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Although children and young adults with Hodgkin's lymphoma usually have a favorable prognosis, patients with primary refractory disease and some subsets of relapsed patients still have a dismal outcome. Brentuximab vedotin (BV) in combination with bendamustine may represent a suitable salvage therapy; data on 32 patients aged less than 25 years were retrospectively analyzed. Patients received up to six cycles of treatment of BV 1.8 mg/kg on day 1 and bendamustine 90-120 mg/m

Objective of the Study:In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP).Methods:We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol.Results:In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (

Reduced bone mineral density (BMD) is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors; the optimal method to assess BMD is still debated. We studied BMD by quantitative ultrasound (QUS) in 72 ALL survivors, and evaluated any correlation with cumulative doses of steroids and cytotoxic agents. Mean age at diagnosis was 61±45 months, while mean age at QUS was 318.3±129.6 months; mean period of follow-up was 41.2±37.8 months. Mean amplitude-dependent speed of sound z-score was -1.22±1.19. Ten survivors (13.8%) presented a z-score below -2 SD. A negative correlation was found between amplitude-dependent speed of sound z-score and age at diagnosis (P=0.01). A positive correlation was observed with length of follow-up (P=0.01). No correlation was found with cytotoxic drugs. This study represents the largest cohort of childhood ALL survivors studied by QUS. Our results suggest that QUS for its characteristics of being radiation free may be an effective option to assess BMD in pediatric age. In addition, our data outline the importance to improve the awareness about the specific expression of this complication in the pediatric age, concerning the major determinants of bone impairment, which are the disease itself and the phase of bone growth when the disease occurs.

Simple Summary Blinatumomab, a bispecific T-cell engager, binding T-cell CD3 and B-cell CD19 antigens, has remarkably enlarged the treatment options for patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). The aim of our study was to retrospectively assess the safety and efficacy profile of blinatumomab in 39 r/r ALL children treated in seven AIEOP centers in a compassionate or off-label program. This report is among the largest multicentric real-life retrospective analyses on blinatumomab in pediatric r/r BCP ALL. Blinatumomab showed a tolerable safety profile (34.8% of adverse events ≥grade 3, no cytokine release syndrome and no associated toxic deaths) and proved to be very effective (complete remission rate 46% in the 13 patients with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines’ recommendations. Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

Background: Inotuzumab-ozogamicin (IO) is one of the drugs of choice for relapse/refractory (R/R) acute lymphoblastic leukemia (ALL). Patients who received IO in a clinical trial had a CR rate of approximately 81% and a median overall survival of approximately 8 months, superior to best available therapy and numerically comparable with blinatumomab. Toxicities were generally manageable, veno-occlusive disease/ sinusoidal obstruction syndrome (VOD/SOS) was reported as a rare adverse event possibly linked to the drug that require attention, especially during hematopoietic stem cell transplant after IO. Data on IO effectiveness in the real-life setting are generally lacking, for the low incidence of the disease and the high number of possible therapies that are emerging. Methods: INO-CD22 (NCT03898128) is a real-life study collecting data on safety, effectiveness and indirect costs of IO therapy in R/R ALL. Twenty-four Italian institutions enrolled patients who received IO in the post-market expanded access program or with national health system reimbursement. This study was approved by the ethical committee (Prot.9296/2018). Here we present preliminary results of effectiveness and treatment emergent toxicity. Results: From 2014, we collected data of 65 patients who received IO and were evaluable for effectiveness and toxicity. Median age at start of IO was 47 years (IQR 27-61), 35 patients (53.9%) were male, 14 (21.5%) had Ph+ ALL. 12 patients (18.5%) received IO after 1 previous line of therapy, 16 (24.6%) after 2 previous lines, and 37 (56.9%) after more than 2 lines. In our patient set, 37 (56.9%) patients received IO after blinatumomab failure and 24 (36.9%) after an allogenic HSCT. Nine patients (13.8%) received IO after an history of mild to moderate liver-related adverse events. Median number of IO courses administered was 1 (IQR 1-2). Three patients do not complete course 1, as they died for infection (2) and cerebral hemorrhage (1). Of the 60 patients who were alive after a course of IO, 56 have evaluable data, 47 (83.9%) obtained a complete remission with IO. Particularly, CR was obtained in 9/11 (81.8%), 11/15 (73.3%), and 27/30 (90.0%) evaluable patients who received IO as a 1 st, 2 nd or >2 nd salvage, respectively. Twenty-four out of 30 (80.0%) evaluable patients who received IO after blinatumomab failure and 17/18 (94.5%) patients who already received an HSCT achieve CR with IO. With a median follow-up of 25.7 months (95% C.I. 19.8-34.3), median OS was 7.5 months (95% C.I. 5.8-10.0). Median OS was 7.5 months (95% C.I. 2.7-18.6), 9.0 months (95% C.I. 5.8-15.8), and 6.4 months (95% C.I. 4.5-12.8) in patients who received one previous line of treatment, two lines of treatment, and more than two lines of treatment, respectively (figure A). Median PFS was 4.1 months (95% C.I. 0.1-13.21), 6.7 months (95% C.I. 0.1-12.4), and 5.0 months (95% C.I. 3.12-7.9) in patients who received one previous treatment line, two previous lines, and more than two lines, respectively. Patients who received IO after blinatumomab failure had a median OS of 6.0 months (figure C, 95% C.I. 4.7-9.3). Patients who received IO after an HSCT had a median OS of 6.4 months (figure C, 95% C.I. 3.1-24.7). Twenty-five patient (38.5%) received an HSCT after IO therapy, of 22 (88.0 %) in CR, and 1 (6.7%) after further salvage therapies (chemotherapy). During IO therapy, 1 treatment related toxic death and 1 treatment related VOD/SOS, 1 grade 5 infection (AE), 9 grade 3-4 AEs, and 25 grade 1-2 AEs were noted. The most common AEs during IO therapy were Thrombocytopenia (reported in 7 (10.8%) of patients), infections (reported in 6 (9.2%) of patients) and liver tox adverse events (reported in 6 (9.2%) of patients). Overall, 7 VOD-SOS were reported, and the incidence was higher during transplant. Conclusions: Our data confirm in the real-life setting the great effectiveness of IO in term of CR. OS was comparable with data reported in clinical trials, even in a patient population that was not selected with inclusion criteria. OS and CR rate was not dramatically diminished in patients who already received HSCT nor in patients who already received blinatumomab. Safety of IO treatment was confirmed. IO is an easy-to-administer and safe therapy with a very high rate of expected CR in all the contexts and that confer promising expectation of survival. Figure 1 Figure 1. Disclosures Papayannidis: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Astellas: Honoraria; Janssen: Honoraria. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo: Amgen: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria; Jazz Pharmaceutical: Honoraria; Janssen Pharmaceuticals: Honoraria; Bristol Myers Squibb: Honoraria. Lanza: Pfizer: Research Funding; Abbvie: Consultancy; Jazz: Consultancy; Sanofi: Consultancy. Borlenghi: Amgen, Janssen: Consultancy. Sica: Pfizer: Honoraria. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Luppi: Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Gilead Science: Honoraria, Other: Travel grant; Daiichi-Sankyo: Honoraria; Jazz Pharma: Honoraria. Pane: Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy. Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinelli: Stemline Therapeutics: Consultancy; Astellas: Consultancy, Speakers Bureau; Roche: Consultancy; Incyte: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Abbvie: Consultancy; Pfizer: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy.

