Search

Introduction

Colombatti: Global Blood Therapeutics: Consultancy; Novartis: Consultancy; AddMedica: Consultancy.

Autoimmune hemolytic anemia (AIHA) is an uncommon disease of childhood caused by the premature destruction of erythrocytes by autoantibodies. In this rare disease both diagnostic criteria and therapeutic approaches are not well standardized. The Red Cell Working Group of the Pediatric Italian Hematogy and Oncology Association (AIEOP) developed specific recommendations to help Physicians for AIHA management. The document is available on the AIEOP website since November 1st2013.

Origa: Apopharma: Honoraria; Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding. Forni:Apopharma: Other: DSM Board; Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy.

Introduction. Despite the increasing of number of patients with Sickle Cell Disease (SCD) in Italy, due to multi-ethnic migratory phenomena, a large percentage of Caucasian sickle population is already present in Italy mainly with b-thal/HbS genotype. Red cell transfusion is one effective treatment for both acute and chronic complications of SCD, while hydroxycarbamide (HC) is used to reduce the frequency of painful vaso-occlusive crises (VOCs) and decrease the need for blood transfusion.

The availability of imatinib (IM) and thereafter of second-generation tyrosine kinase inhibitors (TKI2) has extended therapeutic options for childhood chronic myeloid leukemia (CML) with a favorable influence on disease outcome and overall prognosis. The aim of this report was to evaluate the response to therapy and long-term outcome of children and adolescents with CML in chronic phase (CP) treated with high-dose imatinib (IM).

Biondi: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Foà:BMS: Consultancy; Ariad: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Before 2000, allogeneic hematopoietic stem cell transplantation (HSCT) was the only potentially curative treatment for children with chronic myeloid leukemia (CML) in chronic phase (CP). The availability of imatinib (IM) and thereafter of second-generation (2G) tyrosine kinase inhibitors (TKIs) has extended therapeutic options for childhood CML. Experience with IM in managing children and adolescents with CP-CML resistant or intolerant to interferon treatment treated prompted us to outline guidelines with the aim of offering a uniform management approach for this category of patients (pts). IM was scheduled in newly diagnosed pts with CML in CP, including those with an HLA identical sibling (HLA+). Cytogenetics on bone marrow (BM) and molecular analysis on peripheral blood (PB) and on BM were suggested at planned time-points. These guidelines have been shared with both pediatric referral centers (P Centers) and reference center for adults and children (AP Centers) in Italy. The guidelines, summarized in Figure 1, have been updated over the years (yrs), with the contribution of colleagues managing adult CML.

No relevant conflicts of interest to declare.

Paroxysmal nocturnal hemoglobinuria (PNH) derives from a non malignant clonal expansion of hematopoietic stem cells (HSCs) harbouring somatic mutations of the X-linked PIG-A gene, leading to the complete or partial loss of glycosylphosphatidylinositol membrane-anchored proteins (GPI-APs) from the cell surface of the HSCs and of their mature progeny. The resulting intravascular hemolysis is caused by uncontrolled activation of the complement cascade and determines hemoglobinuria, anemia, fatigue, renal impairment, pulmonary hypertension, smooth muscle dystonias and thromboembolism, with a bad quality of life. Moreover PNH is usually embedded with a various degree of bone marrow (BM) failure syndromes, from mild cytopenias up to aplastic anemia.We describe 5 PNH patients: 3 males and 2 females; median age was 36 year (18-54). All developed PNH after other haematologic disorders. The first one was a rare case occurring after autologous stem cell transplantation(ASCT) for relapsing non-Hodgkin's lymphoma; the second had experienced an aplastic anemia, successfully treated with immunosuppressive therapy; two were affected by anemia and thrombocytopenia of unspecified nature; in the fifth young patient (18 ys), hereditary spherocytosis had been diagnosed 2 years before, based on erythrocyte membrane protein analysis and splenectomy had been performed. All patients had strong intravascular hemolysis (reticulocytosis, elevated LDH, gross hemosiderinuria); the flow cytometry immunophenotyping study of GPI-APs expression on peripheral blood cells showed large cellular populations of erythrocytes, granulocytes and monocytes which had undetectable expression of GPI-APs, suggesting PNH. According to the previous hematological disorders or therapy (ASCT) in the mentioned series of patients, PNH occurred after 2, 5, 9, 1 and 2 years respectively. Three patients were transfusion dependent. After unsuccessful therapy with prednisone, folate and even cycles of steroid therapy, the terminal complement inhibitor eculizumab (EC) was started. All the patients received vaccination against Neisseria meningitides. EC was infused according to the standard schedule, 600 mg weekly for 4 weeks, followed by 900 mg every other week. EC was started respectively after 7 months, 24 months and 8 years from PNH diagnosis in the first three patients and after 4 months from PNH diagnosis in in the last 2 patients. The intravascular hemolysis was completely controlled in all patients. Only one patient continued but reduced erythrocyte transfusions; she shows significant extravascular hemolysis, building up GPI- C3d coated erythrocytes (DAT ++), and is candidate for splenectomy. Despite the different haematological response all 5 patients experienced a dramatic clinical improvement in the quality of life. In the transplant patient the cytometry showed a progressive reduction and ultimately extinction of the pathological clone; this provided the unique possibility to discontinue treatment after 12 months, then maintaining remission for some years. Probably in this case, EC did not play any direct role in the kinetics of the PNH clone, while the conditions which led to expansion of the clone were somehow unique and possibly related to the ASCT and resulted transient. Our small series, including even 2 rare cases (one pediatric PNH patient and one occurred after ASCT) shows how variable are the clinical and biological spectrum of manifestations in this strange and fascinating disease; moreover its clinical evolution in each single patient remains frequently unpredictable.

