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Alessandra Micozzi,1 Clara Minotti,2 Saveria Capria,2 Claudio Cartoni,2 Silvia Maria Trisolini,2 Giovanni Manfredi Assanto,1 Walter Barberi,2 Maria Luisa Moleti,2 Stefania Santilli,3 Maurizio Martelli,1 Giuseppe Gentile1 1Haematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; 2Department of Haematology, Oncology and Dermatology, Azienda Policlinico Umberto I, Rome, Italy; 3Department of Diagnostics, Azienda Policlinico Umberto I, Rome, ItalyCorrespondence: Alessandra Micozzi, Haematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Via Benevento 6, Rome, 00161, Italy, Tel +39 6 857951, Fax +39 6 44241984, Email alessandra.micozzi@uniroma1.itPurpose: To evaluate the benefits and safety of the empiric antibiotic treatment (EAT) active against KPC-K. pneumoniae in febrile neutropenic patients with acute leukaemia (AL) who are colonised by KPC-K. pneumoniae.Patients and Methods: A 7-year (2013– 2019) retrospective observational cohort study was conducted at the Haematology, Sapienza Rome University (Italy) on 94 febrile neutropenia episodes (FNE) in AL patients KPC-K. pneumoniae carriers treated with active EAT.Results: Eighty-two (87%) FNE were empirically treated with antibiotic combinations [38 colistin-based and 44 ceftazidime-avibactam (CAZAVI)-based], 12 with CAZAVI monotherapy. Successful outcomes were observed in 88/94 (94%) FNE, 46/49 (94%) microbiologically documented infections, and 24/27 (89%) gram-negative bloodstream infections (GNB-BSI). Mortality due to infective causes was 4.2% (2.1% within 1 week). KPC-K. pneumoniae infections caused 28/94 FNE (30%) and KPC-K. pneumoniae-BSI was documented in 22 FNE (23.4%) (85% of GNB-BSI), in all cases patients received active EAT, and 21 survived. KPC-K.pneumoniae-BSI mortality rate was 4.5%. CAZAVI-based EAT showed better results than colistin-based EAT (55/56 vs 33/38, p = 0.037), overall and without EAT modification (41/56 vs 20/38, p = 0.02). Empirical combinations including CAZAVI were successful in 98% of cases (43/44 vs 33/38 for colistin-based EAT, p = 0.01), without modifications in 82% (36/44 vs 20/28, p = 0.02). All deaths occurred in patients treated with colistin-based EAT (4/38 vs 0/56, p = 0.02). CAZAVI-containing EAT was the only independent factor for an overall successful response (HR 0.058, CI 0.013– 1.072, p = 0.058). Nephrotoxicity occurred in 3(8%) patients undergoing colistin-based EAT (none in those undergoing CAZAVI-based EAT, p = 0.02).Conclusion: KPC-K. pneumoniae infections are frequent in colonised AL patients with FNE. EAT with active antibiotics, mainly CAZAVI-based combinations, was effective, safe, and associated with low overall and KPC-K. pneumoniae-BSI-related mortality.Keywords: ceftazidime-avibactam, colistin, haematological malignancies, KPC-K. pneumoniae-BSI mortality rate

Purpose. Peripherally-inserted central catheters (PICCs) are successfully increasingly used in children in onco-hematologic setting. PICC insertion, especially in oncologic patients, can be associated with adverse events (thrombosis, obstruction and infections). Data regarding the use of PICC, as long-term access in pediatric patients with severe hematologic diseases, are still limited. Methods. We retrospectively evaluated the safety and efficacy of 218 PICC, inserted in 154 pediatric patients diagnosed and treated at Pediatric Hematology Unit, Sapienza University of Rome, for severe hematologic disease in a 11-year period (98 acute lymphoblastic leukemias, 20 acute myeloid leukemias, 20 Hodgkin lymphomas, 6 non-Hodgkin lymphomas, 8 severe aplastic anemias, 2 acquired thrombotic thrombocytopenias). Results. The 218 PICC analyzed were in situ for a median dwell time of 160 days (range 12–898). In 38 children, PICC was inserted twice and in 10, three times or more due to hematopoietic stem cell transplant, disease recurrence or PICC-related complications. The overall complication rate was 32%: central-line associated bloodstream infections (CLABSI) occurred in 21% of cases after a median time of 105 days; a catheter-related thrombosis (CRT) in 3% and mechanical complications in 8% of cases. Premature removal for complications occurred in 36.7% of PICC. No death related to PICC complications was observed. Conclusion. In our experience, PICC was a cheap, safe and reliable device for long-term intravenous access in children with severe hematologic illnesses. This has been possible with the help of dedicated PICC team.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with the majority of cases being of B lineage [1]. B-cell precursor ALL (BCP-ALL) is a heterogeneous disease in which risk ass...

