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BACKGROUND Acute myeloid leukaemia (AML) patients are at high risk of invasive aspergillosis (IA) after first induction chemotherapy (CHT). Although IA risk factors have been identified, few data are available on impact of IA, occurring during induction phase, on overall AML outcome. PATIENTS AND RESULTS The end point of this multicentre, case-control, study was to evaluate whether IA, occurring after first induction CHT, can affect treatment schedule and patient's outcome. We identified 40 AML patients (cases) who developed IA during first induction phase, 31 probable (77.5%) and 9 proven (22.5%). These cases were matched with a control group (80 AML) without IA, balanced according to age, type of CHT, AML characteristics and cytogenetic-molecular risk factors. The overall response rate to induction CHT was the same in the 2 groups. In the 40 cases with IA, the overall response rate to antifungal treatment was favourable (80%) but it was significantly affected by the achievement of leukaemia complete remission (CR) with induction CHT. In fact, in cases with AML responsive to induction CHT, responses of IA to antifungal therapy were 96% compared to 21% in cases of AML not responsive to induction treatment (P

BACKGROUND From 2011 to 2014, a total of 71% of the 3834 patients with hematologic malignancies successfully identified a matched unrelated donor (MUD) through the Italian Bone Marrow Donor Registry (IBMDR), corresponding to a transplant efficiency of 62%. STUDY DESIGN AND METHODS From 2006, the Rome Transplant Network (RTN) followed a hierarchical selection strategy for the alternative donor search: first MUD, second cord blood, and third haploidentical donor. Using a low-resolution HLA, a preliminary query (PQ) was performed in all cases with assignment of good or poor score if more or less than 10 MUDs were identified in Bone Marrow Donors Worldwide. Herein we assessed the utility of PQ and of high-resolution (HR) HLA from the start of the search. Moreover, we compared the donor identification and the transplant efficiency between IBMDR and RTN. RESULTS At RTN 79% of 417 patients met a good PQ with a 50% MUD identification versus 12.5% with poor PQ. Our policy led to 78 and 74% of alternative donor identification and transplant efficiency, respectively, higher than IBMDR data equal to 71% (p = 0.007) and 62% (p

A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin3 receptor antagonist (5-HT3-RA) with dexamethasone and neurokin1 receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9–30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.

High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen. Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed. Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events. The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning.

We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36.

Ninety-seven patients affected by high-risk hematological malignancies underwent G-CSF primed, unmanipulated bone marrow (BM) transplantation from a related, haploidentical donor. All patients were prepared with an identical conditioning regimen including Thiotepa, Busilvex, Fludarabine (TBF) and antithymocyte globulin given at myeloablative (MAC = 68) or reduced (reduced intensity conditioning (RIC) = 29) dose intensity and received the same GvHD prophylaxis consisting of the combination of methotrexate, cyclosporine, mycofenolate-mofetil and basiliximab. Patients were transplanted in 1st or 2nd CR (early phase: n = 60) or in > 2nd CR or active disease (advanced phase: n = 37). With a median time of 21 days (range 12-38 days), the cumulative incidence (CI) of neutrophil engraftment was 94 ± 3%. The 100-day CI of III-IV grade acute GvHD and the 2-year CI of extensive chronic GvHD were 9 ± 3% and 12 ± 4%, respectively. Overall, at a median follow-up of 2.2 years (range 0.3-5.6), 44 out of 97 (45%) patients are alive in CR. The 5-year probability of overall survival (OS) and disease-free survival (DFS) for patients in early and advanced phase was 53 ± 7 vs 24 ± 8% (P = 0.006) and 48 ± 7 vs 22 ± 8% (P = 0.01), respectively. By comparing MAC with RIC patient groups, the transplant-related mortality was equivalent (36 ± 6 vs 28 ± 9%) while the relapse risk was lower for the MAC patients (22 ± 6 vs 45 ± 11%), who showed higher OS (48 ± 7 vs 29 ± 10%) and DFS (43 ± 7 vs 26 ± 10%). However, all these differences did not reach a statistical significance. In multivariate analysis, diagnosis and recipient age were significant factors for OS and DFS. In conclusion, this analysis confirms, on a longer follow-up and higher number of patients, our previous encouraging results obtained by using MAC and RIC TBF regimen as conditioning for G-CSF primed, unmanipulated BM transplantation from related, haploidentical donor in patients with high-risk hematological malignancies, lacking an HLA-identical sibling or unrelated donor and in need to be urgently transplanted.

Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Hospitalisation in protected/isolated rooms is a measure, frequently, adopted for hematological patients undergoing to intensive treatment, such as allogeneic (allo) or autologous (auto) stem cell transplantation (SCT), due to a high risk of infections.1 However, the level of evidence about the efficacy of isolation measure during SCT is poor, thus resulting in discrepancy between different centres.1 Prolonged isolation affects quality of life, due to restriction of socio-familiar role and lack of psychological relieve of patients, thus increasing the high burden of symptoms reported by transplanted patients during the first weeks after SCT.2–6 Moreover, isolation could affect psychological status of patient relatives, such as children, frequently not allowed to visit their parent during hospitalisation. Isolation effects on patient undergoing to SCT could …

BACKGROUND: The aim of this retrospective, multicenter study was to compare high- versus standard-dose lenograstim after chemotherapy in collecting target dose of CD34+ peripheral blood progenitor cells (PBPCs) in adult candidates for autologous transplant. STUDY DESIGN AND METHODS: A total of 166 consecutive patients (28 acute leukemias [ALs], 77 lymphomas, 61 multiple myeloma [MM]) underwent 182 mobilization procedures. Only the first were analyzed. The CD34+ cell target was at least 2 × 106, 4 × 106, and 8 × 106/kg and lenograstim started on days +19, +1, and +5 from the end of chemotherapy for AL, lymphomas, and MM, respectively. Eighty-seven and 79 patients, respectively, received 5 and 10 µg/kg/day lenograstim subcutaneously (sc). An analysis to evaluate factors predicting satisfactory procedures and outcome of transplants performed with first-mobilization-procedure PBPCs was conducted. Most patients received 6 mg of pegfilgrastim or 5 µg/kg/day lenograstim sc after transplant. RESULTS: In multivariate analysis, high-dose lenograstim (p = 0.053) in MM and male sex (p = 0.028) were positive predictive factors for reaching cell target. Fludarabine negatively influenced stimulation length (p = 0.002). Apheresis, CD34+ cells mobilized and collected, blood volume processed, side effects, transplants performed, and engraftment time were similar between lenograstim cohorts. Pegfilgrastim versus lenograstim delayed platelet (PLT) recovery times (13 days vs. 11 days, p = 0.036). CONCLUSIONS: High-dose lenograstim more efficiently mobilized MM patients requiring the highest PBPC target but did not influence transplants performed and engraftment time. Male patients mobilized more efficiently. Fludarabine negatively influenced stimulation length. Finally, pegfilgrastim seems to delay PLT recovery.