Background Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. Objectives The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. Patients Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. Results Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months. Conclusions Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high.

Chemotherapy-induced nausea and vomiting (CINV) is a distressing treatment side-effect that could negatively affect children's quality of life (QoL). Different scoring systems for CINV were applied and different antiemetic drugs were used; however, few studies have been performed in children undergoing chemotherapy with Aprepitant. Herein, we report a pediatric experience on efficacy and safety of Aprepitant as part of triple antiemetic prophylaxis, in a cohort of thirty-two children and adolescents with Hodgkin Lymphoma (HL), treated with moderate/highly emetogenic chemotherapy (MEC/HEC) regimens in a single Hemato-Oncology Institution. The triple therapy was compared to standard antiemetic therapy in a cohort of twenty-three HL patients (control group). Aprepitant therapy was associated to a significant decrease of chemotherapy-induced vomiting (p = 0.0001), while no impact on the reduction of nausea was observed; these observations were also confirmed by multivariate analysis (p = 0.0040). Aprepitant was well tolerated and the most commonly reported adverse events were neutropenia and hypertransaminasemia. No significant differences on the toxicity were observed between the two compared groups. Our experience on Aprepitant efficacy and safety, associated with feasibility of orally administration, suggests a possible widespread use of the drug to prevent pediatric CINV.

Maintenance of a balanced expression of the two isoforms of the transcription factor GATA‐1, the full‐length protein (GATA‐1FL) and a shorter isoform (GATA‐1 S), contributes to control hematopoiesis, whereas their dysregulation can alter the differentiation/proliferation potential of hematopoietic precursors thereby eventually leading to a variety of hematopoietic disorders. Although it is well established that these isoforms play opposite roles in these remarkable processes, most of the molecular pathways involved remain unknown. Here, we demonstrate that GATA‐1FL and GATA‐1S are able to differently influence intracellular redox states and reactive oxygen species (ROS) compartmentation in the erythroleukemic K562 cell line, thus shedding novel mechanistic insights into the processes of cell proliferation and apoptosis resistance in myeloid precursors. Furthermore, given the role played by ROS signaling as a strategy to escape apoptosis and evade cell‐mediated immunity in myeloid cells, this study highlights a mechanism through which aberrant expression of GATA‐1 isoforms could play a role in the leukemogenic process.

