Search

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10−4), and high (≥ 5 × 10−4). RESULTS EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( P < .0001), while for myeloid-style–treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (&lt, 5%). The majority of cases are classified as Primary Induction Response (PIR), unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

Acute promyelocytic leukaemia (APL) is a rare subtype ofchildhood acute myeloid leukaemia (AML), accounting for5–12% of all AML cases. Treatment with all-trans-retinoicacid (ATRA) and anthracyclines yields complete remission(CR) rates >90% and 10-year event-free survival (EFS) ratesaround 80%.1–3The recent front-line arsenic trioxide(ATO)-based regimens have further improved the APL out-come by reducing toxicity and preventing relapse.4–6Relapsed APL patients are a rare and heterogeneous group,whose prognosis depends on front-line treatment and timeelapsing between diagnosis and recurrence. Currently, ATOis the treatment of choice for relapsed APL. Due to the rarityof relapsed childhood APL, 17–27% in ATRA- andchemotherapy-1,3,7–9and 4% in ATO-containing regimens,10it will be difficult, in the future, to design future prospectivecomparative trials for these patients. In an attempt to designtherapeutic guidelines, recommendations on management ofrelapsed/refractory paediatric APL have been publishedrecently

Background: Patients treated for paediatric/adolescent (P/A) neoplasia have a high incidence of both benign and malignant thyroid diseases. Given the high incidence of sequelae, literature data show a clinical benefit of morpho-functional thyroid screening in paediatric/adolescent cancer survivors and a careful lifetime follow-up. Patients and methods: The incidence of thyroid alterations was evaluated in a consecutive series of 343 patients treated with chemotherapy (CHE) and radiotherapy (RTE) or only with CHE for P/A tumours between 1976 and 2018 (mean age at time of primary paediatric malignancy 7.8 ± 4.7 years). All patients underwent thyroidal morpho-functional evaluation between 2000 and 2019. Results: 178 patients (51.9%) were treated only with CHE and 165 (48.1%) with CHE+RTE. A functional and/or structural thyroid disease was diagnosed in 147 (42.5%, 24.2% in CHE and 62.4% in CHE+RTE group, p = 0.0001). Of note, 71 (20.7%) patients with no evidence of disease at first evaluation developed a thyroid alteration during the follow-up. Primitive hypothyroidism was diagnosed in 54 patients (15.7%, 11.2% in CHE vs. 20.6% in CHE+RTE group, p = 0.01) and hyperthyroidism in 4. Sixty-three patients developed thyroid nodules (18.4%, 4.0% in CHE and 14.1% in CHE+RTE group, p &lt, 0.001), thyroid cancer was diagnosed in 30 patients (8.7%, 4.5% in CHE and 12.4% in CHE + RTE group, p = 0.007). Conclusions: In patients treated with CHE+RTE, the prevalence of hypothyroidism and nodular pathology, both malignant and benign, were significantly greater than in patients treated with CHE. However, also in the CHE group, the frequency of thyroid disease is not negligible and the pathogenetic mechanisms remain to be clarified. Our data suggest the clinical benefit of morpho-functional thyroid screening in P/A cancer survivors.

Pediatric cancer survivors are at increased risk for psychological distress. We sought to understand the severity and symptoms’ co-occurrence among pediatric survivors compared to controls by rating both self- and parent-reported symptomatology. Forty survivors (22 males; mean age at study time: 12.9 years) participated in the study. Most survivors (85%) had a diagnosis of acute lymphoblastic leukemia. Seventy-nine healthy controls with the same age and gender distribution as the patients were included. A standardized assessment of psychological functioning was conducted by self- and parent-reported symptoms evaluations. The self-reported anxious symptom severity was significantly higher in survivors. A significantly higher proportion of survivors compared to controls had clinically significant anxiety, depression, and combined anxiety symptoms (i.e., social anxiety, separation anxiety, or physical symptoms). In both study groups, the self-reported emotional and somatic symptoms were significantly associated. The multi-informant assessments of the psychological symptoms revealed distinct associations between the child- and parent-reported symptoms in the survivors’ group: the survivors’ self-reports of depressive symptoms, somatic symptoms, and functional impairment were significantly correlated with the parent reports of child behavioral concerns, somatic complaints, and functional impairment, respectively. Conclusion: Self-reported symptoms showed similar comorbidity profiles in survivors and control peers. The multi-informant assessments detected differences in the association of self- and parent-reported symptoms between the survivor and control groups. The present study showed that multi-informant assessment is critical to understanding symptom profiles and to informing intervention with particular regard to parental participation and support.