In a cohort of inpatient hematopoietic cell transplantation (HCT) recipients, we assessed patterns of referral to rehabilitation treatment, functional performance and short-term outcomes in patients who received post-transplant rehabilitation in comparison with those who did not. Among 201 first-time HCT recipients, 53 (26%) were referred to an inpatient rehabilitation provider, had an assessment of functional performance using the Functional Independence Measure scale and underwent rehabilitation treatments to address functional needs. Patients who received rehabilitation therapy were more likely to be females (P = 0.02), older than 60 years of age (P = 0.0146), employed (P = 0.01), have hypertension (P = 0.02), peripheral vascular disease (P = 0.01) and pre-transplant Karnofsky Performance Score (KPS)

Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC

Purpose Empiric antibiotic monotherapy is considered the standard of treatment for febrile neutropenic patients with cancer, but this approach may be inadequate because of the increasing prevalence of infections caused by multidrug resistant (MDR) bacteria. Patients and Methods In this multicenter, open-label, randomized, superiority trial, adult, febrile, high-risk neutropenic patients (FhrNPs) with hematologic malignancies were randomly assigned to receive piperacillin/tazobactam (4.5 g intravenously every 8 hours) with or without tigecycline (50 mg intravenously every 12 hours; loading dose 100 mg). The primary end point was resolution of febrile episode without modifications of the initial allocated treatment. Results Three hundred ninety FhrNPs were enrolled (combination/monotherapy, 187/203) and were included in the intention-to-treat analysis (ITTA). The ITTA revealed a successful outcome in 67.9% v 44.3% of patients who had received combination therapy and monotherapy, respectively (127/187 v 90/203; absolute difference in risk (adr), 23.6%; 95% CI, 14% to 33%; P < .001). The combination regimen proved better than monotherapy in bacteremias (adr, 32.8%; 95% CI, 19% to 46%; P < .001) and in clinically documented infections (adr, 36%; 95% CI, 9% to 64%; P < .01). Mortality and number of adverse effects were limited and similar in the two groups. Conclusion The combination of piperacillin/tazobactam and tigecycline is safe, well tolerated, and more effective than piperacillin/tazobactam alone in febrile, high-risk, neutropenic hematologic patients with cancer. In epidemiologic settings characterized by a high prevalence of infections because of MDR microorganisms, this combination could be considered as one of the first-line empiric antibiotic therapies.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.

Introduction. Multiresistant (MR) bacteria colonization is considered predictive of related bloodstream infections (BSI), which are worrisome among hematological patients (pts). Few data are available about the actual incidence of MR colonization and the probability of developing a BSI in this population. A multicentric prospective observational study has been carried out within the SEIFEM group, with the aim of detecting the incidence of MR bacterial colonization and the probability of developing MR BSI in hematological pts. Patients and Methods. Between March 1st and August 31st 2015, all pts with a hematological neoplasm admitted to 18 Italian Centres participating to SEIFEM were screened for MR colonization with a rectal swab; cultures of other sites were performed if clinically indicated. Patients showing MR bacterial colonization were recorded in a database where the occurrence of any BSI was correlated with age, gender, type and phase of disease, stem cell transplantation (SCT), presence of invasive devices, type of colonizing bacteria. Results. During a 6-month period, 189 pts with MR colonization were observed. Incidence was 8.9% among all admissions (189/2122). Median age was 59y (range 0-89) and M/F ratio 116/73. Eighty-two pts were affected by acute leukemia, 75 by lymphoma, 24 by myeloma, 6 by chronic myeloproliferative/myelodysplastic syndromes and 2 by aplastic anemia. Forty-four pts underwent SCT (28 autologous and 16 allogeneic). Vancomycin resistant enterococci (VRE) were responsible for colonization in 15 (7.9%) pts, extended spectrum beta-lactamases producing (ESBL-P) enterobacteria in 80 (42.3%) and carbapenemase producing (CP) Gram-Negative Rods (GNR) in 108 (57.1%). Thirteen of 14 pts with multiple colonizations had both ESBL and carbapenemase producing enterobacteria. Multivariate analysis of risk factors for type of MDR colonization showed that a complete hematologic remission was associated to ESBL-P enterobacteria colonization, but protective for CP strains (OR 2, 1.1-3.7, p=0.02 and 0.43, 0.23-0.79, p=0.006, respectively). Overall, 62 pts (32.8%) colonized with MR bacteria developed at least one BSI during the period of observation; 36 of them (58.1%; 19% of the whole series) developed BSI by the same pathogen (MRrel-BSI) (2 VRE, 14 ESBL-P E. coli, 2 ESBL-P K.pneumoniae, 1 ESBL-P E. aerogenes, 12 CP K. pneumoniae, 3 CP P. aeruginosa and 2 CP Acinetobacter spp). The rate of MRrel-BSI according to antibiotic resistance was 13.3% for VRE colonization, 19.5% for ESBL-P enterobacteria and 17.6% for CP GNR. CP K. pneumoniae, but not other CP enterobacteria, was predictive of MRrel-BSI (26.7%). In 82% of cases, MRrel-BSI occurred during neutropenia. At multivariate analysis of predictors of BSI, a relapsed/refractory hematological disease was associated to MRrel-BSI (OR 3.1, 1.4-6.7, p=0.005). Unrelated BSI were also observed in 32 pts (51.6%; 16.9% of the whole series), including 6 MR BSI (2 CP P. aeruginosa, 3 CP K. pneumoniae and 1 VRE). After a median follow-up of 80 days (range 0-270), 25 pts died (13.2%). Three-month overall survival (OS) of the entire cohort was 86%±2.9SE, being significantly lower for pts colonized with VRE (71%) and CP (82%) in comparison with those colonized with ESBL-P bacteria (97%, p=0.0018 and 0.0043 respectively) (Fig.1). Death was attributable to CP GNR related BSI in 5 pts and to VRE related BSI in 1. Multivariate analysis showed that CP GNR related BSI (OR 8.3, 2.2-30.5, p=0.001) and VRE related BSI (OR 87.9, 1.1-675.9, p=0.04), together with intensive care unit admission (OR 50.6, 4.5-570.9, p=0.001) were independent predictors of mortality at 30-days from known colonization, whereas having disease in complete remission was protective (OR 0.02, 0.001-0.43, p=0.01). Conclusions. Incidence of MR colonizing bacteria, particularly ESBL-P and CP GNR, affects nearly 10% of italian hematological cancer pts and results in a MRrel BSI in about one fifth of cases, mainly during neutropenia. MRrel-BSI are responsible for more than 50% of BSI observed in MR colonized pts and are significantly more frequent in relapsed/refractory hematologic disease. VRE and CP GNR colonizations but not ESBL-P are associated to lower OS and predict for a higher fatality of related BSI. Among CP enterobacteria, only K. pneumoniae is associated with MRrel-BSI. Empiric antibiotic treatment should be better tailored taking into account these results. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. Design and Methods The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. Results One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Conclusions Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.

