ALBERT

Description: Background: Bendamustine has a proved activity in hematological malignancies including both first line and relapsed multiple myeloma (MM). Moreover Bendamustine is generally well tolerated, with the majority of adverse events mainly limited to myelosuppression. Recently Mark et al published a phase I trial adding escalating doses of Bendamustine to the current standard conditioning of Melphalan 200 mg/m2 (HDM) in patients with MM at their first transplant. No transplant related mortality (TRM) was observed and the regimen was well tolerated. Recently was stated that double autologous stem cell transplantation (ASCT) improve the outcome of patients achieving a poor response after first ASCT. Although HDM is the standard for conditioning in MM, in some cases the CR rate is lower than expected. In this trial we evaluate feasibility and efficacy of the association of Bendamustine and Melphalan (BM) as conditioning regimen to second ASCT in patients with MM. Methods: This study was approved by local ethic committee.Between January and June 2014, 12 patients with MM underwent second ASCT following BM as conditioning regimen. The median age was of 56 years (range 40-66), 8 male and 4 female with a diagnosis of MM, stage IIIA (n=7), IIIB (n=4) and IIA (n=1). All patients received a bortezomib-containing regimen as first-line induction therapy and received Melphalan 200 mg/m2 as conditioning regimen before the first ASCT. All patients urderwent second ASCT following Bendamustine (100 mg/m2 days -4 and -3) and Melphalan (140 mg/m2 day -2) as conditioning regimen. G-CSF were given at day 5 after transplant. Results: A median number of 4.9x106/kg of CD34+ cells (range: 4-6.2) was infused. All patients engrafted, with median time to reach neutrophil〉500/µl and platelet 〉20.000/µl of 12 days (range, 11 to 15) and 14 (range, 11 to 19), respectively. Overall, the BM regimen was well tolerated. Almost all patients experienced mucositis, nausea and diarrhea but all events were of grade 1 or 2 (grade 3 diarrhea occurred in only 1 patient). Four patients (33%) had fever (grade 1 or 2) that was clinically identified in 2 cases (pneumonia and cystitis). The median time of duration of fever was 4 days (range, 2-6). No TRM occurred after at least day + 90 after transplant. Overall, no added toxicity were observed between the first and second ASCT. At day + 90 after first and second transplant response rate was respectively: 1 CR, 10 VGPR, 1 PR and 4 CR, 5 VGPR, 1 PR, 2 too early. Three patients in VGPR after first transplant converted to CR after second ASCT. Conclusion: Bendamustine plus Melphalan is feasible as conditioning regimen for second ASCT in patients with MM. The regimen was well tolerated and the toxicity profile of ASCT with conditioning regimens BM or Melphalan is comparable. Longer follow-up is needed to evaluate conversion rate and survival. References: Mark TM et al. A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2013 May;19(5):831-7. Disclosures No relevant conflicts of interest to declare.

Description: SUMMARY Earthquake forecasts are usually underinformed, and can be plagued by uncertainty in terms of the most appropriate model, and parameter values used in that model. In this paper, we explore the application of two different models to the same seismogenic area. The first is a renewal model based on the characteristic earthquake hypothesis that uses historical/palaeoseismic recurrence times, and fixed rupture geometries. The hazard rate is modified by the Coulomb static stress change caused by nearby earthquakes that occurred since the latest characteristic earthquake. The second model is a very simple earthquake simulator based on plate-motion, or fault-slip rates and adoption of a Gutenberg–Richter magnitude–frequency distribution. This information is commonly available even if historical and palaeoseismic recurrence data are lacking. The intention is to develop and assess a simulator that has a very limited parameter set that could be used to calculate earthquake rates in settings that are not as rich with observations of large-earthquake recurrence behaviour as the Nankai trough. We find that the use of convergence rate as a primary constraint allows the simulator to replicate much of the spatial distribution of observed segmented rupture rates along the Nankai, Tonankai and Tokai subduction zones. Although we note rate differences between the two forecast methods in the Tokai zone, we also see enough similarities between simulations and observations to suggest that very simple earthquake rupture simulations based on empirical data and fundamental earthquake laws could be useful forecast tools in information-poor settings.