Background Following diagnosis, children with cancer suddenly find themselves in an unknown world where unfamiliar adults make all the important decisions. Children typically experience increasing levels of anxiety with repeated invasive procedures and do not adapt to the discomfort. The aim of the present study is to explore the possibility of asking children directly about their medical support preferences during invasive procedures. Procedure Each patient was offered a choice of medical support on the day of the procedure, specifically general anesthesia (GA), conscious sedation (CS), or nothing. An ad hoc assessment tool was prepared in order to measure child discomfort before, during, and after each procedure, and caregiver adequacy was measured. Both instruments were completed at each procedure by the attending psychologist. Results We monitored 247 consecutive invasive procedures in 85 children and found that children in the 4 to 7 year age group showed significantly higher distress levels. GA was chosen 66 times (26.7%), CS was chosen 97 times (39.3%), and nothing was chosen 5 times and exclusively by adolescents. The child did not choose in 79 procedures (32%). The selection of medical support differed between age groups and distress level was reduced at succeeding procedures. Conclusions Offering children the choice of medical support during invasive procedures allows for tailored support based on individual needs and is an effective modality to return active control to young patients, limiting the emotional trauma of cancer and treatment.

The authors describe the sixth pediatric case to date of primary vulvar melanoma associated with lichen sclerosus and propose a practical management for such a rare cancer.

The treatment of neuroblastoma is based on the International Neuroblastoma Risk Group stratification considering life-threatening symptoms, image-defined risk factors (IDRFs), presence and site of metastases, biology, and histopathology. The authors present an infant with bilateral nonmetastatic adrenal neuroblastoma with favorable biology. Both tumors were resectable and without IDRFs, but bilateral resection was considered mutilating, so it was decided to operate one side only. The authors suggest considering bilaterality among IDRFs.

Burkitt lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) account for most cases of non-Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre-phase followed by 2-6 high-dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment-related death, 2 developed second malignancy and 20 relapsed. At a median follow-up time of 5 years, overall survival was 93% (±1%) and event-free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Munster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).

Treatment intensification was considered a suitable strategy to increase the cure rate of lymphoblastic lymphoma (LBL) in children.The AIEOP LNH-97 trial was run between 1997 and 2007 for newly diagnosed LBL in patients aged less than 18 years. Treatment schedule was based on the previous, LSA2-L2 derived, AIEOP LNH-92 protocol. Modifications included: increased dose of upfront cyclophosphamide and methotrexate, use of l-Asparaginase during induction therapy, intensive block therapy for slow responders, and late intensification ("Reinduction") for patients with advanced stage disease. Total therapy duration was 12 months for stage I and II, and 24 months for stage III and IV. Central nervous system prophylaxis did not include cranial irradiation.114 eligible patients were enrolled, 84 males and 30 females; median age was 9 years. Complete remission was obtained in 98% of patients. After a median follow-up time of seven years, 29 patients failed due to progression of disease (n = 2), relapse (n = 25), or second malignancy (n = 2). The 7-year overall survival was 82% (standard error [SE] 4%) and the 7-year event-free survival was 74% (SE 4%). No subgroup showed significantly different event free survival. None of the patients died of front line chemotherapy-related toxicity.Treatment intensification was associated with good outcome in children and adolescents with LBL, with limited toxicity. Prognosis after relapse was better for patients who underwent allogeneic hematopoietic stem cell transplantation. Measurements of biological markers and treatment response are necessary for achieving further improvement through more accurate identification and stratification of patients at risk of disease relapse.