A 9-month-old boy with life-threatening multiresistant pure red cell anemia/autoimmune hemolytic anemia within the frame of a possible, undiagnosed immune-mediated disease was initially treated with prednisone. Further-line therapies of the following 7 relapses included immunoglobulins, rituximab, cyclophosphamide, and alentuzumab followed by other maintenance treatments as cyclosporine, methotrexate, and mycophenolate. After all the administered therapies failed, the patient was successfully treated by splenectomy followed by fludarabine and then sirolimus as maintenance treatment. Relapses might have been caused by the lack of a complete debulking of triggering cells and/or ineffective maintenance therapy. Splenectomy and sirolimus may have played a complementary role in the management of both situations.

Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like (Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1 rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs). Herein we report the case of a 10 year-old girl who received diagnosis of precursor B-ALL on February 2018. She started therapy according to observational protocol ALL 2017 of the Italian Association of Pediatric Hemato-Oncology (AIEOP). After pre-phase, the patient resulted prednisone poor responder and continued induction therapy, including daunorubicin, vincristine, PEG-L-Asparaginase, prednisone and intrathecal methotrexate. Bone marrow evaluation showed persistence of disease on day 15 (88% of lymphoblasts) and 33 (60% of blasts) in flow cytometry. At the end of IA induction phase, Minimal Residual Disease (MRD) in RT-PCR showed high positivity (marker 1 = 7.2x10-1, marker 2= 8.11x10-1). At this time, further molecular studies, using RNA targeted next generation sequencing (PanCancer, Illumina), revealed the presence of EBF1-PDGFRβ gene fusion. Since the patient was resistant to conventional therapy and literature's evidences demonstrated potential sensitivity of EBF1-PDGFRβ to TKIs therapy, we decided to add dasatinib, a second generation TKI, to IB induction, with cyclophosphamide, cytarabine and 6-mercapthopurine. After one week of therapy, clinical course was complicated by Klebsiella Pneumoniae sepsis, followed by digestive hemorrhage. Since we retained that the hemorrhagic event could be related to dasatinib, the drug was temporarily discontinued. However, bone marrow evaluation, after only 10 days of dasatinib administration, showed hematologic remission (3% of lymphoblast) and MRD reduction >1 logarithm (markers 1=1-10-2 e markers 2= 9.9 x 10-3). Given the resistance to chemotherapy alone and the excellent response to dasatinib but its related toxicity in combination, we decided to start immunotherapy with blinatumomab, a bi-specific CD3-CD19 monoclonal antibody, alternated to dasatinib, in order to achieve MRD negativity before to proceed with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling. The patient received 2 courses of blinatumomab for 28 days continuous infusion (15 mcg/mq days 1-28), interspersed by 15 days of dasatinib (60 mg/mq/day). After the first cycle the patient achieved complete hematological remission and MRD negativity. MRD negativity was confirmed after first course of dasatinib, second course of blinatumomab and second course of dasatinib. Dasatinib, given alone, was well tolerated and no serious adverse event were reported. Actually, the patient is undergoing HSCT by HLA-identical sister. To our knowledge, only few cases of EBF1-PDGFRβ ALL, treated with TKIs, are described in literature and this is the first in which MRD negativity was obtained with a sequential combination of dasatinib and blinatumumomab, a chemo-free approach, showing efficacy and good tolerability. This case highlights also that screening for targetable lesions at diagnosis or in case of resistance to induction phase is mandatory to identify patients who might benefit from alternative therapies as TKIs, immunotherapy or their combination. A longer follow-up is required to definitively establish the long-term efficacy of this biological approach in our patient. Nevertheless, it is interesting to speculate that alternative treatment with TKIs or immunotherapy could avoid, in the future, an intensive chemotherapy, or probably a transplant approach in selected patients, in order to achieve a durable cure in these Ph-like patients. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.

New imaging techniques have been introduced to assess the extent and severity of disease in multiple myeloma (MM) patients. The aim of our study was to compare newer imaging modalities-such as (18)F-FDG PET/CT, (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) scintigraphy, and MRI-to assess their relative contribution in the evaluation of MM patients at diagnosis.Thirty-three newly diagnosed patients with MM were prospectively studied. Diagnosis and staging were made according to standard criteria. All patients underwent whole-body (18)F-FDG PET/CT, whole-body (99m)Tc-MIBI, and MRI of the spine and pelvis within 10 d, and imaging findings were compared.(18)F-FDG PET/CT was positive in 32 patients (16 focal uptake, 3 diffuse uptake, 13 focal and diffuse uptake), (99m)Tc-MIBI was positive in 30 patients (6 focal, 11 diffuse, 13 focal and diffuse uptake), and MRI of the spine and pelvis was positive in 27 patients (6 focal, 13 diffuse, 8 focal and diffuse uptake). (18)F-FDG PET/CT showed a total of 196 focal lesions (178 in bones and 18 in soft tissues), of which 121 were in districts other than the spine and pelvis, whereas (99m)Tc-MIBI visualized 63 focal lesions (60 in bones and 3 in soft tissues), of which 53 were in districts other than the spine and pelvis. In the spinal and pelvic regions, (18)F-FDG PET/CT detected 75 focal lesions (35 in spine and 40 in pelvis), (99m)Tc-MIBI visualized 10 focal lesions (1 in spine and 9 in pelvis), and MRI detected 51 focal lesions (40 in spine and 11 in pelvis).In whole-body analysis, (18)F-FDG PET/CT performed better than (99m)Tc-MIBI in the detection of focal lesions, whereas (99m)Tc-MIBI was superior in the visualization of diffuse disease. In the spine and pelvis, MRI was comparable to (18)F-FDG PET/CT and (99m)Tc-MIBI in the detection of focal and diffuse disease, respectively. Because myelomatous lesions may often occur out of spinal and pelvic regions, MRI should be reserved to the evaluation of bone marrow involvement of these districts, whereas (18)F-FDG PET/CT can significantly contribute to an accurate whole-body evaluation of MM patients. Finally, whole-body (99m)Tc-MIBI, despite its limited capacity in detecting focal lesions, may be an alternative option when a PET facility is not available.