Background. KPC-K.pneumoniae bloodstream infection (KPC-KpBSI) mortality rate in patients with hematological malignancies is reported about 60%. The initial treatment active against KPC-K.pneumoniae is crucial for survival and KPC-K.pneumoniae rectal colonization usually precedes KPC-KpBSI. We evaluated the impact on KPC-KpBSI mortality of the preemptive use of antibiotics active against KPC-K.pneumoniae, as opposed to inactive or standard empiric antibiotics, for the empiric treatment of febrile neutropenia episodes in patients with hematological malignancy identified as KPC-K.pneumoniae intestinal carriers. Methods. We compared the outcomes of KPC-KpBSIs occurring in high-risk patients with hematological malignancy known to be colonized with KPC-K.pneumoniae, during two time periods: March 2012-December 2013 (Period 1, initial approach to KPC-K.pneumoniae spread) and January 2017-October 2018 (Period 2, full application of the preemptive strategy). The relative importance of the various prognostic factors that could influence death rates were assessed by forward stepwise logistic regression models.Results. KPC-KpBSI-related mortality in patients with hematological malignancies identified as KPC-K.pneumoniae carriers dropped from 50% in Period 1 to 6% in Period 2 (pK.pneumoniae carriers were treated with initial active therapy in 56% and 100% of cases in Period 1 and Period 2, respectively (pConclusions. In high-risk patients with hematological malignancies colonized by KPC-K.pneumoniae, the empiric treatment of febrile neutropenia active against KPC-K.pneumoniae reduced KPC-KpBSI-related mortality to 6% and prevented fatal breakthrough KPC-KpBSI.

The aim of the study was to observe the effectiveness of a photo-biomodulation (PBM) protocol for the prevention of oral mucositis (OM) in patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT). A case-control study was conducted on 40 patients undergoing aHSCT. The patients were divided into two groups, the preventive group (PG) included 20 patients (7 females and 13 males) who were subjected to intra-oral PBM for five sessions a week, starting one day before the conditioning regimen and continuing until the 10th day after transplantation (D+10). In each session, ten points on the at-risk mucosal surfaces were irradiated using a double diode laser that emits two wavelengths simultaneously at 650 nm and at 904&ndash, 910 nm with the following parameters at each point: energy of 4 J, and power of 88.9 mW. The control group (CG) included 20 patients (10 females and 10 males) who were not subjected to laser therapy and were selected retrospectively to compare the obtained results. For all patients, OM was assessed by the World Health Organization (WHO) grading scale. Eight patients in the PG did not experience OM during their hospitalization period (with grade 0). Severe OM was observed in 40% of the patients in the PG, while in the CG, severe OM was shown in 85% of the patients. The mean duration of OM in the PG was significantly lower than that of CG (4.7 days in the PG and 15 days in the CG) (p &lt, 0.001). The study demonstrated that the preventive PBM protocol reduced the severity and duration of OM in patients undergoing aHSCT.

Central venous catheters (CVC) are essential for the management of patients with hematologic malignancies, facilitating chemotherapy infusion, antibiotics, parenteral nutrition, blood products, and blood samples collection. In this population, peripherally inserted central catheters (PICC) seem to be associated with lower complications, compared with conventional percutaneously inserted devices (CICC). Data on the PICC in allogeneic hematopoietic stem cell recipients (allo-HSCT) are limited. We have prospectively evaluated the safety and efficacy of 100 polyurethanes or silicone PICC, inserted into 100 adult allo-HSCT recipients, at the Hematology of Sapienza University of Rome (Italy), between October 2012 and August 2017. The median duration of PICC placement was 117 days. Overall, 68% of patients maintained the device for the entire transplant procedure and PICC were removed after day 100 from allo-HSCT; of these, 44% did not experienced any PICC-related complications. Catheter-related bloodstream infections (CRBSI) occurred in 32% of patients (2.5/1000 PICC days), associated with thrombosis in 8 cases. CRBSI were observed in 42% of patients with polyurethane and 20% with silicone PICC (p = 0.02). Catheter-related thrombosis occurred in 9% of patients, never requiring anticipated PICC removal. Mechanical complications occurred in 15% of cases (1.2/1000 PICC days). On the whole, adverse events were manageable and did not affect transplant outcome. No deaths related to PICC-complications were observed. PICC are a safe and reliable long-term venous access in allo-HSCT recipients.