Background. During the last years, hematopoietic stem cell transplant from haploidentical donor is increasing by using the unmanipulated graft. We report the results of allogeneic bone marrow transplantation (BMT) from haploidentical donor primed with G-CSF in patients (pts) with high-risk acute myeloid leukemia (AML), who received an uniform TBF (Thiotepa, Busulfan, Fludarabine) conditioning regimen including antitymocyte globulin and an identical GVHD prophylaxis combining MTX+CSA, MMF and an anti-CD25 monoclonal antibody (Basiliximab). Patients and Methods. Since August 2005 to December 2014, 165 pts with high-risk hematological malignancy underwent unmanipulated BMT from fully haploidentical donor primed with 4µg/kg/day of G-CSF over 7 days. Of these 165 pts, 71 (median age 49 yrs, (range5-66) were affected by high-risk AML and were in early (CR1 and CR2: n=58) or advanced (>CR2 or active disease: n=13) phase at time of transplant. All pts received the same myeloablative (MAC: n=47) or reduced intensity (RIC: n=24) TBF conditioning regimen including antithymocyte globuline for 4 days (days-4 through -1) and an identical graft-versus-host disease (GVHD) prophylaxis consisting of the classical association of MTX+CSA combined with MMF from day +7 to day +100 and the administration of 20 mg of Basiliximab at days 0 and +4. The donor were represented by: son (n=25); brother (n=18), mother (n=11), daughter (n=8), sister (n=6) and father (n=3). Anti-infective management, supportive care and transfusion policy were identical for all pts. The experience was conducted at 2 Institutions: Stem Cell Transplant Unit at University Tor Vergata of Rome (n=45) and at Civil Hospital of Pescara (n=26), Italy. Results. All pts engraftedwith full donor chimerism: median time 20 days (range, 11-35) and CI 94±3%. With a median follow-up (FU) of 3.9 yrs (range, 0.7-7.4), the 7-yrs probability of overall survival (OS) and disease free survival (DFS) for all pts was 45±6% and 43±6%, respectively. OS calculated by disease status at transplant was 53±7% at 7 yrs for 58 pts transplanted in early phase and 0.0% at 4 yrs for 13 transplanted in advanced phase (p=0.0027), DFS was 49±7% and 15±10% at 7 and 2 yrs (p=0.007), respectively. TBF-MAC Regimen: 47 pts (median age 43 yrs, range 5-63), in early (n=38) or advanced (n=9) phase at transplant received a TBF-MAC regimen. For all these pts the CI of engraftment was 94±4% at a median of 20 days (range, 12-35). The 100 day CI of acute GVHD (AGVHD) grade II-IV and III-IV was 32±7% and 6±4%, respectively. The CI of extensive chronic-GVHD (CGVHD) was 19±7%. In the patients transplanted in early phase the CI of transplant related mortality (TRM) at 6 months and 7 yrs was 21±7 and 27±7%, respectively. The CI of relapse at 1 and 7 yrs was 16±6% and 24±7%, respectively. With a median FU of 3.9 yrs (range, 1.3-7.4), the 7-yr probability of OS and DFS was respectively 60±8% and 52±8% with a plateau of the curve from 2 yrs after transplant. None of the 15 variables considered in multivariate analysis (Cox and Fine and Gray models) influenced significantly the outcomes. TBF-RIC Regimen: 24 pts (median age 61.5 yrs, range 41-66) were conditioned with TBF-RIC. All pts engrafted with full donor chimerism (CI 96±6%). The 100 day CI of AGVHD grade II-IV and III-IV was 33±10% and 13±7%, respectively. The CI of extensive CGVHD was 8±8%.Four pts were in advanced and 20 in early phase at transplant. For these last pts, the CI of TRM at 6 months and 6 yrs was 15±8% and 25±10%, respectively. The CI of relapse at 1 and 6 yrs was 15±8% and 27±11%, respectively. With a median FU of 4.1 yrs (range, 0.8-6), the 6-yr probability of OS and DFS was respectively 42±12% and 41±12% with a plateau of the curve from 2 yrs after transplant. In multivariate analysis, no significant factor was identified. Conclusions. Although the number of pts does not allow an extensive analysis of the results, the homogeneity of our series in terms of diagnosis, patient selection, conditioning regimen and GVHD prophylaxis supports the conclusion that haploidentical, G-CSF primed, unmanipulated BMT is a valid alternative for high-risk AML pts lacking an HLA identical sibling. The regimen of GVHD prophylaxis is highly effective and can be proposed in alternative to the use of post-transplant cyclophosphamide, proposed by the Baltimore group. Finally, TBF-RIC regimen can be confidently offered to unfit or older AML pts candidate to an haploidentical transplant. Disclosures No relevant conflicts of interest to declare.

[Graphic][1] Introduction. Multiresistant (MR) bacteria colonization is considered predictive of related bloodstream infections (BSI), which are worrisome among hematological patients (pts). Few data are available about the actual incidence of MR colonization and the probability of developing a BSI in this population. A multicentric prospective observational study has been carried out within the SEIFEM group, with the aim of detecting the incidence of MR bacterial colonization and the probability of developing MR BSI in hematological pts. Patients and Methods. Between March 1st and August 31st 2015, all pts with a hematological neoplasm admitted to 18 Italian Centres participating to SEIFEM were screened for MR colonization with a rectal swab; cultures of other sites were performed if clinically indicated. Patients showing MR bacterial colonization were recorded in a database where the occurrence of any BSI was correlated with age, gender, type and phase of disease, stem cell transplantation (SCT), presence of invasive devices, type of colonizing bacteria. Results. During a 6-month period, 189 pts with MR colonization were observed. Incidence was 8.9% among all admissions (189/2122). Median age was 59y (range 0-89) and M/F ratio 116/73. Eighty-two pts were affected by acute leukemia, 75 by lymphoma, 24 by myeloma, 6 by chronic myeloproliferative/myelodysplastic syndromes and 2 by aplastic anemia. Forty-four pts underwent SCT (28 autologous and 16 allogeneic). Vancomycin resistant enterococci (VRE) were responsible for colonization in 15 (7.9%) pts, extended spectrum beta-lactamases producing (ESBL-P) enterobacteria in 80 (42.3%) and carbapenemase producing (CP) Gram-Negative Rods (GNR) in 108 (57.1%). Thirteen of 14 pts with multiple colonizations had both ESBL and carbapenemase producing enterobacteria. Multivariate analysis of risk factors for type of MDR colonization showed that a complete hematologic remission was associated to ESBL-P enterobacteria colonization, but protective for CP strains (OR 2, 1.1-3.7, p=0.02 and 0.43, 0.23-0.79, p=0.006, respectively). Overall, 62 pts (32.8%) colonized with MR bacteria developed at least one BSI during the period of observation; 36 of them (58.1%; 19% of the whole series) developed BSI by the same pathogen (MRrel-BSI) (2 VRE, 14 ESBL-P E. coli , 2 ESBL-P K.pneumoniae , 1 ESBL-P E. aerogenes , 12 CP K. pneumoniae , 3 CP P. aeruginosa and 2 CP Acinetobacter spp). The rate of MRrel-BSI according to antibiotic resistance was 13.3% for VRE colonization, 19.5% for ESBL-P enterobacteria and 17.6% for CP GNR. CP K. pneumoniae , but not other CP enterobacteria, was predictive of MRrel-BSI (26.7%). In 82% of cases, MRrel-BSI occurred during neutropenia. At multivariate analysis of predictors of BSI, a relapsed/refractory hematological disease was associated to MRrel-BSI (OR 3.1, 1.4-6.7, p=0.005). Unrelated BSI were also observed in 32 pts (51.6%; 16.9% of the whole series), including 6 MR BSI (2 CP P. aeruginosa , 3 CP K. pneumoniae and 1 VRE). After a median follow-up of 80 days (range 0-270), 25 pts died (13.2%). Three-month overall survival (OS) of the entire cohort was 86%±2.9SE, being significantly lower for pts colonized with VRE (71%) and CP (82%) in comparison with those colonized with ESBL-P bacteria (97%, p=0.0018 and 0.0043 respectively) (Fig.1). Death was attributable to CP GNR related BSI in 5 pts and to VRE related BSI in 1. Multivariate analysis showed that CP GNR related BSI (OR 8.3, 2.2-30.5, p=0.001) and VRE related BSI (OR 87.9, 1.1-675.9, p=0.04), together with intensive care unit admission (OR 50.6, 4.5-570.9, p=0.001) were independent predictors of mortality at 30-days from known colonization, whereas having disease in complete remission was protective (OR 0.02, 0.001-0.43, p=0.01). Conclusions. Incidence of MR colonizing bacteria, particularly ESBL-P and CP GNR, affects nearly 10% of italian hematological cancer pts and results in a MRrel BSI in about one fifth of cases, mainly during neutropenia. MRrel-BSI are responsible for more than 50% of BSI observed in MR colonized pts and are significantly more frequent in relapsed/refractory hematologic disease. VRE and CP GNR colonizations but not ESBL-P are associated to lower OS and predict for a higher fatality of related BSI. Among CP enterobacteria, only K. pneumoniae is associated with MRrel-BSI. Empiric antibiotic treatment should be better tailored taking into account these results. ![Figure 1][2] Figure 1 Disclosures No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif [2]: pending:yes