The treatment of meningeal relapse in acute lymphoblastic leukemia (ALL) remains a challenging clinical problem. Liposomal cytarabine (DepoCyte®) permits to decrease frequency of lumbar punctures, without loss of efficacy, because intrathecal levels of the drug remain cytotoxic for up to 14 days. We investigated the efficacy and safety of intrathecal DepoCyte in six children with meningeal relapse, treated in two pediatric institutions. DepoCyte was well tolerated in all patients, who achieved complete clearance of blasts from the cerebrospinal fluid after the first three intrathecal drug administrations. Five of the six patients were concurrently treated with high-dose administration of systemic cytarabine, without additional neurological side effects. Our results suggest that DepoCyte is a valid option for children with ALL experiencing meningeal relapse; it deserves further investigation in intensive treatment regimens, taking into due consideration potential neurotoxicity.

Background Amyloidosis is a systemic disease characterized by the extracellular deposition of amyloid fibrils in different organs and tissues. The thyroid gland may be affected by diffuse or nodular amyloid deposits, along with multiple myeloma (MM) (Amyloid Light-Chain Amyloidosis, AL amyloidosis) or chronic inflammatory diseases (Amyloid A Amyloidosis, AA amyloidosis), but thyroid gland involvement rarely appears as the first clinical manifestation in both conditions. The present study reports a case of primary thyroidal nodular amyloid goiter diagnosed by fine-needle cytology (FNC) in an elderly patient. Case report A 66-year-old female patient presented with dysphagia and hoarseness; the patient suffered from rheumatoid arthritis but did not have kidney failure or altered thyroid function. Ultrasound examination (US) showed a 30 mm irregular, hypoechoic area in the left thyroid lobe. FNC showed abundant, dense and amorphous material similar to the one stained in purple at Diff-Quik stain and pinkish at the Papanicolaou. Spindle cells with thin, bland and bent nuclei were scattered in this material; few thyroid follicular cells were also present. An alcohol-fixed smear was stained with Congo red: the amyloid material appeared cherry red and it also showed apple-green birefringence when observed with a polarizing microscope. A differential diagnosis between different thyroid pathologies was considered and the cytological diagnosis of nodular amyloid goiter was pointed out. The patient underwent thyroid lobectomy and the subsequent histological examination confirmed the cytological diagnosis. Conclusions FNC is a safe and effective procedure for the diagnosis of thyroid amyloidosis. Congo red-stained smears can be used to demonstrate the presence of amyloid material, showing the typical green birefringence under polarized light. An early and accurate cytological diagnosis may suggest an hematological screening and the appropriate treatment for the thyroid nodule.

The toxicity and effi cacy of intrathecal liposomal cytarabine (LC) were evaluated in children with central nervous system (CNS) relapsed/refractory acute leukemia/lymphoma. Thirty patients (male:female ratio 21:9; median age 9.4 years) with CNS relapsed/ resistant disease were treated with intrathecal LC at dosages adjusted for age. Twenty-seven (90%) patients simultaneously received systemic chemotherapy, including concurrent highdose cytarabine or methotrexate in 21 (70%) cases. Of 28 patients evaluable for response, 25 patients (89%) achieved CNS complete remission and three (11%) partial remission. The median number of intrathecal LC administrations per patient was 4. The cerebrospinal fl uid was cleared after a median of 3 intrathecal LC administrations. Neurological toxicity ≥ grade 3 occurred in four (13%) patients. No permanent sequelae were observed. The median overall survival was 20.9 months and the 5-year probability of survival was 46%. These encouraging data suggest that intrathecal LC is well tolerated and eff ective in children with relapsed/refractory CNS leukemia/lymphoma.