Indolent non-Hodgkin lymphomas (iNHL) remain incurable with standard approaches. The timing of autologous stem cell transplant (ASCT) is changing following the introduction of new drugs that can potentially defer the transplant, improved reduced intensity conditioning (RIC) and haploidentical allogeneic SCT (allo-SCT).The most relevant aspects concerning the role of hematopoietic stem cell transplantation in the management of iNHL are discussed. Literature search methodology included examination of PubMed index and meeting presentations. Expert commentary: ASCT is not currently employed as consolidation in first-line, being reserved to patients with refractory/relapsed disease. The curative potential of graft-versus-lymphoma (GVL) after RIC allo-SCT could be particularly beneficial in patients with iNHL relapsing after ASCT. This scenario could be modified in the near future by better definition of high-risk patients at diagnosis, by the improvement of minimal residual disease (MRD) evaluation and by the introduction of new drugs in the therapeutic algorithm.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

Indication and timing of trough plasma-voriconazole (VCZ)-concentration (t-PVC) measurement during VCZ treatment is a debated issue. Patterns of t-PVC were prospectively evaluated in pediatric (50 courses) and adult (95 courses) hematologic patients. Efficacy patterns were defined: adequate, t-PVC always ≥1 mcg/ml; borderline, at least one t-PVC measurement1 mcg/ml but median value of the measurements ≥1 mcg/ml; inadequate, median value of the measurements1 mcg/ml. Toxicity patterns were defined: favorable, t-PVC always ≤5 mcg/ml; borderline, one or more t-PVC measurements5 mcg/ml but median value of the measurements ≤5 mcg/ml; unfavorable, median value of the measurements5 mcg/ml. In children and adults the mean t-PVCs were higher during intravenous treatments. The t-PVC efficacy pattern was adequate, borderline and inadequate in 48%, 12%, and 40% of courses, respectively, in children, and in 66.3%, 16.8%, and 16.8% of courses, respectively, in adults. Adequate efficacy pattern was more frequent in children with body weight above the median (≥25 kg) (OR 4.8; P = .011) and in adults with active hematological disease receiving intravenous therapy (OR 3.93; P = .006). Favorable toxicity pattern was more frequent in children receiving VCZ daily dosage below the median (14 mg/kg) (OR 4.18; P = .027) and in adults with body weight below the median (68 kg) (OR 0.22; P = .004). T-PVC measurement is generally needed, however, a non t-PVC guided approach may be considered in heavier adults receiving intravenous VCZ. The risk of supratherapeutic levels does not seem an absolute indication for t-PVC monitoring.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

In Italy in 2016, acute flaccid myelitis developed in a woman who had received a hematopoietic stem cell transplant. Enterovirus D68 viral genome was detected in respiratory and cerebrospinal fluid samples, and the viral protein 1 sequence clustered with lineage B3. Immunocompromised adults may be at risk for enterovirus D68–associated neurologic complications.

Purpose of review Knowledge of the epidemiology and the risk factors of invasive fungal diseases (IFDs) in hematopoietic stem cell transplant (HSCT) recipients is a critical determinant of the prevention, diagnosis and therapeutic antifungal strategy. Transplant procedures are characterized by a continuous evolution; therefore, an update of the epidemiological findings of IFDs in HSCT populations is needed. Recent findings In the last few years, the incidence and the clinical risk factors of IFD, mainly in allogeneic HSCT populations, have been investigated in prospective, multicenter studies. New findings in the different types and phases of transplant may be considered for a redefinition of the level of risk of IFD after HSCT. Furthermore, recent studies have uncovered associations between host's and/or donor's genetic variants and immunological risk for IFDs, in particular invasive aspergillosis. Summary Evolution of the transplant procedures was followed by an important change in the epidemiology and clinical risk of IFD after allogeneic HSCT. A new stratification of subpopulations according to different clinical infectious risk and genetic susceptibility may be considered to predict those patients most vulnerable to IFD and update tailored antifungal strategies.