We retrospectively studied a consecutive series of 100 patients with acute leukemia and aspergillosis to evaluate the clinical findings and risk factors for colonization of the central nervous system (CNS) by Aspergillus species. The diagnosis of CNS aspergillosis was made in 14 patients on the basis of the following criteria: neurological signs of CNS involvement (13 of 14 patients); cerebral CT scan findings (9 of 12); microbiological findings (6 of 12); and histological findings at autopsy (11 of 11). The majority of patients had severe neurological complications (i.e., hemiparesis or seizures), due mainly to brain abscesses or mycetomas. Autopsies were performed on 11 of 14 patients and provided evidence that CNS localization was secondary to invasive aspergillosis; in each case, the most likely primary focus of infection was the lung. Although all patients had received oral antimycotic prophylaxis and had received timely empirical antifungal treatment, they all died within a median time of 5 days from the onset of neurological symptoms. Analysis of the characteristics of patients with invasive aspergillosis did not reveal any difference between those with CNS localization and those without CNS localization.

OBJECTIVES Aim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia. PATIENTS AND METHODS From January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases. RESULTS 1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study. Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded. Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy. IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment. A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. | | || | | APL | npAML | p | | Number of pts | 103 | 881 | | | Mean age | 51 | 55 | 0.01 | | m/f | 50/53 | 448/433 | N.S. | | Performance status (WHO) 0-1 >1 | . 76 27 | . 284 597 | .

Patients and Methods. At the Rome Transplant Network, a JACIE accredited metropolitan transplant program, a matched-pair analysis has been conducted on 116 of 255 patients transplanted between January 2008 and December 2012. The patients transplanted from Id Sib (n=58) or Haplo related donors (n=58) were completely matched for the following features: patient age, gender, diagnosis (7 subgroups), disease phase (early: CR1+CR2; advanced: >CR2+active disease), myeloablative or reduced intensity conditioning regimen consisting of Thiotepa, i.v. Busulphan and Fludarabine (TBF) association, donor age and donor/recipient sex, AB0 and CMV combinations. As GVHD prophylaxis, all patients received the standard CSA and MTX combination with the addition of ATG, MMF and Basiliximab in Haplo bone marrow recipients. The transfusion policy, supportive care and antinfectious prophylaxis were identical for all patients. Results. By comparingId Sib to Haplo recipients, the cumulative incidence (CI) of grade II-IV and III-IV acute-GVHD was 18±5% vs 42±7% (p=0.002) and 7±3% vs 14±5% (p=ns), respectively. The CI of extensive chronic GVHD was 23±6% for both patient series. The 5-year CI of TRM was 30±6% vs 36±6% (p=ns), respectively. The main causes of TRM were infections and the 6-month CI of Infection Related Mortality (IRM) was 26±6% in Haplo transplant and 10±4% in Id Sib (p=0.04). Although not statistically significant, the 5-year CI of relapse was higher in Id Sib (40±7%) than in Haplo recipients (28±6%). With a median follow-up of 3.5 years (range, 1 - 6), the 1- and 5-year disease free survival (DFS) was respectively 50±7% and 37±6% for Id Sibs and 45±7% and 36±6% for Haplo (Figure 1). Since 2 years after transplant, DFS curves of Id Sib and Haplo patients remained at plateau and were overlapping. Conclusions. This analysis considered a high number of factors for matching patients, who were grafted according to an identical transplant program. We can conclude that as consequence of a more intensive GVHD prophylaxis and therapy ensuing from higher incidence of >II grade acute GVHD, Haplo recipients are mainly exposed to a risk of early infection mortality. On the other hand, Id Sib patients seem to express less graft-versus-tumor activity with increasing risk of relapse after transplant. The identical long-term DFS justifies to consider the unmanipulated bone marrow transplant from haploidentical donor a valid alternative for patients lacking an HLA identical sib. Finally, it can appear at present provocative, but certainly realistic in perspective, the hypothesis that the donor choice in a familiar setting will mainly take into account other favourable donor/recipient combined characteristics rather than HLA compatibility. Figure 1 - Disease Free Survival Figure 1. - Disease Free Survival Disclosures No relevant conflicts of interest to declare.

Background Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be useful to monitor the local epidemiology ,the frequency and the disease patterns. Aim The aim of this retrospective analysis is to determinate the local epidemiology and the prevalence at autopsy of IFI, occurring in hematological malignancies at a single center over a eleven years period. Methods We have retrospectively reviewed 161 patients – median age 62,5 yrs, range 22 -83 - with hematological malignancies, who underwent autopsy between 2002 -2012. Acute Myeloid Leukemia (AML) were 77, Acute Lymphoid Leukemia (ALL) 11, Lymphoproliferative disorders (LPD) 56 and other disorders 17. Acute leukemia pts received systemic antifungal prophilaxis, whereas the others not absorbable prophilaxis. None patients received transplant procedures. An experienced pathologist evaluated the organ involvement and the IFI pathologic pattern. Fisher’s Exact test was used to recognize the IFI prevalence, the main occurring pathogens and the involved site; a p-value of Results The analysis of 161 consecutive autopsies identified 40 pts.(25%)resulting to have IFI; of these, 22 were AML (55%) ,6 ALL (15%),11LPD (28%) and 1 other. Aspergillus spp. infection was detected in 20 cases (50%), Mucor spp in 8 (20%) and Candida spp. in 12 (30%). Moulds were prevalent in acute leukemia pts. and Aspergillus spp. is the leading pathogen with respect to Candida and Mucor spp. (p 0,0396),with a statistically significant prevalence in ALL (p 0,0186).The site more involved resulted lung (p 0.0002). Whereas the standardized EORTC/MSG criteria applied in vivo were conclusive for IFI in 6 pts ( 15%) only, the postmortem findings revealed fungal infections in further 34 pts (85%). Conclusion This analysis confirms that the IFI diagnosis is still an unresolved issue in hematological malignancies. Acute leukemias remain the subset with the higher prevalence of mould infections. As in other largest studies, in our experience Aspergillus spp and lung proved to be the most recurrent pathogen and site of involvement. At now, the diagnostic methods are not still completely able to identify the underlying IFI, thus the autopsy rate should be increased to achieve a better knowledge of epidemiology and to critically review previous misdiagnosis. Disclosures: No relevant conflicts of interest to declare.