Clofarabine is a promising new chemotherapeutic agent that is active in the treatment of pediatric acute leukemia. Forty children (16 with acute myeloid leukemia [AML], 24 with acute lymphoblastic leukemia [ALL]), aged 1-20 years (median 7.6 years) with relapsed or refractory ALL or AML were treated because of resistance to first-line treatment (n =5), or for first (n =22), second (n =11) or third relapse (n =2). They received clofarabine (40 mg/m(2)/day) associated with etoposide (100 mg/m(2)/day) and cyclophosphamide (440 mg/m(2)/day) administered as one or two induction cycles (5 days of chemotherapy) in an attempt to reach complete remission (CR) or CR without platelet recovery (CRp). This was followed by 1-3 consolidation cycles (4 days of chemotherapy) for a maximum of four cycles. Seven (44%) out of 16 and 10 (42%) out of 24 evaluable children with AML and ALL, respectively, responded to treatment. The most common adverse events were infections and gastrointestinal and hepatic toxicity. Thirteen (76%) out of 17 responders underwent hematopoietic stem cell transplant. The 24-month overall survival was 25%, while it was 59% among patients who responded to the first induction cycle. Our study suggests that this drug regimen is well tolerated and can be effective in heavily pretreated pediatric patients with relapsed or refractory acute leukemia.

We recently published a study aiming to verify the frequency of amyloid deposits in the bone marrow of patients with multiple myeloma (MM) who did not present any signs or symptoms of systemic amyloidosis, applying the Congo red technique on bone marrow smears obtained by aspiration from the posterior iliac spine. The results suggested that nearly 40% of patients affected by MM may have amyloid deposits in their bone marrow. Subsequently, this finding has not been confirmed by another study performed with histological specimens of bone marrow in a similar clinical setting. To explain this discrepancy, we performed a comparative study on the bone marrows of 36 patients affected by MM, evaluated by both cytological and histological techniques. The results of this study confirm the high frequency of amyloid deposits in the bone marrow of patients affected by MM when the analysis is made on cytological smears, and indicate that the presence of amyloid on marrow smears is confirmed by core biopsies simultaneously performed in only 25% of cases. Should further studies confirm our findings, cytological assessment could be considered a sensitive technique to detect bone marrow amyloid deposits.

Central nervous system (CNS) complications during treatment of childhood acute lymphoblastic leukemia (ALL) remain a challenging clinical problem. Outcome improvement with more intensive chemotherapy has significantly increased the incidence and severity of adverse events. This study analyzed the incidence of neurological complications during ALL treatment in a single pediatric institution, focusing on clinical, radiological, and electrophysiological findings. Exclusion criteria included CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy, late-onset encephalopathy, or long-term neurocognitive defects. During a 9-year period, we retrospectively collected 27 neurological events (11%) in as many patients, from 253 children enrolled in the ALL front-line protocol. CNS complications included posterior reversible leukoencephalopathy syndrome (n = 10), stroke (n = 5), temporal lobe epilepsy (n = 2), high-dose methotrexate toxicity (n = 2), syndrome of inappropriate antidiuretic hormone secretion (n = 1), and other unclassified events (n = 7). In conclusion, CNS complications are frequent events during ALL therapy, and require rapid detection and prompt treatment to limit permanent damage.

Palonosetron to prevent nausea and vomiting in children undergoing BMT: efficacy and safety

International audience; Systemic AL amyloidosis is associated with nearly 15% of cases of multiple myeloma, but data on the frequency and significance of amyloid deposits in the bone marrow of patients affected by multiple myeloma without clinical signs of systemic amyloidosis are scanty. Bone marrow smears of 166 unselected patients affected by multiple myeloma (126 at diagnosis and 40 after treatment) were stained with Congo red and studied by transmission and birefringence microscopy. Both focal and diffuse storages were considered positive. Overall, 67 patients were positive and 99 were negative to Congo red and apple-green birefringence. In particular, 51 of the 126 patients studied at diagnosis and 16 of the 40 patients with advanced disease were positive. Seventeen patients were reassessed after a mean follow-up of 32 months (range: 6–91): disappearance of amyloid deposits was verified in three cases, all responsive to bortezomib-based regimens. The preliminary data available suggest that amyloid deposition in the marrow of myeloma patients is frequent, as it can be traced in nearly 40% of cases. We failed to find correlations between bone marrow amyloid deposits and immunoglobulin type, disease stage, plasma cells percentage, hemoglobin, calcium, creatinine, albumin, or βmicroglobulin. Significantly higher incidence of moderate/severe peripheral neuropathy was found in patients with marrow amyloid exposed to potentially neurotoxic antineoplastic agents. Further studies and prolonged follow-up are needed to validate our findings and to define possible prognostic aspects.

The (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. CommercialBTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. CommercialBTZsamples, reconstituted according to the reported commercial instructions and stored at , were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material), the N-(1-(1-hydroxy-3-methylbutylamino)-1-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration) and the (S)-N-(1-(3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration), identified on the basis of their chemical and spectroscopic properties. TheBTZ1andBTZ2finding suggests that, under the common condition of use and at , commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process.

Cardiac involvement in primary systemic amyloidosis, due to amassing of fragments of light chains, is detected in the majority of cases. We report the case of a 56-year-old woman who came to our observation because of symptoms of congestive heart failure. Diagnosis of restrictive cardiomyopathy was made by echocardiographic examination, which showed right ventricular hypertrophy, disarray of interventricular septum and restrictive flow pattern at the mitral valve. Primary systemic amyloidosis was diagnosed by abdominal fat pad biopsy. Laboratory findings confirmed biopsy results, leading to the definite diagnosis of restrictive cardiomyopathy due to IgA kappa monoclonal gammopathy in primary systemic amyloidosis.