We report a case of EBV encephalitis in a seven‐yr‐old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis. Blood and CSF PCR analyses were negative for the most common viruses involved in immunocompromised patients including EBV. A cerebral biopsy was performed, which showed intense gliosis and perivascular lymphocytic cuffing. PCR analysis performed on brain tissue was positive only for the EBV genome, while extensive investigations for other viral infections were negative. The patient's neurological symptoms rapidly worsened and he died two months later. This case report suggests that in patients presenting neurological and radiological signs of encephalitis after an HSCT, an EBV involvement should be considered, even in the absence of CSF and blood PCR virus detection.

Background. Hematologic and, to a lesser extent, molecular relapsed/refractory in adult acute lymphoblastic leukemia (R/R ALL) is associated with a poor outcome, with low rates of subsequent complete remission (CR) and short survival. Blinatumomab has shown to be effective in both settings. Aims and methods. In this retrospective, single center study we aimed at: 1) evaluating the efficacy of blinatumomab in both hematologic and molecular R/R patients enrolled in clinical trials and in a real life setting; 2) identifying predictive factors impacting on overall and disease free-survival (OS and DFS), and 3) establishing the feasibility and the role of a subsequent allogenic stem cell transplantation (HSCT). Thirty-six adult patients (≥18 years) in hematologic or molecular R/R ALL were treated with blinatumomab between January 2012 and March 2017. Blinatumomab was administered either in the context of a clinical trial (Blast, MT103-211, Tower, Alcantara), in a compassionate use program or according to AIFA (Agenzia Italiana del Farmaco) guidelines. Blinatumomab was administered as continuous infusion for 4 weeks, followed by a 2-week wash out. A stepwise dose of 9 µg/day during the first week of cycle 1 followed by 28 µg/day thereafter, was administered for hematologic R/R cases and a flat dose of 15 µg /m2/day for molecular R/R patients. Patients who witnessed a response received up to 4 additional cycles or underwent a HSCT; patients showing after 1 cycle an increase in the blast count or of minimal residual disease levels, discontinued treatment. Results. Thirty-six patients were analyzed: 21 (58.4%) were in hematologic R/R and 15 (41.6%) in molecular R/R. Four patients had high-risk genetic features (2 BCR/ABL1 and 2 MLL/AF4). Thirteen patient were treated in the context of a clinical trial. All patients received at least one cycle of blinatumomab. At the end of the first cycle, among the 21 hematologic R/R pts, 14 (67%) achieved a CR and 10/14 (71%) also a CMR, while in the molecular R/R group 12/15 (80%) achieved a CMR. As expected, the rate of CMR was significantly higher in the molecular R/R cases as opposed to hematologic R/R (80% vs 52%, p=0.05). Notably, all 4 patients treated for a primary refractory disease, achieved a CR and CMR after the first cycle as opposed to hematologic relapsed cases (p=0.08). With a median follow-up of 33.9 months (range 1-89), the overall OS and DFS at 3 years are 34% and 42.5%, respectively. OS was significantly better for molecular R/R cases than for hematologic R/R cases (54.2% vs 26.1%, p=0.05), while no significant differences were observed in DFS. OS and DFS are 100%, respectively, for refractory cases. Median OS is 6.75 months for hematological R/R, while it is not reached for molecular R/R. Median DFS is 26 months for both groups. Predictive factors for non-response were the status of disease prior to blinatumomab (hematologic vs molecular R/R) and primary refractoriness. A better, though not significant, outcome was observed for patients treated in first rather than in subsequent relapse, and in cases without molecular aberrations (p=0.07, p=0.09). Overall, 14 patients - 9 with molecular and 5 with hematologic R/R at enrollment - underwent a HSCT: 8 are in continuous CR (median follow-up: 17 months, range 5-73). Among the 22 patients who did not receive a HSCT, including 16 molecular and 6 hematologic R/R at enrollment), 7 are in continuous CR (median follow-up: 51 months, range 10-89). Due to the small sample size, we cannot define the role of transplant; transplant-related mortality (TRM) was observed in 3/14 (21.4%). Treatment was well tolerated: the most common adverse events were pyrexia (55%), infectious events (33.3%) and neurotoxicity (19.4%); hematologic toxicity was rare and more frequent in hematologic R/R. Conclusions. Treatment with blinatumomab was safe and effective. As expected, patients treated in molecular R/R had better survival rates than hematologic R/R patients. Despite the small number, all primary refractory patients responded to blinatumomab, suggesting that in these cases immunotherapeutic strategies can be extremely effective, irrespective of a chemo-insensitive disease. HSCT did not impact on OS and DFS, possibly due to the small number of the cohort. Finally, no differences in terms of adverse events, DFS or OS were observed between patients treated in the context of a clinical trial or in a real-life setting. Disclosures Chiaretti: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Foà:Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees.