Abstract 1195 Poster Board I-217 The policy of the Rome Transplant Network (RTN), a metropolitan network of transplant Centers, for patients candidates to an allogeneic hematopoietic stem cell transplant (HSCT) and lacking an HLA identical sibling is the contemporary search for one the HSC alternative sources such as Matched Unrelated Donor (MUD),Cord Blood Unit (CBU) or Haploidentical Related Donor (HRD). The main aim of the RTN policy is the identification of a suitable donor in order to perform transplant in adequate timing. The selection criteria for MUD consist of a 8/8 HLA loci matching tested at low resolution for class I HLA and at high resolution (HR) for class II; one difference in C Ag is considered acceptable in case of both I and II class HR identity. CBU's selection criteria are instead based on cell doses (TNC≥2.5×107/kg and CD34+≥1× 105/kg) and on a HLA-compatibility ≥to 4/6 HLA Ag. From April 2006, the haplodentical option was also simultaneously considered, so all closer family members have been tested for the HLA. Here, we report the results of the intention to treat (ITT) analysis on the potential therapeutic impact of our transplant policy. Data were obtained from RTN database. From April 2006 to date, 196 pts have been candidated to receive an allogeneic HSCT for hematological disease. Sixty-six out of 196 (34%) underwent HSCT from HLA identical sibling, while a search process for an alternative donor was activated for 130 pts. Of 130 pts, 9 (7%) lost the eligibility to transplant early during the search process and 19 (15%) died of early disease progression in most cases: a suitable MUD or CBU had been identified for 13 of 19 within 3 months from the start of the search and only 6 pts (5%) died without an alternative donor had been found. To date, 73/102 evaluable pts (72%) lacking an HLA identical sibling have been transplanted (n=66: 23 MUD; 24 CBU; 19 HRD) or are willing to proceed towards the transplant (n=7: 3 MUD;2 CBU; 2 HRD). In summary, for all 196 candidates to an allogeneic transplant the eligibility was confirmed for 187 (95%), a suitable donor could be identified for 181 (92%) of all pts or 97% of the eligible ones and an allogeneic transplant could be performed for 168 (86%) of all candidates or 93% of those eligible. From this ITT analysis, we can conclude that, by adopting the RTN policy of widespread donor search and multiple transplant options, the allogeneic transplant can be offered as potential therapeutic procedure to a large majority of pts. Disclosures: No relevant conflicts of interest to declare.

Background. Relapsed/refractory high grade NHL is a very aggressive pathology characterised by a poor prognosis. High dose therapy followed by peripheral blood stem cell (PBSC) rescue is to date the gold standard therapy. The results of high dose therapy are influenced by remission status after II line therapy as patients who undergo transplantation in complete response have better progression free survival with respect to those in partial response. While Rituximab+chemotherapy has become the approach of choice in 1st line-therapy, this type of schedule has not yet been largely applied in 2nd line therapy. In the aim of testing the efficacy of 2nd line-combined immuno-chemotherapy we designed a protocol including Rituximab + IEV/MINE. Methods. The planned treatment consists of 3 cycles of IEV or MINE (>65 y patients), plus Rituximab (375 mg/sqm) given on day +1 and on day +14 every cycle. G-CSF was administered from day 7 to ANC recovery and was continued until the CD 34+ collection after the third cycle. From April 2002 to July 2008 30 consecutive patients – 19 males and 11 females, median age 57 y (range 21–73 y) with refractory (12) and relapsed (18) Diffuse Large B Cell Lymphoma (DLBCL) entered the study. According to IPI score 20/30 patients were intermediatehigh risk; 21/30 had extranodal disease. Results. 27 patients completed treatment and are evaluable; 3 pts are not evaluable because of lethal infection after Ist cicle (2pts) and lost to follow up (1pt). 21/27 (78%) were responders: 12 (44%) achieved CR, 9 (33%) PR, while 6 progressive disease (PD) were withdrawn. Hematological toxicity including WHO grade III or IV neutropenia, anemia and thrombocytopenia was recorded in 19, 8 and 14 pts, respectively. Target CD 34 harvest was reached in 19/27 (70%) pts with CD 34+ median value 7,03 × 106/Kg. Among the responders 4 pts failed CD 34 harvest. 17/27 (63%) patients underwent transplantion, 11 autologous stem cell transplantation (ASCT) and 6 (>60 y) reduced intensity allogeneic-SCT. Of transplanted patients 4 (2 in CR post Mini Allo-SCT, 2 in relapse post ASCT) died 6, 2,10 and 10 months after transplantation, respectively. The remaining 13 (4 mini-alloSCT and 9 ASCT) are alive in CR which is lasting for 23 months median time (11–73). As of July 2008 15/27 (55%) patients are alive: 14 CR and 1 PR. Median follow up post R-IEV/MINE is 28 months (range 12–77), PFS was 38% and median OS is 32 months (range 7–90). Conclusions. Our experience, if limited to a small series of patients, shows that the addition of Rituximab to second line chemotherapy: increases response rate even in adverse IPI score cases, allows to obtain a good CD 34 harvest, represents an effective in vivo purging agent.

In patients undergoing ASCT, RBC transfusions are depending on donor availability and correlated with early and late side effects such as immune reactions and infections. Three weeks long acting Darbepoietin is currently available, but its role in ASCT in terms of efficacy, safety and cost has not yet been established. Aim: This pilot study was activated in ASCT patients to test the impact of Darbepoietin on the haemoglobin level; RBC transfusion requirement; the total cost of Darbepoietin therapy during the first 30 days after ASCT. Material and methods. From September 2006 to June 2007, 10 patients - 5 males, median age 57 years (range 20–71) - with Multiple Myeloma (MM n=7) in 1st response, Non-Hodgkin (NHL n=2) and Hodgkin (HL n=1) Lymphoma in 2nd complete remission entered the study. As conditioning regimens, the patients received Mel 200 (n=8) or BEAM (n=2). Baseline Hb and Epo median values were: 12,1g/L (range 10.3 – 16.2 g/L), and 28.7mU/mL (range, 4.1–220 mU/L), respectively. The median value of CD34+ cells infused was 4.99 x109/L (range 3.04 – 5.07) and the median time to engraftment was 10 days (range 8–11). To prevent anaemia, patients were given i.c. single dose 500 U Darbepoietin on day +1, associated with iron therapy and B12 vitamin /weekly, plus folinic acid and B6 vitamin/daily. RBC transfusion was mandatory for Hb level ≤ 8g/L. Results: At day +30, in 9/10 patients (7 MM, 1 NHL and 1HL) the median Hb value was 13.2 g/L (range 10.2 – 15.1g/L), and none of them were transfused. Only 1 NHL received 1 RBC unit on day +7 because of Hb was 8g/L; in this case, the baseline dosage of Epo was high (220 mU/L). On the follow-up (median time 4 months, range 1–11), no thromboembolic events or other side effects occurred. Finally, in our Country the price of 1 vial Darbepoietin and 1 RBC transfusion (packed, filtered and irradiated) is 744.60 and 340 euro, respectively. Therefore,, the cost of the entire supportive therapy in our 10 patients has been 7.786 euro. Comments Despite the small number of patients, from this pilot study we can drawn the conclusion that Darbepoietin seems an effective and safe therapy and could represent an appropriate support in ASCT patients with baseline low/normal Epo level. Only a prospective, randomized study on a large number of patients will be able to answer the question on the Darbepoietin cost-efficacy in ASCT.

