthermore, fludarabine is equally effective in younger (< or =65 years) and older (>65 years) patients. Fludarabine has significant activity as monotherapy in previously treated CLL, producing objective response rates of up to 94% in typically small-scale, noncomparative studies, with the majority of studies yielding rates of 30-60%. In a phase III multicenter study, the overall remission rate was significantly higher with fludarabine than with CAP (48 versus 27%) among the subset of treatment-refractory patients (n=96). For those patients who are refractory to or have relapsed following conventional chemotherapy (chlorambucil, CAP and CHOP), fludarabine can be considered the treatment of choice for second-line therapy. Moreover, patients with relapsed CLL may benefit from retreatment with fludarabine if they have previously demonstrated sensitivity to the drug. Standard-dose i.v. fludarabine has an established safety profile and comparable tolerability to anthracycline-based regimens (CAP and CHOP) in terms of its myelosuppressive and immunosuppressive effects, and offers the advantage of a markedly lower incidence of gastrointestinal effects (nausea/vomiting) and alopecia.

[Chronic lymphocytic leukemia]. / Leucémie lymphoïde chronique.

The last years have yielded important new insights into the biological characteristics of chronic lymphocyte leukemia cells, which have lend to modify the diagnosis and prognosis criteria of the disease. The diagnosis is now based on morphology and immunophenotyping of blood lymphocytes, making the bone marrow examination unnecessary. However, detection of a clonal expansion of B-lymphocytes in the blood is far to be synonymous of leukemia, and even less an argument for starting a treatment. Prognosis classifications based on clinical and blood counts are now refined with genotyping and cytogenetics. These new tools should improved the therapeutic strategies in the next future.

Fully automated radiosynthesis of 2-[18F]fludarabine for PET imaging of low-grade lymphoma.

PURPOSE: An efficient and fully automated radiosynthesis of 2-[(18)F]fluoro-9-ß-D-arabinofuranosyl-adenine (2-[(18)F]fludarabine, [(18)F]-5) based on a GE TRACERlab™ FX-FN module has been developed. PROCEDURES: A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [(18)F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [(18)F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established. RESULTS: The labeling precursor 3 was obtained in 45% overall yield. Nucleophilic substitution with K(18)F/K2.2.2 afforded protected 2-[(18)F]fludarabine ([(18)F]-4) in 73 ± 4%, radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [(18)F]F(-) activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [(18)F]-5 in 67 ± 3% yield after 20 min at 70 °C based on HPLC profile. CONCLUSIONS: The process afforded pure 2-[(18)F]fludarabine in 48 ± 3% yield (decay corrected to the EOB) in 85 min, with a specific activity of 310 ± 72 GBq/µmol at the end of synthesis (EOS) and a radiochemical purity up to 99%.