Description: [1]  We model inter-event times and Coulomb static stress transfer on the rupture segments along the Corinth Gulf extension zone, a region with a wealth of observations on strong–earthquake recurrence behavior. From the available information on past seismic activity we have identified eight segments without significant overlapping that are aligned along the southern boundary of the Corinth rift. We aim to test if strong earthquakes on these segments are characterized by some kind of time–predictable behavior, rather than by complete randomness. The rationale for time–predictable behavior is based on the characteristic earthquake hypothesis, the necessary ingredients of which are a known faulting geometry and slip rate. The tectonic loading rate is characterized by slip of 6 mm/yr on the westernmost fault segment, diminishing to 4 mm/yr on the easternmost segment, based on the most reliable geodetic data. In this study we employ statistical and physical modeling to account for stress transfer among these fault segments. The statistical modeling is based on the definition of a probability density distribution of the inter-event times for each segment. Both the Brownian Passage–Time (BPT) and Weibull distributions are tested. The time–dependent hazard rate thus obtained is then modified by the inclusion of a permanent physical effect due to the Coulomb static stress change caused by failure of neighboring faults since the latest characteristic earthquake on the fault of interest. The validity of the renewal model is assessed retrospectively, using the data of the last 300 years, by comparison with a plain time–independent Poisson model, by means of statistical tools including the ROC diagram, the R–score, the probability gain and the log–likelihood ratio. We treat the uncertainties in the parameters of each examined fault source, such as linear dimensions, depth of the fault center, focal mechanism, recurrence time, coseismic slip, and aperiodicity of the statistical distribution, by a Monte Carlo technique. The Monte Carlo samples for all these parameters are drawn from a uniform distribution within their uncertainty limits. We find that the BPT and the Weibull renewal models yield comparable results, and both of them perform significantly better than the Poisson hypothesis. No clear performance enhancement is achieved by the introduction of the Coulomb static stress change into the renewal model.

Description: In this paper, we compare the forecasting performance of several statistical models, which are used to describe the occurrence process of earthquakes in forecasting the short-term earthquake probabilities during the L’Aquila earthquake sequence in central Italy in 2009. These models include the Proximity to Past Earthquakes (PPE) model and two versions of the Epidemic Type Aftershock Sequence (ETAS) model. We used the information gains corresponding to the Poisson and binomial scores to evaluate the performance of these models. It is shown that both ETAS models work better than the PPE model. However, in comparing the two types of ETAS models, the one with the same fixed exponent coefficient ( alpha) = 2.3 for both the productivity function and the scaling factor in the spatial response function (ETAS I), performs better in forecasting the active aftershock sequence than the model with different exponent coefficients (ETAS II), when the Poisson score is adopted. ETAS II performs better when a lower magnitude threshold of 2.0 and the binomial score are used. The reason is found to be that the catalog does not have an event of similar magnitude to the L’Aquila mainshock (M w 6.3) in the training period (April 16, 2005 to March 15, 2009), and the ( alpha) -value is underestimated, thus the forecast seismicity is underestimated when the productivity function is extrapolated to high magnitudes. We also investigate the effect of the inclusion of small events in forecasting larger events. These results suggest that the training catalog used for estimating the model parameters should include earthquakes of magnitudes similar to the mainshock when forecasting seismicity during an aftershock sequence.

Description: Abstract 4541 Introduction: Limited data demonstrate to what extent preventing fungal exposures is effective in preventing infection and disease. Further studies are needed to determine the optimal duration of fluconazole prophylaxis in allogeneic recipients to prevent invasive disease with fluconazole-susceptible Candida species during neutropenia. Oral, nonabsorbable antifungal drugs might reduce superficial colonization and control local mucosal candidiasis, but have not been demonstrated to reduce invasive candidiasis. Anti-fungal prophylaxis is recommended in a subpopulation of autologous recipients with underlying hematologic malignancies with prolonged neutropenia and mucosal damage. Methods: This is a retrospective study of 1007 SCT performed in our center between 1992 and 2009 in 809 consecutive patients, irrespective of diagnosis. HEPA filter and environmental monitoring (air, water, surfaces) are attributes of our transplant center. Results: The main characteristics of the patients are reported in Table 1. Systemic prophylaxis was used according to the guidelines (Table 2): fluconazole in the nineties, then itraconazole and from 2004 was either abolished or substituted with non-adsorbable prophylaxis in transplants with standard risk. Secondary prophylaxis was prescribed for high risk patients (with infectious fungal history, suggestive iconography, positive fungal biomarker). In 17 years our Center has never been colonized by mould. Only 3 probable aspergillosis infections and 4 proven fungal infections (fusarium, mucor and 2 aspergillosis) were diagnosed, all in allogeneic patients (2 haplotipical, 1 singenic, 1 sibiling, 1 MUD and 2 mismatched), resulting in death in all cases. No infection was documented in autologous setting, while the infection rate in allogenic setting was 3.6% with an incidence rate of 1.1 infection per 10000 transplants/year. These results are significantly lower than published reports. Conclusion: Systemic antifungal prophylaxis should not be performed in autologous SCT patients. The abuse of systemic prophylaxis targeting yeasts has influenced the change of epidemiology in the transplant setting with prevalence of mould infections. The identification of high risk patients is useful to select patients for systemic antifungal or secondary prophylaxis to reducing overtreatment, incidence of resistant strains and costs. Disclosures: No relevant conflicts of interest to declare.