Osteonecrosis of the maxillary or mandibular bone is an infrequent but often severe event occurring in patients who undergo prolonged treatment with bisphosphonates. Histology is in some cases mandatory to differentiate it from neoplastic osteolysis, but a biopsy can further contribute to bone damage. Functional imaging obtained by a tracer that shows oncotropic properties, such as Tc99msestamibi, in comparison to a non-tumor-specific substance such as FDG-PET, can support the differential diagnosis, thus avoiding invasive procedures. Four patients affected by multiple myeloma and jaw osteonecrosis were prospectively evaluated by sestamibi and FDG-PET scans. Local diagnosis was performed by clinical, radiological and, in some cases, histological evaluations. Each patient was studied by Tc99m-sestamibi, performed by planar anterior and posterior whole-body scans and SPECT of the head and neck, and by PET/CT. Two nuclear medicine physicians, unaware of the final diagnosis, reviewed the images. No sestamibi uptake was evident in the four patients with jaw osteonecrosis, while FDG-PET/CT showed focal uptake in all of them. Our study suggests that the combined use of sestamibi scintigraphy and FDG-PET/CT could support the clinical diagnosis of oral osteonecrosis avoiding the risks of a surgical biopsy. Studies on higher number of patients are necessary to validate these preliminary observations.

The advent of more intensive chemotherapy and the improvement of supportive cares have dramatically changed the natural history of childhood acute lymphoblastic leukemia (ALL), with current estimated 5-year overall survival of about 80%. The increased survival rate and the establishment of follow-up survey for long term survivors (LTS) have allowed the identification of late chemo-radiotherapy adverse effects on psychological and general health. We retrospectively evaluate the incidence and type of sequelae and / or late effects in a cohort of 301 childhood ALL LTS, followed in a single pediatric AIEOP center. From June 1986 to June 2013, 301 LTS (154 male and 147 female), aged Mean FU time (time from the stop therapy to the last control) was 6 years (range 1.8-26.8 years). The majority of LTS were teenager or young adults : 35% ranged between 15 and 20 years; 19.7% was more than 21 years old and the 45.3% was less than 14 years old. During FU, 16 late recurrences (5.3%) were identified and 3 secondary malignancies (0.99%) such as one mesenteric paraganglioma and two Acute Myeloid Leukemia in second complete remission ALL LTS. 40 patients (13.3%) received cranial radiotherapy during treatment. 39 LTS (13%) reported at least one sequelae. The most frequent sequelae were neurological and orthopedic (6% and 3% respectively) as summarized in Figure 2 151 LTS (50.17%) presented at least one late effect as showed in Figure 3. In our experience at least one late effect occurred in 50.17% of LTS; these late complications affect negatively the quality of life of survivors. Endocrine-metabolic events are the most frequent late effect (34,5%). 13% of LTS have at least one sequelae mainly neurological and orthopedic. Prevention and/or early identification of complications during follow-up survey of LTS are crucial in order to decrease the long-term health risks associated with curative treatment for childhood ALL. Disclosures: No relevant conflicts of interest to declare.

Abstract 4121 Background Mixed acute leukemias are an heterogeneous category of poorly differentiated leukemias, affecting people of all ages. These forms of leukemias are very rare, 3-5% of all acute leukemias, and are characterized by co-expression of myeloid and lymphoid associated-antigens on the same leukemic cells. The therapeutic approach is not defined because, often, mixed leukemias switch their lineage of origin during treatment and the prognosis is very poor. We describe a novel, never reported before, cytogenetic abnormality in a child with a mixed acute leukemia. Methods On January 2009, a nonsyndromic 5 year-old boy was admitted at our Institution for an acute hyperleukocytosic leukemia (WBC > 100.000/L). The patient showed spleen enlargement and massive mediastinal lymphadenopathy. Morphological diagnosis of acute leukemia was based on the French-American-British criteria and the immunophenotypic diagnosis was performed by flow cytometry using a large panel of leukemia-associated antibodies (myeloid and B/T lymphoid markers). Cytogenetic analysis was performed on unstimulated overnight culture of bone marrow, followed by RHG-banding. The expression of T-cell receptor and rearrangement of heavy chain immunoglobulin was assessed by molecular methodology. Results Morphologic evaluation showed lymphoid blasts according to the FAB-L2 classification with same aberrations such as myeloid blebs and prominent nucleoli. The immunophenotype showed mixed expression of myeloid markers (MPO > 3%, CD33, CD11a, CD11b, CD117) and T lymphoid antigens (surface CD7, CD99 and cytoplasmic CD3) and an aberrant lineage-B expression (CD19). On the basis of these data the diagnosis of acute mixed leukemia was carried out. Cytogenetic analysis showed trisomy of chromosome 7, a chromosomal aberration never reported before in acute myeloid or lymphoid leukemia (figure 1). Ig or T-cell receptor gene rearrangements were not identified as well as translocations commonly found in either lymphoid and myeloid leukemias. The treatment was initially performed according to the acute lymphoblastic leukemia protocol (AIEOP ALL2000) but unresponsiveness as seen up to day +12 required a shift to a mixed personalized protocol with cyclophosphamide, dexamethasone and L-asparaginase associated with more specific drugs for myeloid lineage such as high dose cytarabine and etoposide. After a febrile aplasia, bone marrow reconstitution showed about 75% of mixed blasts. So the child shifted to a rescue protocol with fludarabine, cytarabine, idarubicine (FLA-Ida) repeated 2 times with a good haematological and cytometric response (0,9% of blasts). For consolidation of remission, was performed 1 cycle with clofarabine, cyclophosphamide and etoposide followed by 1 cycle with clofarabine and cytarabine with a minor response (1,9% of blasts by immunophenotype). Actually, the child is undergoing an unrelated mismatched transplant. Conclusion At the best of our knowledge, this case is the first report of trisomy 7 in a mixed acute leukemia in childhood. The only cytogenetic aberration known so far in pediatric mixed leukemias are: isochromosome 7, monosomy 7, or inversion 7 as well as translocations such as t(1;7), t(4;7) or t(7;15). Trisomy 7 is also described in some mesenchymal and neurogenic neoplasms such as brain, colon, ovary, prostate, bladder and kidney tumors and also in some non-neoplastic inflammatory disease such as rheumatoid arthritis and osteoarthritis. In haematological field, trisomy 7 is reported only in few cases of myeloma, non-Hodgkin lymphoma and amyloidosis. The prognostic significance of this cytogenetic aberration in mixed acute leukemias is still unknown. Disclosures: No relevant conflicts of interest to declare.