Background AML is an aggressive disease. Current pediatric protocols ensure a 60% survival rate (Pession A et al, Blood 2013), reaching a plateau of intensiveness. Nevertheless, patients with primary induction failure (PIF) (10%) or relapse (30%) after stem cell transplantation (SCT) still have a very poor outcome. Novel therapeutic strategies are needed. Case 1. In January 2013, a 13 year-old female with FAB-M1-AML, presenting with chromosome 11 monosomy, was enrolled on AIEOP-AML-2002/01 protocol (Pession A et al, Blood 2013) and showed a PIF after two cycles of induction phase. Leukemic blasts arose in a low peripheral blood cell (PBC) count, even in response to second line treatment (I-BFM-AML-relapse2001 protocol). A third line experimental therapy, azacitidine (AZA) and rapamycin, failed to induce remission. Low PBC count with blasts still remained. Based on a bright expression of CD117/cKit, detected by flow cytometry, we designed a salvage therapy with AZA (75mg/mq/day for 7 days, every 21 days), in association with Imatinib Mesylate (375 mg/mq/day). We observed an increase of PBC count, with rapid disappearance of blasts. After two courses of AZA-Imatinib, the patient achieved complete remission. Subsequently she underwent SCT from an unrelated donor (UD) (Nov/2013). Nine months later, immune-suppressive therapy was withdrawn and we confirmed complete remission with a 100% donor engraftment. She is currently alive and in remission. Case 2. In October 2013, a 13 year-old male with FAB-M5-AML, presenting with a complex karyotype and specific molecular markers (FLT3-ITD and NSD1-NUP98), was enrolled on AIEOP-AML-2002/01 protocol. He achieved complete remission after induction phase. Nearby SCT-UD program, he presented colonization with two multi-resistant-gram-negative bacteria. For this reason, he was shifted to a haplo-identical SCT program. He received two haplo-SCT from his mother (April/2014) and his father (June/2014) respectively, after which he showed a bone marrow relapse (Sept/2014). Based on his low performance status, we designed a salvage therapy with cytosine arabinoside (100 mg/day i.v. in a total 8-days/cycle) Sorafenib (600 mg/day orally, already started before the first haplo-SCT), in association with PEG-Asparaginase (Oncaspar) at 3500 UI/i.v. weekly for 4 administrations. Surprisingly we observed an increasing signs of cutaneous grade II graft-versus-host-disease (GVHD), confirmed by flow cytometry analysis (high T-cell suppressors/NK cells), consistently with an increasing rate of donor's DNA (Dec/2014). Therefore, after a second cycle, the patient achieved the complete remission (Jan/2015) and a third haplo-SCT (Feb/2015) was given, using NK-alloreactive donor cells from his mother. Currently, the patient is alive and in complete remission with 100% donor. Conclusion. Our experience suggests that innovative combinational therapies are able to rescue patients with PIF or relapsed AML after SCT, the worst candidates. Association of a tyrosine kinase inhibitor with a demethylating agent showed a synergistic effect on leukemic blasts. More interestingly, PEG-LASP combined an anti-leukemic effect to an immune-modulation on donor's lymphocytes, as shown by immunophenotypic analyses. Disclosures Off Label Use: We used Imatinib Mesylate and PEG-L-Asparaginase in two children with AML: an off-label use for indication and age. .

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, originating from a neoplastic deviation of B or T lymphocyte. Cytogenetic, cytofluorimetric, and genomic analyses clearly defined several subtypes of ALL. However, the leukemogenic process is characterized by different pathways' alteration which are still to be determined, in the attempt to identify specific targets to be druggable. In this review, we explore the main molecular pathways, which are commonly shared between different subtypes of pediatric ALL. These cell-signaling pathways affect many functions, including cell proliferation, apoptosis, migration, and differentiation. The PI3K/AKT/mTOR pathway is one of the most studied, with higher expected promises of being targetable. RAS pathway is also widely studied in all types of cancer. The Wnt/Beta catenin has been recently studied in ALL. Finally, CXCL12/CXCL4 axis has a crucial role in regulating hematopoietic stem cell and bone marrow niche. The complete characterization of these pathways will allow us to design a specific patient–disease profile associated with a tailored treatment, with the highest grade of efficacy and the lowest grade of toxicity.

