ALBERT

Beschreibung: Abstract 6 Acute promyelocytic leukemia (APL) is a curable disease, and contemporary treatment based on the combination of all-trans retinoic acid (ATRA) with anthracyclines results in overall survival (OS) rates of around 90% at five years. Unfortunately, the treatment outcome of patients with APL in developing countries is significantly less. A recent Brazilian study had reported an OS of 53% with a first 5-days mortality of 13.4%. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, México and Uruguay. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. Results of the immunofluorescence for PML was obtained within hours and upon confirmation of the diagnosis, patients were enrolled in a protocol identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin. Supportive care aimed at maintaining platelet counts above 30,000/μl and fibrinogen levels above 150 mg/dl. In each country, cases were discussed every other week through internet and whenever needed international experts were involved. As of June 2009, 102 (70 Brazil, 25 Mexico, 7 Uruguay) APL patients were enrolled. The median age was 34 y (range: 9–72y) with 55 males (54%).The median white blood cell counts (WBC) at baseline was 3.6×109 /L(range: 0.2–149.7). The distribution of the relapse risk score at diagnosis according to PETHEMA-GIMEMA criteria was 14 low (14%), 54 intermediate (53%) and 34 high risk(33%) respectively. The incidence of low risk APL appeared lower than the values reported in developed countries. Of 102, 97 patients have toxicity and response data available. Of these 97, 12 (12.3%)experienced at least three symptoms/signs of differentiation syndrome (DS) and 77 (79%) patients achieved a complete remission (CR). Twenty-three deaths occurred and the cause of deaths included 9 hemorrhage, 8 infection, 2 DS . The 7 and 30 day mortality rates were 8% and 19.6%, respectively, and the one- year overall survival was 75% (95%CI:68%–84%). The median follow-up time among survivors was 14 months (range: 1.3–35). Among 77 patients who achieved CR, the 1-year OS and disease-free survival from the date of CR was 95% (95% CI: 89%–100%). Only one patient relapsed. For patients surviving a minimum of 30 days the outcome was similar to that reported by the twin PETHEMA-LPA 2005 protocol in European patients. Prognostic factors for overall survival were examined using log-rank test as well as multivariate Cox models. Factors predicting OS were a high relapse risk score at baseline (1-year OS: 59% for high, 87% for intermediate, 91% for low, p=0.0007) and age. The 1-year OS was 85% for age

Beschreibung: Purpose: To evaluate efficacy, safety, Disease-Free Survival (DFS) and Overall Survival (OS) in patients with indolent non-Hodgkin’s lymphoma (NHL) treated with chemotherapy vs. immunotherapy vs immunochemotherapy as first-line therapy, an up-date report. Methods: Patients with indolent NHL were randomized to receive: (A) Rituximab x 6/w, (B) CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisone) x 6 or (C) R-CNOP x 6, at standard doses. Results: 195 patients were included, 183 are evaluable for OS and toxicity (A:62, B:55 and C:66), 144 are evaluable for overall response rate (ORR) and DFS (A:53, B:41 and C:50). Clinical characteristics: 89 male (45.6%), mean age 59±14 (±SD), 148 (75.9%) in stage (III/IV), without significant differences between groups. Overall Response Rate (CR+PR) was: A: 84.9%, B:83.4% and C:90% (P=0.545). Neutropenia grade 3/4 was more frequent in the chemotherapy groups: A: 4.8%, B: 23.6% and C:18.2% (P=0.001) as it was the infectious toxicity (grade 2/4): A:4.8%, B:5.5% and C:15.2% (P=0.07). DFS at 24 months was: A 68%, B:65% and C:70%, (P=0.93) and the OS was A:87%, B:84% and C:78%. P=0.89. Conclusions: We did not find any important differences, between groups, regarding the Overall Response Rate, Disease Free Survival and Overall Survival at 24 months. However, single agent rituximab was better tolerated, with less toxicity in comparison with the chemotherapy containing groups. Based on these findings, it maybe reasonable to use immunotherapy only, as first-line therapy for patients with indolent NHL.