Clofarabine is a new promising chemotherapic agent active in the treatment of pediatric acute leukemia. We planned to utilize the same drugs’ combination currently evaluated in USA as phase II study salvage therapy: clofarabine (40mg/m2/day) in combination with etoposide (100mg/m2/day) and Cyclophosphamide (440mg/m2/day) (CLOVE). We planned to treat the patients (pts) (aged 1–18) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) with 1 or 2 induction cycles (5 days chemotherapy) to reach complete remission (CR) or complete remission without platelet recovery (CRp) and with 1 or 2 consolidation cycles (4 days chemotherapy). ALL patients (pts) received intrathecal methotrexate at day 6 and AML patients intrathecal cytarabine at Day 0. Prednisone was added (0,5 mg/Kg/day) to prevent systemic inflammatory response syndrome (SIRS). Fourteen children (5 AML, 9 ALL) were treated, median age 5,7 years (range 1,75–16,5), 7 pts in first, 3 pts in second and 4 pts in third relapse. Four AML pts had one prior bone marrow transplantation (BMT): 1 autologous, 1 matched familiar donor and 2 matched unrelated donor (MUD) transplants. Five ALL pts had one prior BMT : 2 autologous, 1 syngenic and 2 MUD. The AML pts were in first relapse, and three of them were refractory to FLAG-X protocol: 3/5 (60%) achieved remission (1CRp, 2 CR), response data are currently pending for1 patient (day + 20 first induction), and 1 patient died for disease progression. The remission rate of nine ALL pts was 66% (4 CR, 2CRp). Infection grade 3 was observed in one patient, diarrhea and abdominal pain occurred in 4 pts. Febrile neutropenia was e common toxicity. Severe muscles pain with functional impairment was observed in two pts (1 AML, 1 ALL) 7 days post induction cycle: the gabapentin therapy in association with prednisone was efficient and the symptom quickly disappeared. One ALL patient refractory to first induction cycle, died after second cycle (day + 6) for cardiac failure. One ALL patient relapsed after CLOVE induction, after two more cycles he obtained partial response (BM Blast cells 10% ), and he underwent MUD transplantation and died for infection. The overall survival is 58 %, 7/9 (77 %) responders are alive. The median survival is 3 months (range 20 days –10 months). Four out 9 responding patients proceeded to BMT from unrelated donor, and three of them are alive and in CR. No unexpected transplant related toxicity was encountered. We confirm that the association of Clofarabine with Etoposide and Cyclophosfamide is active in heavily pretreated relapsed or refractory pediatric acute leukemia. patients.