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) still represents a major challenge. We report the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP) with allogeneic hematopoietic stem cell transplantation (HSCT) in children with Ph+ ALL from 1990 to 2008. Sixty-nine patients received HSCT from either a related (37, 54%) or an unrelated (32,46%) donor. Twenty-five patients (36%) underwent transplantation before 2000 and 44 (64%) after 2000. Twenty-three patients (33%) received lmatinib mesylate treatment before HSCT and seven (10%) after HSCT. After a median follow-up of 56 months, the overall survival (OS) probability was 51% (95% confidence interval [Cl], 38-63), the leukemia-free survival (LFS) was 47% (95% CI, 34-59), transplantation-related mortality (TRM) was 17% (95% CI, 10-30), and relapse incidence (RI) was 36% (95% CI, 26-50). Transplantation in first complete remission, female gender, and lower WBC count at diagnosis were associated with a better LFS in both univariate and multivariate analyses. Patients with p210 transcript had a trend for a worse prognosis compared with those who had the p190 transcript. Our series confirms the role of HSCT in the eradication of Ph+ ALL. Early HSCT is recommended once morphologic remission is obtained. Biol Blood Marrow Transplant 18: 852-860 (2012) (C) 2012 American Society for Blood and Marrow Transplantation

Abstract 3585 Introduction: The prognosis of paediatric patients (pts) with Acute Myeloid Leukemia (AML) has significantly improved over time not only in standard risk (SR) but also in high risk (HR) children. Pts < 1 year of age (infants) affected by AML are generally considered to be at HR. This is due to the prevalence of prognostically unfavourable clinical and cytogenetic/molecular features and to a greater vulnerability to treatment toxicities. We analyzed clinical and biological characteristics, as well as outcome of infants treated with the AIEOP AML 2002/01 protocol, comparing them to those of older children. Patients and Methods: Between 12/2002 and 06/2011, 63 infants with AML other than promyelocytic leukaemia were treated with the AIEOP AML 2002/01 protocol. Children with Down syndrome were excluded. Clinical and biological features compared to the ones of 3 different age groups (1–10 years) are reported in Table 1. Treatment was administered according to the following risk-based stratification: pts with isolated CBF-b+ leukemia achieving complete remission (CR) after the first induction course were considered to be at Standard Risk (SR), whereas all the others were assigned to the HR group. The treatment schedule administered to infants was: 2 courses of 7-day induction therapy (idarubicin, cytarabine and etoposide: ICE 3+5+7) and 2 consolidation courses based on high-dose cytarabine (HD-Ara-c), combined with either etoposide during the first course (AVE 3+4) or mitoxantrone during the second course (HAM 3+2). After consolidation, infants were eligible to allogeneic (ALLO) HSCT in first CR from a HLA-identical relative, if available, or from alternative donors, namely unrelated donors or HLA-mismatched relatives. CR rate, early death (ED), induction failure (IF), overall survival (OS) and event free survival (EFS) of infants were calculated and compared to those of other age groups. Results: Compared to pts of other age groups, infants had significantly more CNS involvement at diagnosis (P=0.002), were assigned to the FAB M7 subtype (P=0.000) and to the HR risk group (P=0.001) (Table 1). The median white blood cell (WBC) count at diagnosis was higher in infants (P=0.028), being 71,298×103/ml (range 3,100–653,000). Comparing pts with available cytogenetic data in the different age groups, infants showed a significantly higher incidence of 11q23/MLL-rearrangements (P=0.001). The incidence by partners of 11q23/MLL-rearrangements were 10%, 7%, 1%, 4% and 14% for t(9;11), t(10;11), t(11;19), t(1;11) and other translocation partners, respectively. Infants had CR, ED and IF rates of 84%, 8% and 8%, respectively, with no statistically significant differences with other age groups. Forty-five out of 63 infants (71%) received an ALLO HSCT in first CR. With a median follow up time of 57 months (range 3–130) the 8-year probability of OS and EFS of infants were 74% and 58%, respectively, with no significant differences compared with the other age groups. Conclusions: Infants < 1 year of age at diagnosis enrolled in the AIEOP AML 2002/01 protocol presented with a significantly higher incidence of prognostically unfavourable features, like high WBC count, FAB M7 subtype, 11q23/MLL-rearrangements and CNS involvement. Despite this, a treatment strategy including a wide use of ALLO HSCT in first CR for these pts resulted in a final outcome which was not statistically different from that observed in the other age groups. Our results compare favourably with previously published data on infants with AML. Disclosures: No relevant conflicts of interest to declare.