Beschreibung: Background: Severe infectious events after chemotherapy (CHT) are potentially life-threatening. This is directly related to neutropenia. Granulocyte colony-stimulating factor is used as supporting therapy to prevent neutropenia. Peg-filgrastim has been available in Mexico since 2005 and there is not any report about the use of this drug in Latin America. Aim: To evaluate grade 4 neutropenia and infections related to neutropenia while using peg-filgrastim. Methods: Patients between the ages of 18–65, with NHL (de novo or relapsed) with ≤ 30% bone marrow involvement were eligible. CHT was selected by each institution. Complete blood counts were obtained on days 0 (day before chemotherapy), 7, and 14. Outcomes: Fifty three patients with NHL were included (one withdrew from study after the 2nd cycle of CHT). Three hundred and fourteen cycles were analyzed. Clinical characteristics: Age (mean ±SD): 51.8(±13.5), male: 47%, ECOG ≥ 2:32%), Advance stage (III/IV Ann Arbor): 53%, adjusted IPI (Intermediate/High):60.4%, First-line CHT 72%, second-line CHT 28%. Median neutrophil count (ANM) on day 0 was 8.69 ×109/L (IC95%: 6.44 to 10.94, previous each CHT), ANM on day +7 was 7.9×109/L (IC95%: 5.34 a 10.45) and day +14 ANM was 8.61 ×109/L (IC95%: 6.74 a 10.48) see figure 1. Neutropenia grade 4 was observed in 12.8% of the cycles, being more frequent on day 7 (90%) it means chemotherapy nadir, see figure 2. Severe infectious events were registered in 0.63% of the global cycles (two pneumonias, one of them when ANC was over 2 ×109/L) and non-severe in 1.91% being more frequent superior tract infections. No delays in CHT administration or deaths were reported. Conclusion: Peg-filgarstim could decrease the frequency of grade 4 neutropenia the day before the next administration of CHT as well as the incidence of severe and non-severe infections in young patients.

Beschreibung: Introduction: Patients with aggressive NHL may respond to treatment, but 4-year DFS is 〈 40%. Rituximab has shown activity as monotherapy in patients even in refractory or relapsing post-MOT patients. Besides, preliminary results from maintenance therapy studies are promising. Objective: To determine if maintenance with Rituximab in first complete remission increases disease-free survival and overall survival compared to observation. Methods: A clinical trial with post-remission randomization was carried out, including patients with Aggressive Non-Hodgkin Lymphoma, stages IIb- III- IV, with ECOG 0–2, and ≥15 years old. All patients received the Rituximab + CHOP/CHOP-Like regimen during induction to remission (IR), and those with Complete Remission (CR) were randomized to receive rituximab-based maintenance therapy biannually (2 x 375 mg/sc) vs observation. Results: 217 patients have been enrolled to IR, age 52±14 years old, 114 (52.5%) masculine, 174 of them (80.2%) presented remission; 149 CR, 25 PR. Two (0.9%) patients showed stable disease, 25 (11.5%) developed disease progression, and 16 (7.4%) died. Out of the 174 patients with remission, 96 patients have received maintenance therapy for over 6 months, 45 in the rituximab group, and 51 in the observation group, with a median follow-up of 14.4 months (pt 25– 75, 7.74 – 21.88 months). To date only 1 patient per group had a progress and none has died. During IR -considering the maximum toxicity developed per patient -, acute toxicity was remarkable: fever I, II in 13%, III–IV 1%, and chills I, II 8.2%, III 1%. And not acute: anemia I,II 54%, III 1.9, IV 1.4%, neutropenia I,II 46.1%, III 18.4, IV 2.8% and infection I,II 16.4%, III 1.0%, and IV 1.4%. Discussion: Overall response to Rituximab + CHOP regimen is very good (80.2%), and to date 96 patients included in maintenance therapy with a median follow-up of 14.4 months, the difference between the groups is not evident yet; therefore, surveillance should be continued.

Beschreibung: Follicular lymphoma is frequently associated with the chromosomal rearrangement t(14;18)(q32;q21), which joints one of the JH segments of the heavy chains of immunoglobulins (IgH) gene in 14q32 with the Bcl-2 gene in 18q2, originating a chimeric protein. The frequency of this marker is unknown in the Mexican population. OBJECTIVE: To determine the incidence of the Bcl2-IgH rearrangement in Mexican patients with follicular lymphoma and its frequency as a marker of minimal residual disease after therapy. PATIENTS AND METHODS: 200 patients (102 male and 98 female) were evaluated; the analysis was made in peripheral blood samples (PB) in 64 cases (32%) or bone marrow (BM) in 136 (68%). Genomic DNA was obtained and the Bcl-2/IgH rearrangement was amplified by both PCR and nested PCR using primers for JH and exon-intron 3 region of Bcl-2 (MBR and MCR regions). The Bcl-2/IgH rearrangement was used as a marker to determine minimal residual disease (MDR) in 90 out of 200 patients in clinical remission, with a follow up ranging from 12 to 60 months; The incidence and tissue type analysis were compared using chi-square statistics. RESULTS AND DISCUSSION: We found a positive Bcl-2/IgH rearrangement in 80% of the Follicular NHL cases, with a breakage in the MBR region in 160 cases and in MCR in 10 cases, in the remaining 30 patients the Bcl-2/IgH was negative. We detected the Bcl-2/IgH rearrangement more frequently in the BM samples (86%) than in the PB (42%) (p