Recent reports indicated the clinical feasibility and biological therapeutic potentiality of epigenetic treatments with VPA + ATRA or ATRA alone and suggested the capability of these agents in rendering neoplastic cells more sensitive to chemotherapy. Therefore, we designed treatments consisting of LoDAC preceded by the sequential administration of VPA+/LoATRA or LoATRA alone, according to the clinical condition of patients, to treat AML patients not eligible for intensive therapy. Aims of this study were to evaluate: the efficacy of these approaches in term of response rate and toxicity; the biological changes occurring in the leukemic clone in relation to the clinical response, by a multiparametric in vivo translational experimental approach.From September 2006 to June 2007, 5 patients (pts) with de novo and 5 with relapsed AMLs were enrolled. The median age was 66 years (range: 46–81 yrs), the mean percentage of BM leukemic infiltration was 60% (range 30–81%);as cytogenetics 5 pts showed complex karyotype. Four patients (1= de novo; 3=relapsed) received an induction treatment with VPA+LoATRA+LoDAC (VPA):VPA at the initial dose of 10 mg/kg/die orally escalated, to reach the therapeutic VPA plasma levels (>50μg/ml),days 1–55, LoATRA 25 mg/m2/die orally, days 7–55 and LoDAC 40 mg/sc at day (d)10 and 45 for 7 d. In responders, therapy was repeated up to a maximum of 3 cycles with a 20 days rest period. Six patients (4 = de novo; 2 = relapsed), received LoATRA alone (days 1–55) because of coexisting co-morbidities , followed by LoDAC as described. Peripheral blood (Pb) and BM samples for biological studies were collected at d 0,7,14,21,35,55. Responses were evaluated after the first cycle of therapy according to the IWC criteria. A complete remission (CR) was observed in 4 cases (2 relapsed = VPA; 2 de novo= LoATRA), while 2 de novo pts (LoATRA) showed a major response (MR).In the 6 responders PB recovery (Hb>9g/dl; PMN>1000/m 3and PLTS>50.000/m3), was observed within a median time of 42 d (range: 35–50 d), while the median time of BM blast clearance was 35 d (range 25–50 d). Of the remaining 4 pts, 1 died during induction, at 45 d for cardiac failure, 3 maintained a stable disease and died 7, 5 and 3 months(mo) later. As to July 2007, 2 pts (Lo ATRA) persisted in CR at 2 and 4 mo, while 2 pts (VPA) relapsed at 3 and 4 mo from CR. Five pts are still alive at 4+, 5+, 5+, 5+, and 9+ mo.Biological assays showed that in mononuclear samples from the 4 CR patients, phenotypic changes including: the increased percentage of cells in S phase; cytochemical changes (myelo-monocytic differentiation); decreased expression of early myeloid/progenitor immunophenotypic markers (HLA-DR, CD34, CD117), which paralleled the increase of late myeloid differentiation markers (CD11b, CD15 or CD14), started to be measurable before LoDAC administration. In conclusion, the sequential therapy with VPA and/or LoATRA + LoDAC are well tolerated out-patient therapies that enabled a CR in a sizeable portion of our cases. In addition, these treatments induce AML blast phenotypical changes that may increase their sensitivity to LoDAC, whose molecular basis is currently under investigation.

Background: CNS involvement in acute lymphoblastic leukemia/AUL is a well-recognized event and CNS prophylaxis is considered mandatory. In NHL, meningeal relapse occurs more rarely, ranging from 4–14% depending on histology, anatomical location and biological parameters. Flow cytometric analysis of cerebrospinal fluid (CSF), however, detected occult lymphomatous meningitis in 22% of NHL cases at risk at diagnosis (Hegde et al. Blood2005;105:496). CNS prophylaxis is currently recommended only in high-risk disease (stage IV/high IPI score) and in patients with extranodal NHL. Sustained-release liposomal cytarabine (DepoCyte®), which is licensed for meningeal relapse in NHL, has proved effective in treating lymphomatous and leukemic meningitis (Glantz et al. J Clin Oncol1999;17:3110; Sancho et al. Haematologica2006;91:ECR02). Intrathecal (IT) liposomal cytarabine is distributed throughout the CSF and has an extended half-life, allowing administration once every 2–4 weeks (Chamberlain et al. Arch Neurol1995;52:912). We therefore tested the efficacy of liposomal cytarabine in CNS prophylaxis for elderly patients with aggressive NHL or AUL, with the aim of testing the safety of IT treatment in elderly patients and the efficacy of liposomal cytarabine in preventing lymphoma/leukemia CNS relapse. Methods: From June to November 2005, 4 patients > 70 years of age entered the study. Diagnoses were: 2 stage IV, IPI 3, diffuse large B-cell lymphoma (DLBCL); 1 mantle cell lymphoma (MCL), and 1 AUL; 2 patients had extranodal bulky disease (1 psoas muscle, 1 retro-orbital plus paranasal sinus involvement). As first-line treatment, the 3 NHL cases were given R-CHOP every 21 days for 6 cycles. The patient with AUL received conventional 3-drug induction (vincristine/idarubicine/prednisone) every week for 3 weeks, followed by 3 courses of L-VAMP (vincristine/cytarabine/intermediate-dose methotrexate/leucovorin rescue) and then conventional maintenance (6-mercaptopurine/methotrexate and monthly re-induction with vincristine/prednisone). All patients received CNS prophylaxis with IT liposomal cytarabine 50 mg followed by systemic steroid injection. In NHL cases, IT therapy was given the day before systemic chemotherapy for a total of 4 administrations; in AUL, prophylaxis was given every 4 weeks during induction and maintenance for a total of 6 doses. Results: Three (2 NHL and 1 AUL) patients achieved a complete response (CR) and 1 (NHL) achieved a partial response, with response durations of 4, 5, 6+ and 8+ months, respectively. As of July 2006, after a median follow-up of 10 months (range 9–12), all patients were alive; 2 (1 DLBCL, 1 AUL) were in continuous CR, and 2 (1 DLBCL, 1 MCL) had progressive disease and were receiving second-line treatment. Isolated relapse of leukemia/lymphoma in the CNS was not seen. Liposomal cytarabine was well tolerated; no drug-related side effects or hematological toxicities were recorded. Conclusions: As occult CNS involvement has been shown to occur in >20% of newly diagnosed patients with high-risk NHL, flow cytometry and cytospin analysis of CSF at diagnosis should be implemented in order to adequately target CNS prophylaxis. Liposomal cytarabine should be the drug of choice for CNS prophylaxis, particularly in elderly patients.