Patients with severe aplastic anemia (SAA) without a sibling donor receive immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG). In the case of no response to IST, a voluntary unrelated donor (VUD) search is usually started. This study analyzes the outcome of ATG-refractory SAA patients activating a VUD search. Of 179 patients, 68 had at least one HLA-A, –B, and –DR matched donor identified and underwent HSCT while 50 also with a donor were not transplanted because of early death (8), late response to IST (34), transplant refusal (1), or other (7). Conversely, 61 had no matched donor, 13 of those ultimately received a mismatched HSCT. All but one received marrow stem cells. Among patients aged

Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation

Myeloid sarcomas (MS) involving orbits, skull, skin, lymph nodes, breast, the central nervous system and lungs are well documented in the literature [1]. MS may develop during the course of acute m...

Background Antibodies directed against alloantigens are implicated in the pathogenesis of several immune reactions complicating transplantation, including humoral rejection after solid organ transplantation. Mesenchymal stem cells (MSCs) have immunomodulatory capacity, since in vivo they may prolong skin graft survival in the animal model and can rescue patients with life-threatening graft-versus-host disease. Methods To investigate whether MSCs exert an inhibitory effect on antibody production during allostimulation, we stimulated peripheral blood mononuclear cells, obtained from healthy controls or sensitized patients undergoing dialysis for end-stage renal failure, in mixed lymphocyte culture (MLC), and evaluated immunoglobulin production either in the absence or in the presence of third-party allogeneic MSCs. We also evaluated the effect of MSCs on B-cell allostimulation performed adding to MLC a polyclonal stimulus delivered by an agonist anti-CD40 monoclonal antibody. Results We found that the addition of MSCs at the beginning of MLC considerably inhibited immunoglobulin production in standard MLC, irrespective of the MSC dose employed. Conversely, immunoglobulin secretion induced by direct CD40-CD40L binding was not significantly inhibited. Furthermore, we demonstrated, in one sensitized patient, that secretion of donor-specific anti-HLA class I antibodies detected both in baseline serum and in the supernatant of control MLC was inhibited by the addition of MSCs. Mechanistically, the addition of MSCs induced a striking decrease of IL-5 production in the cultures. Conclusions Our findings suggest that third-party MSC are able to suppress allo-specific antibody production in vitro, and may therefore help overcome a positive cross-match in sensitized transplant recipients.

We analysed the long-term outcome of 35 children and adolescents (

The immunologic reconstitution is ultimately responsible of the clinical outcome of patients who have undergone an allogeneic stem cell transplantation (SCT). The occurrence of graft-versus-host disease (GVHD), which represents the major cause of morbidity and mortality after the transplant correlates with the concentration in the peripheral blood (PB) of regulatory T cells (Tregs). In this study we aim at demonstrating that not only the concentration but also the functional capacities and the degree of activity of Tregs act as an important regulator of alloreactivity and may help to predict the risk of acute and chronic GVHD in the post-transplant period. Sixteen patients who underwent an allogeneic SCT were evaluated at 1 year from transplant. Tregs were expanded from the PB of these patients and from 8 normal donors; their expansion capacity, phenotype, suppressor activity and IL-10 production were measured. Tregs expanded from patients without GVHD exerted a higher suppressive function on the proliferative reaction of T cells and showed a higher IL-10 production capacity compared to patients with acute or chronic GVHD. These results document that the functional activity and the suppressor capacity of Tregs after an allogeneic SCT may protect from GVHD, and support the design of clinical protocols based on the infusion of expanded and activated Tregs.

The use of peripherally inserted central catheters (PICC) as an alternative to other central venous access devices (CVAD) is becoming very frequent in cancer patients. To evaluate the impact of complications associated to these devices in patients with hematologic malignancies, we revised the catheter-related bloodstream infections (CRBSI) and the catheter-related thrombotic complications (CRTC) observed at our institute between January 2009 and December 2012. A total of 612 PICCs were inserted into 483 patients at diagnosis or in subsequent phases of their hematologic disease. PICCs were successfully inserted in all cases. The median duration of in situ PICC placement was 101 days (interquartile range, 48–184 days). A CRBSI occurred in 47 cases (7.7 %), with a rate of 0.59 per 1000 PICC days. A CRTC was recorded in 16 cases (2.6 %), with a rate of 0.20 per 1000 PICC days. No serious complication was associated to these events. Cox regression analyses of variables associated to CRBSIs and to CRTCs showed that only the type of disease (acute leukemia compared to other diseases) was significantly associated to a higher incidence of CRBSIs, while no feature was predictive for a higher risk of CRTCs. PICCs represent a useful and safe alternative to conventional CVAD for the management of patients with hematologic malignancies.