Beschreibung: PCR monitoring for EBV reactivation is commonly used to confirm the diagnosis of EBV-LPD in alloSCT recipients. Previous studies using multiple PCR approaches have suggested a correlation between high EBV copy number and impending EBV-LPD, potentially allowing for the administration of preemptive rituximab and/or donor leukocytes prior to disease onset. However, subpopulations of alloSCT recipients with EBV reactivation at higher risk for EBV-LPD remain incompletely defined. We sought to determine the demographic factors among alloSCT recipients that affect the predictive value of our EBV PCR assay. Quantitative real-time PCR was performed on serum samples obtained from alloSCT recipients using primers that amplify a portion of the BNRF1-p143 locus. Clinical patient information was retrieved from institutional research databases. Patients who did not undergo appropriate EBV PCR screening (n=13), had a history of EBV-LPD prior to alloSCT (n=1) or received rituximab for prophylaxis against EBV-LPD (n=2) were excluded. 187 alloSCT recipients underwent EBV PCR monitoring between 7/03–7/05, of whom 58 (31.0%) were 500 copies/mL) at some point after alloSCT. The prevalence of EBV reactivation was similar in recipients of TCD and conventional allografts (28.8% vs. 31.5%). Among patients with EBV reactivation, the risk for EBV-LPD did not differ based on age, sex, underlying disease, donor relation or HLA disparity. However, of the 56 patients with EBV reactivation, 5/32 (15.6%) recipients of TCD allografts and 0/24 (0.0%) recipients of conventional allografts developed EBV-LPD (p500 for 〉6 months and 3 had ≥1 PCR value 〉100K. In our study population, the utility of the EBV PCR was maximized in recipients of TCD allografts with PCR values 〉500 (Table). In conclusion, EBV reactivation is common among recipients of both conventional and T cell depleted allografts, but preemptive therapy guided by EBV PCR should be primarily directed toward the latter. The effects of in vivo TCD with agents such as alemtuzumab on EBV reactivation and EBV-LPD are under investigation. Utility of the EBV PCR for predicting EBV-LPD and for guiding preemptive therapy in all patients and in only those who received T cell depleted allografts Patient group PCR cutoff (copies/mL) Sensitivity Specificity Positive predictive value Negative predictive value Number needed to treat The highest PCR value within 1 year prior to LPD presentation was used for patients with LPD. All patients 〉500 100% 72% 9% 100% 11.2 〉1,000 80% 77% 9% 99% 12.5 〉5,000 40% 85% 7% 98% 20 〉10,000 40% 88% 9% 98% 14.6 〉100,000 20% 98% 25% 98% 4.4 T cell depleted 〉500 100% 75% 16% 100% 6.4 〉1,000 80% 77% 14% 99% 7.6 〉5,000 40% 85% 11% 97% 12.7 〉10,000 40% 89% 14% 97% 8.9 〉100,000 20% 98% 33% 96% 3.4

Beschreibung: Some dinoflagellate species have shown different physiological responses to certain turbulent conditions. Here we investigate how two levels of turbulent kinetic energy dissipation rates (ε = 0.4 and 27 cm² s−3) affect the PSP toxins and ecdysal cyst dynamics of two bloom forming species, Alexandrium minutum and A. catenella. The most striking responses were observed at the high ε generated by an orbital shaker. In the cultures of the two species shaken for more than 4 days, the cellular GTX(1+4) toxin contents were significantly lower than in the still control cultures. In A. minutum this trend was also observed in the C(1+2) toxin content. For the two species, inhibition of ecdysal cyst production occurred during the period of exposure of the cultures to stirring (4 or more days) at any time during their growth curve. Recovery of cyst abundances was always observed when turbulence stopped. When shaking persisted for more than 4 days, the net growth rate significantly decreased in A. minutum (from 0.25±0.01 day−1 to 0.19±0.02 day−1) and the final cell numbers were lower (ca. 55.4%) than in the still control cultures. In A. catenella, the net growth rate was not markedly modified by turbulence although under long exposure to shaking, the cultures entered earlier in the stationary phase and the final cell numbers were significantly lower (ca. 23%) than in the control flasks. The described responses were not observed in the experiments performed at the low turbulence intensities with an orbital grid system, where the population development was favoured. In those conditions, cells appeared to escape from the zone of the influence of the grids and concentrated in calmer thin layers either at the top or at the bottom of the containers. This ecophysiological study provides new evidences about the sensitivity to high levels of small-scale turbulence by two life cycle related processes, toxin production and encystment, in dinoflagellates. This can contribute to the understanding of the dynamics of those organisms in nature.