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.

Purpose To study minimal disseminated disease (MDD) in children with Burkitt's lymphoma (BL) and to determine its impact on prognosis. Patients and Methods We established a simplified long-distance polymerase chain reaction (LD-PCR) assay that can amplify up to 15 to 20 Kb of DNA sequence, making it possible to detect the t(8;14) at the genomic level with sensitivity of 10−4. We prospectively studied diagnostic biopsies and bone marrow aspirates from 134 patients affected by BL. Results A specific LD-PCR product was detected in 96 (72%) of 134 BL biopsies. Among 84 patients with t(8;14) positivity on tumor biopsy and bone marrow (BM), 26 (31%) had LD-PCR–positive BM, and 15 (18%) were positive at standard morphologic analysis. Twenty (85%) of 26 MDD-positive patients belonged to the R4 risk group, according to Berlin-Frankfurt-Munster definition. The 3-year progression-free survival was 68% (SE, 10%) in MDD-positive patients in R4 compared with 93% (SE, 5%) in MDD-negative patients in R4 (P = .03). By multivariate analysis (including MDD, sex, lactate dehydrogenase, CNS involvement), only MDD was predictive of higher risk of failure (hazard ratio, 4.7; P = .04). Conclusion MDD identifies a poor-prognosis subgroup among children with high-risk BL. To improve disease control in these patients, a more effective risk-adapted therapy, possibly including anti-CD20 monoclonal antibody, should be considered.

Neurological complications are a not rare event during treatment of childhood cancer. Severe neurological events can be explained by recurrence of disease, chemotherapy toxicity, and other life-thr...

Abstract 1578 Poster Board I-604 Background T-ALL accounts for about 15% of pediatric ALL and still represents a clinical challenge, because more than 20% of children experience a recurrent disease which has a dismal prognosis. Characterization of molecular alterations with prognostic impact may be useful for an early identification of patients at high risk of failure in whom more intensive treatments, including hematopoietic stem cell transplantation (HSCT) may be considered. CALM-AF10 results from a recurring t(10;11)(p13;q14-21) chromosomal translocation and is the most frequent fusion transcript in both adult and pediatric patients with T-ALL. Its presence has been associated with a poor prognosis (Asnafi V et al. Blood 2003; van Grotel M et al Haematologica 2006). The aim of the present study was i) to define the incidence of CALM-AF10 among homogeneously treated children with T-ALL and ii) to evaluate the outcome of these patients. Materials and Methods We studied 201 patients with T-ALL, diagnosed and enrolled between 9/2000 and 12/2007 in the ALL-2000 protocol and the subsequent modified 2000 study (ALL-R-2006) of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) which consist of an intensive chemotherapy strategy based on BFM-ALL schedules. Patients were mainly stratified according to prednisone response evaluation (good response: blast count at day 8 less than 1000/mmc) and detection of minimal residual disease (MRD) performed at day 33 (Timepoint 1) and at day 78 (Timepoint 2). When both TPs were negative children were considered to be at Standard Risk (SR); patients with TP1 and/or TP2 positive and TP2 '10-3 were considered to be at Intermediate Risk (MR); children with TP2 positive ≥10-3 belong to the high risk (HR) group. Patients with prednisone poor response and MRD-HR were considered eligible for HSCT from a sibling donor in first complete remission. Event free survival (EFS) and overall survival (OS) estimates with 95% CIs were calculated through the Kaplan-Meier method and differences compared with the log-rank test. RT-PCR reactions for detection of CALM-AF10 were performed as previously reported (Asnafi V et al Blood 2003) Results Ten patients resulted not eligible and were excluded from analysis. Among the 191 evaluable children with T-ALL, 14 (7,3%) were positive for CALM-AF10. Twelve (85%) of these patients were males. Median age was 8 years (range 2 – 13). Immunophenotyping showed thymic/intermediate features in 6 cases, mature in 5, early in 1, biclonal in 1 and unknown in 1, respectively. Eight cases showed a poor prednisone (PDN) response. Based on a randomized study performed in induction in the frame of the ALL-2000 protocol on the efficacy of PDN vs dexametasone (DXM) 8 children were treated with PDN and 3 with DXM The remaining 3 cases, belonging to the ALL R-2006 protocol, were treated with DXM (n=2) and PDN (n=1). MRD-based stratification allowed the allocation of 3, 8 and 3 patients in the SR, MR and HR, respectively. Four cases relapsed (3 in the central nervous system and 1 in the bone marrow). EFS at 5 years of the 14 CALM-AF10 positive T-ALL children versus the 177 who were negative was 70.1% vs 63.9%, respectively (p-value log-rank=0.61). Small numbers did not allow to fully evaluate the impact of different variables such as initial steroid treatment (PDN vs DXM) or the MRD-based risk-group assignment Conclusions This study performed in a vast cohort of children with T-ALL shows that CALM-AF10 is found in about 7% of children with T-ALL and that does not predict a poor outcome when an intensive chemotherapy strategy is employed. Disclosures No relevant conflicts of interest to declare.