Intensive chemotherapy significantly improves the outcome of pediatric acute lymphoblastic leukemia (ALL) but unfortunately increases the incidence and severity of acute adverse events. The current study analyses the incidence of central nervous system (CNS) complications during ALL treatment in a single pediatric institution. CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy and leukoencephalopathy and neurocognitive defects after treatment were excluded by the study. From September 2000 to July 2008, two hundred and forty ALL patients (pts) were treated in our Institution according to BFM-AIEOP ALL 2000 protocol. Twenty-four out of 240 patients (10 %) (15 females and 9 males, median age at the event 7.7 years, range 2–16 years) developed CNS complications during treatment. Thirteen presented tonic-clonic seizures, four showed dyskinesia and dyslalia, one presented visual impairment and enuresis, and six had loss of consciousness. In 18 pts a rapid resolution of the event was obtained by administration of benzodiazepines or barbiturates; 6 pts required admission in intensive care unit, instead. Only two out of twenty-four patients presented neurological sequelae (one pts with recurrent seizures and one pts with right limb disability). Co-morbidity at the time of neurological accident included: blood pressure increase (6 pts), electrolytes imbalance (4 pts), LDH increase (4 pts), coagulation disorders (6 pts), hepatic enzyme increase (2 pts), severe anemia (1 pts), severe thrombocytopenia (4 pts), renal failure (1 pts), and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (1 pts). Radiological scanning (either CT or MRI) and electroencephalography (EEG) performed within 48 hr from the onset of the clinical symptoms revealed different etiologies: 8 posterior reversible leukoencephalopathies (PRES), 3 cerebral bleedings, 2 ischemic cerebral diseases, 2 methotrexate toxicity, 1 SIADH, 2 temporal lobe epilepsy and 6 unidentified problems. In conclusion this retrospective study on CNS complications during ALL treatment shows that the most frequent neurological accident (33%) is the PRES.

The importance of genetic alterations and their prognostic impact is of growing interest in multiple myeloma (MM). Chromosome 13 abnormalities (del 13q and monosomy) have been associated with lower response rate and shorter survival in patients affected by MM, indipendently from the type of detection (karyotype versus FISH) and the type of treatment (standard versus high-dose chemotherapy). The presence of these abnormalities also in monoclonal gammopathy of uncertain significance (MGUS), suggests that they are an early genetic event, even thought it is not clear if they have a role in disease progression or represent only an initiation event. Alterations involving the immunoglobuline heavy chain locus on 14q32 are also frequent events in plasma cell dyscrasias. The variety of partner genes suggests that it may contribute to tumor progression. The most frequent translocation is t(11;14) (30%) and t(4;14) (25%), both of high prognostic impact. In our Institution, 40 MM patients (29 at diagnosis, 8 at relapse and 3 during post CHT follow-up) were studied by conventional cytogenetics and FISH analysis. The mean age was 63.4 (range 32–80), with male prevalence. The serum monoclonal component was IgG and IgA in 26 and 8 patients respectively; 4 patients had light chain only, 1 patient had IgD and one IgG+IgM. At the time of analysis, the stages were: I/II (n=14), IIIA (n=15) and IIIB (n=11). At the time of cytogenetic analysis, the mean bone marrow plasma cell percentage was 47.5% (range 6–100 %). Cytogenetics and FISH analysis were performed simultaneously. An abnormal karyotype was detected in 11/19 successful cultures: 2 patients showed del (13q), one patient monosomy 13, 4 patients had hypodiploid karyotype, 2 patients showed chromosome 1 abnormalities in a hyperdiploid karyotype, 1 patient revealed del 1q in a normal karyotype, 1 patient had hyperdiploid karyotype with +iso11q. FISH analysis, performed with LSI D13S19 (13q14.3) and LSI IgH/CCND1-XT (VYSIS) probes, was informative in all 40 patients: all 3 patients with chromosome 13 abnormalities had del(13q); in addition, 11/40 patients with normal or non informative karyotype showed del(13q) by FISH analysis. The mean of cells carrying del(13q) was 34% (range 15–80%); the highest values were found in patients who showed hypodiploid karyotype or del(13q) or chromosome 13 monosomy by conventional cytogenetic analysis. FISH analysis with a t(11;14) translocation probe showed 1/40 positive patient; in addition, 5 patient showed an extra signal of 11q13, and 5 others showed an extra signal of the IgH gene, suggesting the first over expression of the CCND1 gene and the second a translocation with a different partner chromosome. The impact of chromosome 13 deletion on time to progression and overall survival was analyzed only considering the most sensitive technique used (FISH). The time to progression analysis showed a significantly worse prognosis in del(13q) patients (p=0.0260); overall survival tended to be shorter in patients carrying del (13q), without reaching statistical significance. Our data, even thought in a small series, confirm the negative impact of chromosome 13 deletion on prognosis and survival of MM patients. We would like to emphasize the usefulness of a very sensitive technique such as the FISH analysis, for the assessment of genetic alterations in the context of clinical trials specifically designed for MM patients with adverse prognostic features.

Hypereosinophilia as first clinical presentation has rarely been reported in paediatric acute lymphoblastic leukaemia. It is commonly associated with specific cytogenetic abnormalities. Although eosinophilia is considered a reactive, non-neoplastic epiphenomenon, it adversely affects patient outcomes, both in children and adults. We describe herewith two paediatric patients who had marked eosinophilia at onset of acute lymphoblastic leukaemia. We point out the importance of a correct differential diagnosis in persistent, unexplained peripheral hypereosinophilia. Clinicians should keep in mind that eosinophilia can be part of the overall pattern of acute leukaemia and therefore needs to be properly investigated. We also provide some recommendations for an appropriate approach to hypereosinophilia - related morbidities.