Background: To evaluate the incidence and the outcome of fungal infections in patients (pts) affected by hematological malignancies (HM). Methods: A retrospective study, conducted over 1999–2003, in pts with HM, admitted in 18 Italian Hematology divisions in tertiary cares or university hospitals, who developed proven or probable fungal infections. Results: The population included 11,802 pts: 3,012 AML (25.5%), 1,173 ALL (9.9%), 596 CML (5%), 1,104 CLL (9.4%), 1,616 MM (13.7%), 3,457 NHL (29.3%), 844 HL (7.2%). Pts who underwent HSCT were included in a different analysis. A fungal infection occurred in 538 pts, with an incidence of 4.6%; in particular we registered 346 episodes sustained by moulds (incidence 2.9%) and 193 by yeasts (1.6%). The incidence rate depends upon underlying malignancy (12.3% in AML, 6.5% in ALL, 2.7% in CML, 0.6% in CLL, 0.5% in MM, 1.6% in NHL, 0.9% in HL). Among moulds, the etiological agents were Aspergillus (310 episodes, incidence 2.8%), Mucorales (13 pts, 0.1%), Fusarium (15 pts, 0.1%), and other rare fungi (7 pts, 0.1%). Among yeasts we registered septicemia due to Candida (175 pts, 1.6%). Other yeast infections were caused by Cryptococcus (8 pts, 0.1%), Tricosporon (7 pts, 0.1%) and other rare agents (2 pts). We did not observed an increase of A.terreus infections while the number of episodes sustained by A.flavus increased from 1999 to 2003 (RR 2.10; IC95% 0.8–5.49; p-value 0.117). The overall mortality rate was 1.8%. Among 538 pts with fungal infection 39% died for this complication, with differences between aspergillosis (42%), zygomycosis (63%), fusariosis (53%) and candidemia (33%). There was not variation in mortality rate during the study period; comparing these pts with those observed in our previous studies during the period 1987–1988 we observed a significant reduction of death due to aspergillosis (RR 1.90; IC 95% 1.17–3.09), but no differences in mortality rate due to Candida. Conclusions: Our study confirms the general trends already described: infections due to moulds are more frequent than those caused by yeast. Aspergillus remains the main etiologic agent, followed by Candida. The other agents (Mucorales, Fusarium, Trichosporon) remain rare. AML represents the most frequently involved category. The mortality rate due to aspergillosis is actually about 40%, with a remarkable decrease when compared to past years; as for candidemia, we observed a reduction in the incidence, but not in the mortality rate.

In ANLL, during intensive induction,invasive fungal infections (IFI) related to prolonged neutropenia,mucosal damage,steroids, geographical and center variations is the main factor wich can influence disease outcome The optimal prophylactic regimen has not yet to be identified. The AmB lipid formulations let to treat IFI in refractory or intolerant patients. The efficacy of these drugs appears to be related both to improved tissue penetration along with sustained bioactivity of drug levels in lung, brain, kidneys, liver and spleen.(Anaissie et al.2004).On this basis,, in a cohort of adult (>18y) ANLL patients,during induction,we applied a pilot study for IFI prophylaxis in the aim to test the efficacy and safety of a single large dose of L-AmB.The primary endpoint was to evaluate the incidence of documented or suspected fungal infection during and up to four weeks after prophylaxis discontinuation.PATIENTS: From September 2004 to May 2005 18 consecutive adult ANLL (4 APL) patients −12 M,6 F, median age 56 y (range 39–75)- entered in this study. Intensive induction chemotherapy included standard /high dose cytosine-arabinoside + antracyclines +etoposide or fludarabine and retinoic acid + antracyclines in the 4 APL. METHODS: The criteria of inclusion were:1)neutropenia (PMN RESULTS:13 (72%) patients achieved complete hematological remission,1 was resistant and 4 died during induction aplasia. (2 for Aspergillosis). Overall median neutropenia duration was 22 d (range 17 – 45). The median dosage of L- AmB administered was 900 mg x dose( range 750 – 900);a second single dose at the same dosage was given in four cases. During L-AmB infusion, 2 patients had CTC grade II allergy, treated by i.v. steroids, thus drug infusion could be completed; no patient had renal or hepatic toxicity.Of the 18 enrolled patients,14 (80%) met the primary endpoint of the studys since none of them developed fungal infection, while the remaining 4 cases had IFI: 2 Candida spp.sepsis and 2 invasive Aspergillosis.On the basis of these encouraging clinical results, in further consecutive 5 patients we tested L-AmB PK profile at the following times: 0,12,24 hour,7th and 14 th day from drug administration.The median L-AmB PK results (lower standard rate 0,15mg/l + − standard deviation) are: 0 h < 0,15 1 h 8,92 +/− 4,25 4 h 51,26 +/− 26,7 24 h 3,92 +/− 11,77 7° d 1,39 +/− 1,97 14° d 0,27 +/− 0,092 CONCLUSION:despite the low number of patients involved,in our experience a single large L-AmB dose (15mg/kg) did show an effective and safe approach for the IFI prophylaxis, since 80% of treated patients did not experience fungal infection;furthemore preliminary kinetic results show high plasma levels that are slowly eliminated. These data have to be confirmed in larger series of ANLL adult patients to define which may be the best dosage to achieve a good and prolonged tissue concentrations.

The prognostic significance of the pretreatment growth characteristics of marrow blasts was examined in 37 patients with acute nonlymphocytic leukemia (ANLL) treated with a similar therapeutic regimen. Initial mitotic index (MI) and in vitro 3H-thymidine labeling index (LI) were broadly distributed showing no correlation to other initial variables, such as age or absolute blast count. No relationship whatsoever was observed between the pretreatment LI, MI and either the likelihood of achieving a complete remission or the remission and survival length. We conclude that the initial growth characteristics of marrow blasts do not play a significant role in predicting the therapeutic response in ANLL; age, modality of therapy and, possibly, the dynamic perturbations of the proliferative activity of the blast cells induced by treatment should be regarded as more reliable prognostic indicators in ANLL.

A retrospective study on a consecutive series of 116 patients affected by acute leukaemia with documented pulmonary filamentous mycosis (FM) admitted between 1987 and 1992 to 14 tertiary-care hospitals in Italy was made in order to evaluate the characteristics of those patients who developed fatal massive haemoptysis. In 59/116 cases of pulmonary FM the infection was the principal cause of death and in 12 of these patients a massive haemoptysis was responsible for death. The diagnosis of FM infection was made ante-mortem in only four out of these 12 patients. The autopsy was performed in 11/12 patients and documented a FM infection. The mycetes isolated were: Hyphomycetes spp. (three patients), Mucorales spp. (two patients), Aspergillus spp. (seven patients). At the time of the massive haemoptysis the mean neutrophil count was 7.2x109/1, and no patient had relevant thrombocytopenia (mean 184x109/1, range 28-350) or coagulative abnormalities. The mean time which elapsed between resolution of chemotherapy-induced neutropenia (WBC