Description: Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p

Description: Introduction:Biosimilars of filgrastim have been available since 2008 and are now in widespread use also for stem cells (SCs) mobilization. There are no previously published data on the use of biosimilar G-CSF for peripheral blood (PB) SCs collection only in patients with Multiple Myeloma (MM) as they always had been presented aggregated with other different hematological malignancies. Here we report the use of a biosimilar filgrastim (Zarzio®) compared with a matched historical control group in PBSCs in patients with de-novo MM treated with reference product (Neupogen®) and scheduled to receive a double autologous transplantation. Material and Methods: A total of 26 consecutive patients received biosimilar filgrastim after cyclophosphamide (CTX) 4g/m2 chemotherapy for PBSCs mobilization between January and July 2014, this group was compared with a matched historical control cohort (n=26) who had been treated with originator filgrastim between 2012 and 2013. In both groups G-CSF was administered 5 μg/kg/day until almost a minimal count of 4 x106 CD34+ cells/kg was collect. Monitoring of peripheral blood CD34+ cell concentrations began as soon as WBC recovery reached 1x109/L and leukapheresis was initiated when the CD34+cell concentration reached 10/mL. Results: Characteristics (age, gender, body weight, type of induction CHT, radiation therapy) were similar in both groups. The median peak CD34+ cells value was 187.8 ± 159.5 x ml in the biosimilar group compared with 223.7 ± 206.5 x ml in the originator group (P=n.s.). The median number of leukapheresis necessary to harvest a minimal count of 4 and 8 x10E6 CD34+/kg was similar in both biosimilar and originator groups: 1.4 ± 0.6 vs 1.3 ± 0.6 (P=n.s.) and 1.8 ± 0.8 vs 1.4 ± 0.7 (P=n.s), respectively. One and 3 patients failed to mobilize 4 and 8 x 10 E /kg CD34+ cells in the biosimilar group compared with 3 and 8 patients in the originator group (P=n.s), respectively). Short-term hematological reconstitution was evaluated for all transplanted patients. Number of CD34+ cells reinfused at the first transplant were 4.8 ± 0.75x10E6/Kg in the biosimilar group compared with 5.1 ± 0.75x10E6/Kg in the originator group (P=n.s.). Median time to neutrophil engraftment (〉500/μl) was similar in both the biosimilar and originator groups (10.7 ± 0.8 vs 10.3 ± 1.1 days; P=n.s), as was platelet recovery (13.6 ± 1.8 vs13.4 ± 1.2 days; P=n.s. Conclusions:Our study shows that biosimilar filgrastim administered following chemotherapy is equivalent to originator filgrastim for autologous stem cell mobilization and PBSCs collection when used with the same schedules and doses in a MM real life setting. Long-term follow-up is required to confirm the safety of biosimilar and originator G-CSF. Disclosures No relevant conflicts of interest to declare.

Description: Radioimmunotherapy (RIT) with 90Y-Zevalin® combined with high dose therapy and autologous stem cell transplantation (ASCT) is gaing increasing importance for the treatment of relapsed or refractory non Hodgkin Lymphoma (nHL). We evaluated the feasibility and the clinical results of the addition of 90Y-Zevalin® at standard dose to BEAM regimen (Z-BEAM) in nHL pts who failed to achieve complete remission (CR) after previous chemoimmunotherapy. Methods. Between October 2005 and June 2008, 53 patients were enrolled in 11 italian centers. The treatment strategy is shown in figure 1. Salvage treatment consisted of 2 courses of R-DHAP. PBSCs were collected after mobilization with DHAP and G-CSF plus in vivo purging with Rituximab. Patients’ characteristics are shown in table 1. Results. The median CD34+ cells infused was 5.5 x10^6/Kilograms (range 2.55–34). All patients engrafted. The median number of red blood cell and platelet transfusion were 4 (1–7) and 6 (1–8), respectively. The median time to platelet and neutrophil counts higher than 20x10^9/L and 0.5x10^9/L were 14 (range, 9–60 days) and 10 days (range, 8–20), respectively. Mucosites occurred in all pts (grade III in 20 and grade IV in 5 patients). Febrile neutropenia occurred in 39 pts (74%). Eight pneumonitis and 12 blood stream infections, mainly by Gram+, were documented. One patient developed an atrial fibrillation. Five pts were not evaluable for response because too early. The 90-day overall response rate was 86% with 74% of CR. Three relapses (relapse rate 9%) and four progression were documented at a median follow-up of 247 days post Z-BEAM (range, 125–818). The potential factor to predict CR was: at last PR before Z-BEAM (p=0.06). Fourthy patients are alive at a median follow-up of 175 days post HST (range, 6–590): thirty pts in CR (57%), three pts in PR (5.5%), three pts in progressive disease (PD, 6%)(fig. 2). Fourtheen pts died (26%): 5 deaths due to TRM before day 90, 1 for ARDS (+230), 1 TRM post a subsequent RIC allotransplant (+95) and 6 due to PD (median follow-up 110 days, range 97–150). The Kaplan-Meyer estimated 3y-EFS is 64%. Five early deaths before day-90 occurred: 2 due to septic shock (day +6 and +39), 1 to pneumonitis (+22), 1 for BK viral encephalites (+61) and 1 to MOF (+14). The Kaplan-Meyer estimated Treatment Related Mortality (TRM) is 9.3%. Two statistically risk factors for 90-day TRM (p