In allogeneic hematopoietic stem cell transplant recipients with bone marrow (BM) suppression, cytomegalovirus (CMV) pp65 antigenemia and DNA were detectable in peripheral blood leukocytes (PBL) and BM cells. A relationship between CMV infection of PBL and BM cells has been found.

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.

Background PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. The combination of thrombosis, splenomegaly, and thrombocytopenia (TST) is challenging because anticoagulants are indicated but thrombocytopenia may increase the bleeding risk. Splenectomy could alleviate thrombocytopenia and reduce portal pressure, but it can cause post-operative thromboses and opportunistic infections. We therefore sought to determine whether selective splenic artery embolization (SSAE) is a safe and effective alternative to splenectomy for TST in patients with PNH. Methods Four patients with PNH and TST received successive rounds of SSAE. By targeting distal vessels for occlusion, we aimed to infarct approximately 1/3 of the spleen with each procedure. Results Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT. Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. One patient, who had had only a partial response to eculizumab, responded to SSAE not only with an improved platelet count, but also with an increase in hemoglobin level and decreased transfusion requirement. Conclusions These data indicate that SSAE can decrease spleen size and reverse hypersplenism, without exposing the patient to the complications of splenectomy. In addition, SSAE probably reduces the uptake of opsonised red cells in patients who have had a limited response to eculizumab, resulting in an improved quality of life for selected patients.

Strongyloides stercoralis infections may be documented in low-endemicity areas, particularly in immigrants from endemic areas. The case of a patient from Bangladesh, an immigrant to Italy who developed a S. stercoralis infection after allogeneic stem cell transplant, is described, and 7 further cases are reviewed. Because of the atypical clinical presentation, the low predictive role of the eosinophil count, and the low sensitivity of the microbiological tests, diagnosis of strongyloidiasis is a challenging problem. When a case of S. stercoralis infection is suspected, previous exposure may be the only clue to guide the diagnostic approach.

The CIBMTR score predicts survival of AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: a retrospective analysis of the Gruppo Italiano Trapianto Di Midollo Osseo

To assess the effectiveness of the search for an unrelated donor on the outcome of patients with high-risk acute lymphoblastic leukemia, we analyzed prospectively 136 patients who underwent a search for cord blood (CB) and an unrelated volunteer donor (UD) at the same time. The probability of finding a donor was 58.2%, 70.3%, and 75.7% at 3, 6, and 12 months, respectively. The median time to find a donor was 1.8 months for CB and 3.5 months for UD. Of the 99 patients with a donor, 38.4% failed to undergo the transplant because of a relapse observed at a median of 4 months from the start of the search. In univariate analysis, absence of relapse during the search (p < 0.0001) and transplant (p = 0.004) showed a positive impact on long-term survival. In multivariate analysis, relapse during the search remained the key factor affecting survival (p < 0.0001). Since an extension of the search beyond 3 months enables only a slight increase in the probability of finding a donor compared to the increased risk of relapse, the time of the search should not exceed the 3-month time point. The simultaneous search for CB and UD increases the likelihood of performing a timely transplant.

Aim of the study was to correlate the clinical outcome of eighteen patients who have undergone an allogeneic stem cell transplant (SCT) with the concentration in the peripheral blood (PB) of lymphocyte subpopulations evaluated at 1 year from transplant. The occurrence of acute GVHD and CMV infection correlated with the concentration of Tregs in the PB; CMV infection also correlated with the content of NK cells. The obtained results document that the concentration of Tregs in the PB after an allogeneic SCT may protect from GVHD and from CMV infection; the potential anti-viral role of NK cells is confirmed.

Posterior reversible encephalopathy syndrome (PRES) is an ncommon but distinctive clinico-radiologic entity characterized y headache, seizures, visual disturbance and altered mental funcion associated with reversible white matter edema affecting the osterior parietal and occipital lobes of the brain [1,2]. Etioloies of PRES include hypertension, cytotoxic medications, sepsis, reeclampsia or eclampsia and multiple organ dysfunction [3]. In he context of allogeneic stem cell transplantation (HSCT), severe eurotoxicity is reported in a substantial number of patients, being yclosporine-A (CSA) most frequently indicated as the medication esponsible for the neurological alterations [4–6].