[Show abstract][Hide abstract] ABSTRACT: Pediatric Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were “monomorphic” with immunoblastic histology, and 5 cases were “polymorphic” with histologic aspects reminiscent of nodular lymphocyte–predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non–germinal center (non-GC) origin (CD10−/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.
[Show abstract][Hide abstract] ABSTRACT: We report a case of EBV encephalitis in a seven-yr-old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis. Blood and CSF PCR analyses were negative for the most common viruses involved in immunocompromised patients including EBV. A cerebral biopsy was performed, which showed intense gliosis and perivascular lymphocytic cuffing. PCR analysis performed on brain tissue was positive only for the EBV genome, while extensive investigations for other viral infections were negative. The patient's neurological symptoms rapidly worsened and he died two months later. This case report suggests that in patients presenting neurological and radiological signs of encephalitis after an HSCT, an EBV involvement should be considered, even in the absence of CSF and blood PCR virus detection.
Full-text · Article · Nov 2014 · Pediatric Transplantation
[Show abstract][Hide abstract] ABSTRACT: Abstract Toxicity and efficacy 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 relapse/resistant disease were treated with intrathecal LC at dosages adjusted for age. Twenty-seven (90%) patients simultaneously received systemic chemotherapy, including concurrent high-dose cytarabine or methotrexate in 21 (70%) cases. Of 28 patients evaluable for response, 25 patients (89%) achieved CNS complete remission and 3 (11%) partial remission. The median number of intrathecal LC administrations per patient was 4; the cerebrospinal fluid was cleared after a median of 3 intrathecal LC administrations. Neurological toxicity ≥ grade 3 occurred in 4 (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 effective in children with relapsed/refractory CNS leukemia/lymphoma.
Full-text · Article · May 2014 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome.
We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naïve T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p=0.035).
These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover, they speak in favor of the hypothesis that IDO can be targeted, in adjunct to current chemotherapy approaches, to improve the clinical outcome of children with AML.
[Show abstract][Hide abstract] ABSTRACT: The outcome of adults and children with Acute Promyelocytic Leukemia (APL) has dramatically changed since the introduction of all trans retinoic acid (ATRA) therapy. Based on the results of several multicenter trials, the current recommendations for the treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the remission induction and consolidation, and ATRA combined with low-dose chemotherapy for maintenance. This has improved the prognosis of APL by increasing the complete remission (CR) rate, actually > 90%, decreasing the induction deaths and by reducing the relapse rate, leading to cure rates nowadays exceeding 80% considering both adults and children.1–9 More recently the combination of ATRA and arsenic trioxide (ATO) as induction and consolidation therapy has been shown to be at least not inferior and possibly superior to ATRA plus chemotherapy in adult patients with APL conventionally defined as non-high risk (Sanz score).10
Childhood APL has customarily been treated on adult protocols. Data from several trials have shown that the overall outcome in pediatric APL appears similar to that reported for the adult population; however, some clinical and therapeutic aspects differ in the two cohorts which require some important considerations and treatment adjustments.
Preview · Article · Apr 2014 · Mediterranean Journal of Hematology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: In allogeneic hematopoietic stem cell transplant recipients with bone marrow (BM) suppression, cytomegalovirus (CMV) pp65
antigenemia and DNA were detectable in peripheral blood leukocytes (PBL) and BM cells. A relationship between CMV infection
of PBL and BM cells has been found.
Preview · Article · Mar 2014 · Journal of clinical microbiology
[Show abstract][Hide abstract] ABSTRACT: The outcome of high-risk (HR) Acute Lymphoblastic Leukemia (ALL) patients enrolled in AIEOP-BFM ALL 2000 study (NCT00613457) in Italy is described. Overall, 1999 Philadelphia negative ALL patients entered the study. HR criteria were: minimal residual disease (MRD) levels ≥10(-3) at day 78 (HR-MRD), no complete remission (no-CR) at day 33, t(4;11) translocation, Prednisone Poor Response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, maintenance. 312 HR patients (15.6% of the total) had 5-year event-free survival (EFS) and overall survival (OS) of 58.9%(SE 2.8) and 68.9%(2.6). In hierarchical order, EFS was 45.9%(4.4) in 132 HR-MRD patients, 41.2%(11.9) in 17 patients no-CR at day 33, 36.4%(14.5) in 11 patients with t(4;11), 74.0%(3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival (DFS) in patients with very high risk features (HR-MRD, no-CR at day 33, t(4;11) translocation), given HSCT (n=66) or chemotherapy only (n=88), after adjusting for waiting time to hematopoietic stem cell transplantation (HSCT) (5.7 months). Patients at HR only for PPR have favorable outcome. High risk MRD is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study is registered at the US National Institutes of Health website http://clinicaltrials.gov as "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukaemia" with the protocol identification number NCT00613457.
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia shows marked differences in outcome between children and adults. Since there is limited information on the distribution of clinico-biologic variables in different age cohorts, we analyzed 5202 ALL patients enrolled in the Italian multicenter AIEOP and GIMEMA protocols and stratified them in 9 age cohorts. The highest prevalence of ALL was observed in children, although a second peak was recorded from the 4th decade onwards. Interestingly, the lowest incidence was found in females between 14-40 years, suggesting a protective impact of fertility. Immunophenotypic characterization showed a B-lineage in 85.8% of patients: a pro-B stage, associated to MLL/AF4 positivity, was more frequent in patients between 10-50 years. A T-lineage (14.2%) was rare among small children and increased in 10-40 years patients. The BCR/ABL1 rearrangement increased progressively with age, starting from the 10-14 cohort and impacting for 52.7% of cases in the 6th decade. Similarly, the MLL/AF4 rearrangement constantly increased up to the 5th decade, while the ETV6/RUNX1 rearrangement disappeared from the age of 30 onwards. This study shows that adolescents and young adults are characterized by a male prevalence, greater T-lineage acute lymphoblastic leuekmia percentage, an increase of poor prognostic molecular markers with aging compared to children, and conclusively quantifies the progressive increase with age of BCR/ABL+ patients, potentially manageable by targeted therapies.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the outcome of 482 children with acute myeloid leukemia (AML) other than promyelocytic leukemia enrolled in the AIEOP-AML-2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was broadly used in high-risk (HR) children. Patients with core-binding-factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR, 99 patients), whereas the others (n=383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO)-HSCT was employed, respectively, in 141 and 102 HR patients in CR1 after consolidation therapy. CR, early death and induction failure rates were 87%, 3% and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall (OS), event-free (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS and DFS for SR and HR patients were 83%, 63%, 66%, and 64%, 53% and 62%, respectively. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis for EFS, risk group, WBC >100x10(9)/L at diagnosis and monosomal karyotype predicted poorer outcome. These findings indicate that risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML.
[Show abstract][Hide abstract] ABSTRACT: Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor (TKI), is the standard treatment for patients with chronic myeloid leukemia (CML). However, the inhibition in normal cells of two additional targets of IM, platelet-derived growth factor receptor and c-KIT, may be associated with side effects. We followed 4 pre-pubertal CML patients (3 males, 1 female) on prolonged treatment with IM to evaluate growth, pubertal development and bone metabolism. An increase in C-terminal telopeptides of type I collagen, marker of bone resorption, was observed in all patients and a decrease of bone mineral density was recorded in two boys. The growth rate showed a delay in height, which recovered over time in all patients. IM therapy may result in a decelerated growth and a dysregulated bone remodeling in pre-pubertal patients. Bone metabolism and growth velocity should be closely monitored in children treated with TKIs, in order to plan the optimal treatment strategy.