Description: BACKGROUND: Peripheral blood (PB) hematopoietic progenitor cells (HPC) mobilized with G-CSF are the first-choice source for allogeneic stem cell transplantation. We carried out a prospective study on healthy donors (HDs), to identify donor characteristics that could influence the effectiveness of mobilization. STUDY DESIGN AND METHODS: PB-HPC allogeneic donations from sibling HDs were analyzed. We tested somatic variables (sex, age, weight, height, volemia) and blood counts (WBC, platelets, hemoglobin, CD34+ cell count). Two different determinations of CD34+ cells were done in each HD: baseline (before G-CSF administration) and in PB on the morning of the fifth day (after G-CSF administration). HDs received G-CSF subcutaneously at a dose of 10 µg/kg per day. RESULTS: 128 consecutive HDs (66 males) with a median age of 43 years were enrolled. The mean value of CD34+ on day 5 was 90.8 cells/µL, 84.2 cells/µL in females and 97.2 cells/µL in males. The median values of CD34+ on day 5 were 75.5 cells/µL for the overall sample, 74 cells/µL in females and 80 cells/µL in males. On univariate correlation analysis, donor weight r=0.19, P

Description: We report our results of ASCT in patients with Acute Myeloid Leukemia (AML) during the last 16 years. Between December 1991 and december 2007, 90 patients with AML received an ASCT. The main characteristics were reported on table 1. The median patient age was 46 years (range17 – 67 years). The conditioning regimen employed for all patients was Busulphan + Cyclophosfamide. The Overall Survival (OS) (Figure1) was 53,5% with a median follow up of 91,6 months. The majority of patients (81) was transplanted in first complete remission (1st CR), 8 in 2nd CR and 1 〉2nd CR. The OS considering the disease phase at transplant was different: 55,7% vs 16,7%, p 〈 0,01 (one pts with 〉 second CR was excluded from analysis). If we considering also the age stratified in two groups: 17–45 vs 46–67 years, all patients in second CR, included into II group died. We have calculated OS stratified for age in these groups that was 46,2% versus 59,6%, respectively, without statistical differences. We also analyzed the OS distributed for sex and cell source without statistical difference. We have documented a statistically significant correlation between FAB group and survival (Figure 2). In fact, the patients with FAB M2 and M4 (excluded M3) had a superior OS than those with other FAB (60,7% vs 40%, p 〈 0.019)). In 32/40 (80%) patients, the relapse has been documented within 24 months from transplant. The analysis for cytogenetic risk has been performed, but considering only 46 patients assessable. The OS cytogenetic risk-related was 87% for 8 patients with Low Risk, 47% for 36 patients with Intermediate Risk, 2 patients with High Risk died within 11 months from transplant (data not shown). We conclude that autologous bone marrow transplantation is an effective treatment in AML with the possibility of long survivorship, particularly in patients with FAB M2 and M4. In our experience, first complete remission of disease at transplant play an important role and correlates with the longest survival. The analysis of cytogenetic risk reflects the impact of karyotype on OS. Transplant Related Mortality (TRM) has been documented in 6/90 patients, all died before the years 2000. Figure 1 Figure 1. Table 1 Number of patientss 90 Sex (M/F) 42/48 Age (range y) (mean ±SD y) 17–67 46,3±11,4 FAB classification: M0 2 (2,2%) M1 16 (17,8%) M2 28 (31,1%) M3 4 (4,4%) M4 28 (31,1%) M5 11(12,3%) M6 Phase of disease: 1 (1,1%) 1st Complete Remission 81 (90%) 2nd Complete remission 8 (8,9%) 〉 2nd Complete Remission 1 (1,1%) Citogenetic risk (pts evaluable: 46) Low 8 (17,3%) Intermediate 36 (78,2%) High 2 (4,5%) Transplant Related Mortality 6/90 (6,7%)