No relevant conflicts of interest to declare.

Abstract 4227

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), account for approximately 15% of pediatric ALL and about one third of pediatric non-Hodgkin lymphoma, respectively. There are also rare clinical entities the distinction of which resulted arbitrary between leukemia and lymphoma. Since blasts are located on nodes, liver, spleen and bone marrow (BM), these forms are characterized by a problematic evaluation of treatment responses. Moreover, these subtypes have usually demonstrated a low responsiveness to conventional treatment. As matter of fact it is still unclear what is the treatment of choice, but due to the rarity it is an unresolved question. We here report two cases, who were initially treated with an ALL-based protocol and experienced recurrent disease, despite several lines of treatment.An 11-year-old Caucasian male presented with pallor, asthenia, fever and a huge hepato-splenomegaly. Laboratory findings revealed hyperleukocytosis, anemia and thrombocytopenia. LDH level was high (5965 U/L). Morphologic evaluation of peripheral blood (PB) and of BM identified a FAB L2 ALL. Immunologic analyses showed high expression of surface CD3, CD5, CD7, CD56 and TcR γδ. A diagnosis of hepatosplenic γδ T-cell leukemia-lymphoma was made based on these findings and confirmed by the identification of a Vδ1-Jδ1 homoduplex rearrangement in a lymphonode's biopsy. The child was treated according to the AIEOP-ALL 2000 protocol, but failed to respond to induction phase. We shifted him to a non Hodgkin lymphoma (NHL) regimen characterized by chemotherapy courses with high doses of dexamethasone, cytosine arabinoside, cyclophosphamide, asparaginase, daunorubicin and methotrexate. He achieved a morphologic remission after two courses but suffered bone marrow and splenic relapse after three months of therapy. Then another therapeutic approach using Oxaliplatin was tried. But peripheral blasts were still present leading us to the use of a third line treatment with ICE (ifosfamide-carboplatin-etoposide). Peripheral blasts persisted and we tried a salvage therapy with Alemtuzumab (anti-CD52 monoclonal antibody). There was no response and the child died of progressive disease 10 months from diagnosis.An 8-year-old Caucasian female presented with asthenia, dyspnea, peripheral lymphoadenomegaly and cutaneous lesions on scalp. Hematological laboratory findings and morphologic evaluation of PB smear resulted normal. LDH level was high (5260 U/L). Examination of BM, cutaneous and sovraclavear lymphonodal biopsies confirmed a diagnosis of T lymphoblastic leukemia/lymphoma. Chest-abdominal computed tomography scan disclosed pleural effusion, mediastinal and abdominal lympho-nodes enlargement and several hepatic lesions. The child was treated according to the AIEOP-ALL 2000 protocol. Morphologic evaluation of PB smear at day 8 was normal as expected, while the chest radiography showed no response. The restaging after the induction phase demonstrated the persistence of blasts in BM (8-9%) and a minor radiological response. After 2 courses she achieved hematological complete remission but the radiological findings were unmodified. The second line therapy was characterized by chemotherapy courses with idarubicin and high-dose of cytosine arabinoside. She achieved a radiological response but it was very fleeting. Afterwards we tried another therapeutic approach using a fludarabine, mitoxantrone and cytosine arabinoside. There was no response and the child died of progressive disease 5 months from diagnosis. In both cases, there was no HLA-compatible family donor. Thus we immediately started to search for an unrelated one.Our patients' course matched the predictable very poor prognosis despite intensive chemotherapy. Our cases showed a disease with distinctive clinical, histopathologic and phenotypic characteristics. Our experience suggests that i) a better molecular characterization of these rare entities is mandatory; ii) an ALL-based therapy seems to be ineffective and these cases are addressed to experimental protocol; iii) once the diagnosis has been formulated, it may be important to plan for an allogeneic BMT, as soon as first remission would be achieved.No relevant conflicts of interest to declare.