Abstract 17 Introduction: The prognosis of paediatric patients (pts) with Acute Myeloid Leukaemia (AML) has significantly improved over time, the published current probability of event-free survival (EFS) being in the order of 40–50%. We report the results of the AIEOP LAM 2002/01 Protocol, a multicentric prospective study conducted by Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Treatment was stratified according to the risk group at which the pt was assigned and the study was designed to evaluate if a large use of haematopoietic stem cell transplantation (HSCT) in high-risk (HR) pts was able to increase the 5-year EFS above 50%. Patients and Methods: Between 12/2002 and 12/2007, 217 children with de novo AML other than promyelocitic leukaemia were enrolled; 205 of them are evaluable. Children with Down syndrome were excluded. Pts with isolated AML1-ETO fusion transcript or anomalies of CBF-b achieving complete remission (CR) after the first induction course were considered to be at Standard Risk (SR), whereas all the others were assigned to the HR group. After 2 courses of 7-day induction therapy (idarubicin, cytarabine and etoposide: ICE 3+5+7), pts achieving CR received 2 consolidation courses, including high-dose cytarabine (HD-Ara-c), combined with either etoposide in the first course (AVE 3+4) or mitoxantrone in the second course (HAM 3+2). After consolidation, SR pts received a further cycle of 3-day HD-Ara-c, while HR children underwent either allogeneic (ALLO) or autologous (AUTO) HSCT depending on the availability of an HLA-identical relative. Children Results: 34 (16%) and 171 (84%) pts were assigned to SR and HR groups, respectively. Overall, 82% of 205 pts achieved CR after induction, the early death and induction failure rate being 4,3% and 11,7%, respectively. Pts in CR Relapsed in 35%, died in 5%. With a median follow-up of 43 months (range 4-86), the 5-year probability of overall survival (OS), EFS, and disease-free survival (DFS) for the whole cohort were 70%, 55%, and 63%, respectively. In the SR group OS, EFS and DFS were 97%, 78% and 78%, respectively, while in the HR group were 64%, 50% and 60%, respectively. Notably, EFS for the 25 children with M7-AML was 54%; 24 infants had an EFS of 62%. WBC count at diagnosis did not influence EFS. In the HR group, the EFS of pts who did or did not have FLT-3 internal tandem duplication was 31% and 51%, respectively (p Conclusions: AIEOP LAM 2002/01 study resulted in an EFS superior to 50%. The early-death rate was particularly low. The risk stratification adopted allowed to identify 2 groups with distinct prognosis (Fig1) and deserving post-remissional treatment of different intensity. The EFS of M7-AML and infant pts compares favourably with previously published results. Notably, among pts given ALLO-HSCT, the outcome was not influenced by the type of donor employed. Disclosures: No relevant conflicts of interest to declare.

Purpose Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) –oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting. Patients and Methods A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index ≥ 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non–T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase. Results The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission. Conclusion Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and

Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Natural killer (NK) cell lymphomas are rare in the USA and Europe but more common in Asia and Central America although very rare among children. We report a case of Epstein-Barr virus-positive NK lymphoma/leukemia, that showed peculiar features represented by a very long clinical course with a significant interval between the first clinical signs and the diagnosis, detection of neoplastic cells in the peripheral blood but not in the bone marrow, and good response to treatment and clinical outcome.