PURPOSE: The aim of this retrospective study was to compare 5 vs 10 mcg/kg/day of lenograstim (Leno) (Myelostim 34®) in collecting target dose of CD34+ peripheral blood progenitor cells (PBPC) in adults candidate to autologous transplant. Univariate and multivariate analysis were carried out in order to identify factors predicting for satisfactory procedures. Material and Methods: From 01/’04 to 06/’08, 166 consecutive patients from 2 Institutions participating to the Rome Transplant Network with acute leukemias in complete remission (AL, #28), lymphomas (#77) and multiple myeloma (MM, #61) underwent 182 CD34+ PBPC mobilization procedures with Leno following standardized regimens. Only the 1st procedure for each patient was considered for the analysis. The target dose of CD34+ cells was ≥ 2 x106/kg for AL, ≥ 4 for lymphomas and ≥ 8 for MM with Leno starting at day +19, +1 and +5 from the end of chemotherapy, respectively. Eighty-seven patients received 5 mcg/kg Leno subcutaneously once a day (Leno5 cohort), while 79 patients were given Leno twice a day for a total dose of 10 mcg/kg (Leno10 cohort). Quantitative variables were compared by using analysis of variance (ANOVA); for qualitative parameters we used the chi-square test. A multivariate logistic model was used to analyze associations between some baseline characteristics and effectiveness to reach the required CD34+ cell target dose. Linear analysis was used to determine the relative significance of the same characteristics as predictive variables for stimulation length. Enter and remove limits were p=0.10 and 0.15, respectively. The SPSS (13.0) statistical program was used for analysis. Results: Age, sex, diagnosis and relative target dose, previous therapy including fludarabine, radiotherapy, number of previous chemotherapy regimens were not significantly different between the 2 cohorts. No statistically significant difference was observed in terms of number of apheresis performed, amount of blood processed, total number of CD34+ PBPC x103/mL mobilized and CD34+ cells x106/kg collected between the 2 cohorts. Reaching of the target dose and stimulation length are reported in table by Leno dose administered. | | | # reaching the target | Mean days ±SD | |:---------:| -------------------------- | --------------------- | ------------- | ----- | | Diagnosis | CD34 + cell target x106/kg | Leno5 | Leno10 | p | Leno5 | Leno10 | p | | AL | ≥ 2 | 14/19 (74%) | 5/9 (56%) | ns | 11.2 ±6.4 | 6.2 ±3.1 | 0.035 | | Lymphomas | ≥ 4 | 25/37 (68%) | 33/40 (83%) | ns | 9.3 ±2.4 | 9.7 ±1.8 | ns | | MM | ≥ 8 | 21/31 (68%) | 27/30 (90%) | 0.034 | 8.7 ±2 | 7.6 ±1.8 | 0.033 | | Total | | 60/87 (69%) | 65/79 (82%) | 0.047 | 9.5 ±3.6 | 8.5 ±2.3 | 0.038 | Forty-one patients did not reach the cell target. Of these, 16 underwent in any case PBPC transplant with the CD34+ cell dose collected. Of the remaining 25 patients, 9 were excluded from further attempts of PBPC mobilization, while 16 underwent 1 or 2 additional procedures and 10 of them were later transplanted. Overall, of 166 patients, 151 [Leno5 #76 (87%), Leno10 #75 (95%); p=ns] were able to be submitted to transplant. No Leno-related adverse event was observed in both the patient cohorts. In multivariate analysis, factors predicting for reaching the required CD34+ cell target dose were sex, with a negative impact of female sex (p=0.028), and Leno dose, with a positive impact of high dose, although exclusively restricted to MM patients (p=0.05). Finally, the multivariate analysis identified previous therapy not including fludarabine as the only factor significantly correlated with a shorter stimulation length (p=0.002). Conclusion: High dose Leno showed a higher capacity of harvesting only in MM patients for whom the CD34+ cell target was the highest to be collected. Leno dose did not impact on the CD34+ cell collection for AL and lymphoma patients as well as on the proportion of autologous transplants finally performed. As previously reported in healthy donors, in our study patient sex was an independent predictive factor for reaching the required CD34+ cell dose. Finally, fludarabine negatively influenced the length of Leno administration.

Background. Similar probabilities of survival have been reported for patients transplanted from Matched Unrelated Donor (MUD), Umbilical Cord Blood (UCB) or Haploidentical (Haplo) donors as alternative hematopoietic stem cell sources. However, few studies have compared these results with those obtained in patients transplanted from HLA Id-siblings (Id-sib). Moreover, all reported studies are retrospective and the criteria of donor selection were not predefined. We report the intention to treat (ITT) analysis results on 238 patients with high-risk acute myeloid leukemia (AML) prospectively transplanted according to the policy of the Rome Transplant Network (RTN), a metropolitan transplant program established in Rome in 2006. Patients and Methods. For AML patients eligible to an allogeneic transplant, the RTN policy consists of an algorithm of donor choice based on a hierarchy according to the following criteria: 1) HLA identical sibling; 2) MUD ≥8/10 HLA 3) UCB as single unit selected on the base of cell dose and number of HLA disparities (0-1/6 HLA: TNC ≥2.5x107/kg and CD34 ≥1x105/kg; 2/6 HLA: TNC ≥3.5x107/kg and CD34 ≥2x105/kg); 4) G-CSF primed, unmanipulated bone marrow Haplo donor. Myeloablative (MAC) or reduced intensity (RIC) TBF (Tiothepa, Busulfan, Fludarabine) conditioning regimen was identical for all patients, GVHD prophylaxis was uniform for each categories. of transplant Results. From January 2006 to December 2014, 238(89%) out of 303 adult patients candidates to an allogeneic transplant for high-risk AML were considered eligible. Overall, a donor was available for 205 (86%) of 238 eligible patients. At time of the analysis, 17 of these 205 patients (8%) had lost the transplant eligibility and 4 (2%) were still scheduled for transplant, therefore 184/205 (90%) patients with an available donor were finally transplanted from Id-sib (n=76), MUD (n=38), UCB (n=17) or Haplo (n=53) donors. The 8-yrs overall survival (OS) of the 238 eligible patients from time of HLA typing and of the 184 transplanted patients from time of the graft was 40±4%and 43±4%, respectively. By excluding the low number of UCB recipients (n=17), the OS was particularly dismal for the 34 patients transplanted in advanced disease phase (7±4% at 4 yrs), whereas for the 132 patients transplanted in early (CR1+ CR2) phase the 8-yr OS was 56±5%: 58±7% for 61 HLA Id-sib, 50±8% for 40 Haplo and 63±10% for 27 MUD recipients (P=NS). The OS of patients transplanted in early phase was 63±5% for 97 patients receiving MAC and 33±9% for RIC recipients. For these 97 patients, the survival by type of donor was 62±10% either for 47 Id-sib or 28 Haplo and 70±10% for 22 MUD recipients (P=NS). The results were analyzed by various donor/recipient (D/R) combinations such as age, sex and CMV status. The median donor age was 39 years (range, 18-70) and the median patient age was 43 years (range, 16-59): the 8-yr OS of patients (n=30) with younger D/R combination (D Conclusions. RTN policy allowed donor identification in 86% of all eligible AML patients and allowed an allogeneic transplant to be carried out in 90% of them with no substantial differences in terms of long-term survival between initially eligible (ITT analysis) and definitively transplanted patients. Only the definition of a specific transplant policy and the ITT analysis allow to evaluate the real impact of a transplant program. As the probability of survival is not substantially different comparing different donor stem cell sources, the final conclusion which can be drawn from our study is that for patients with AML undergoing an allogeneic transplant, the HLA matching is unlikely to remain the first criterion for donor identification. Other factors such as D/R age, sex and CMV status should drive the search for the best donor. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in Italy during the European Confederation of Medical Mycology of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin B (L-AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.