Abstract 4777

Despite myeloablative and immunosuppressive conditioning therapy, allogeneic bone marrow transplantation (BMT) may fail because of either graft failure or relapse of the malignant disease. In this study we have evaluated the impact of second BMT on long-term disease-free survival (DFS) in 42 patients who were transplanted in our institution between January 1983 and March 2005. GRAFT FAILURE. Eleven patients (4 with aplastic anemia, 4 thalassemia major (TM), 3 chronic myeloid leukemia (CML), 2 acute myeloid leukemia (AML), 1 acute lymphoblastic leukemia (ALL), 1 myelodisplastic syndrome (MDS) received a second BMT for graft failure, either primary (n=8) or secondary (n=3). The median age at time of first BMT was 19 years (range, 3 to 42). The median interval between the first and second BMT was 35 days (range, 27 to 532). Donors were the same of the first BMT. They were HLA genotipically identical (n=8) or HLA phenotipically identical (n=1) or 1 antigen mismatched family members. Four patients died for BMT related causes (2 for acute GvHD, 1 for heart failure and 1 for CNS hemorrhage and rejection). Six patients are now living after a median follow-up of 169 months (range, 52 to 202). Five patients are cured and one had an autologous thalassemia reconstitution and is now living under transfusion treatment. RELAPSE. Thirty-one patients (11 with CML, 9 AML, 9 ALL, 1 MDS, 1 TM) were given a second BMT following relapse of the malignant disease. The median age at time of first BMT was 27 years (range, 1 to 43). The median interval between the first and second BMT was 528 days (range, 115 to 5584 ). Thirty patients received the second BMT from the same HLA genotipically identical family member used for the first transplant. One patient was given the first BMT from a matched unrelated donor and the second transplant from an haploidentical brother. The 6 months transplant related mortality (TRM) was 19%. Six patients died for BMT related causes (4 for acute GvHD, 1 for heart failure and 1 for infection and multiorgan failure). Eight patients had leukaemia relapse following second BMT. Five of them died of chemotherapy complications. One of them, who was reinducted into complete remission and received a third BMT from an unrelated donor, died because encephalopathy. Nineteen patients are living after a median follow-up of 72 months (range, 4 to 236). The 5-years probabilities of overall survival and disease free survival (DFS) were 59% and 52% respectively. The 5-years DFS for AML, CML and ALL patients was 72%, 54% and 12% respectively (p=0.03). The 5-years DFS for 17 patients conditioned with TBI and for 13 patients conditioned with busulphan (BU) was 62% and 31% respectively (p=0.09). This study show that many patients may benefit from a second BMT either following graft failure or leukemia relapse with an acceptable TRM. In particular, patients with AML or CML are the best candidates to be cured from second BMT. TBI conditioning regimen gives better results as compared to BU regimen.

Despite myeloablative and immunosuppressive conditioning therapy, allogeneic bone marrow transplantation (BMT) may fail because of either graft failure or relapse of the malignant disease. In this study we have evaluated the impact of second BMT on long-term disease-free survival (DFS) in 42 patients who were transplanted in our institution between January 1983 and March 2005.