Outcome of primary hemophagocytic lymphohistiocytosis: a report on 143 patients from the Italian Registry.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a severe, life-threatening hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway. Here we investigated the clinical presentation and outcome in a large cohort of 143 patients with pHLH diagnosed in the last 15 years and enrolled in the Italian registry. The median age at diagnosis was 12 months (IQR 2-81), and ninety-two patients (64%) fulfilled the HLH-2004 criteria. Out of 111 patients who received first-line combined therapy (HLH-94, HLH-2004, Euro-HIT protocols), 65 (59%) achieved complete response (CR) and 21 (19%) partial response (PR). Thereafter, 33 patients (30%) reactivated, and 92 (64%) received HSCT, 78 of whom (85%) survived and were alive at a median follow-up from diagnosis of 67 months. Thirty-six patients (25%) died before HSCT and 14 (10%) after. Overall, 93 patients (65%) were alive after a median follow-up of 30 months. Unadjusted predictors of non-response were age.

Histology of pediatric classic Hodgkin lymphoma: From diagnosis to prognostic stratification.

AIMS: Classic Hodgkin lymphoma (cHL) is a common malignancy of the pediatric age. Although clinical-radiological features are routinely used for disease risk stratification, the role of tumor histology has yet to be defined. This study aimed to characterize the clinical-pathological features of a large cohort of pediatric cHL specifically investigating the relevance of tumor histology for the prognostic stratification of patients. METHODS AND RESULTS: The study considered 96 clinically annotated cases of pediatric cHL treated according to the AIEOP-LH2004 protocol. The following histological parameters were considered: (i) cHL variant; (ii) grade of nodular sclerosis (NS); (iii) staining for Bcl2 and p53, and expression of B-cell (BCA) and T-cell antigens (TCA) by Hodgkin/Reed-Sternberg cells. The study population consisted of 51 males and 45 females (median age: 13.6 years) with five-year overall and progression-free survival of 94% and 81%, respectively. Most cases featured NS morphology (96%) with a prevalence of NS1 over NS2 grades. Two NS2 variants were recognized (sarcomatous/syncytial and fibrohistiocytic). A consistent subset of cases disclosed positivity for BCA (34%), TCA (26%), p53 (13%), and Bcl2 (19%). Clinical-pathological correlations showed a more aggressive clinical course for NS2 over NS1 cases. The NS2 fibrohistiocytic variant was associated with the worst outcome. No other histological features correlated with prognosis. CONCLUSIONS: Pediatric cHL is a clinically and histologically heterogeneous neoplasm. The majority of cases disclose NS morphology and aberrant phenotypes are frequently encountered. In the pediatric population, NS grading and NS2 subtyping bear significant prognostic impact.

FDG PET in response evaluation of bulky masses in paediatric Hodgkin's lymphoma (HL) patients enrolled in the Italian AIEOP-LH2004 trial.

PURPOSE: We present the results of an investigation of the role of FDG PET in response evaluation of bulky masses in paediatric patients with Hodgkin's lymphoma (HL) enrolled in the Italian AIEOP-LH2004 trial. METHODS: We analysed data derived from 703 patients (388 male, 315 female; mean age 13 years) with HL and enrolled in 41 different Italian centres from March 2004 to September 2012, all treated with the AIEOP-LH2004 protocol. The cohort comprised 309 patients with a bulky mass, of whom 263 were evaluated with FDG PET at baseline and after four cycles of chemotherapy. Responses were determined according to combined functional and morphological criteria. Patients were followed up for a mean period of 43 months and for each child we calculated time-to-progression (TTP) and relapse rates considering clinical monitoring, and instrumental and histological data as the reference standard. Statistical analyses were performed for FDG PET and morphological responses with respect to TTP. Multivariate analysis was used to define independent predictive factors. RESULTS: Overall, response evaluation revealed 238 PET-negative patients (90.5%) and 25 PET-positive patients (9.5%), with a significant difference in TTP between these groups (mean TTP: 32.67 months for negative scans, 23.8 months for positive scans; p < 0.0001, log-rank test). In the same cohort, computed tomography showed a complete response (CR) in 85 patients (32.3%), progressive disease (PD) in 6 patients (2.3%), and a partial response (PR) in 165 patients (62.7%), with a significant difference in TTP between patients with CR and patients with PD (31.1 months and 7.9 months, respectively; p < 0.001, log-rank test). Similarly, there was a significant difference in relapse rates between PET-positive and PET-negative patients (p = 0000). In patients with PR, there was also a significant difference in TTP between PET-positive and PET-negative patients (24.6 months and 34.9 months, respectively; p < 0.0001). In the multivariate analysis with correction for multiple testing, only the PET result was an independent predictive factor in both the entire cohort of patients and the subgroup showing PR on CT (p < 0.01). CONCLUSION: After four cycles of chemotherapy, FDG PET response assessment in paediatric HL patients with a bulky mass is a good predictor of TTP and disease outcome. Moreover, in patients with a PR on CT, PET was able to differentiate those with a longer TTP. In paediatric HL patients with a bulky mass and in patients with a PR on CT, response on FDG PET was an independent predictive factor.

Long-term results of the AIEOP MH'96 childhood Hodgkin's lymphoma trial and focus on significance of response to chemotherapy and its implication in low risk patients to avoid radiotherapy.

Identify a subset of early-stage HL children (GR1) curable with limited chemotherapy+/-radiotherapy; improve outcome of intermediate (GR2) and high-risk (GR3) patients; establish impact of response to chemotherapy evaluated with conventional imaging (CI). One hundred and sixty GR1-patients received 3ABVD + involved-field (IF) low-dose (LD) (20 Gy) irradiation if mediastinal mass or partial response (PR) after chemotherapy. Eighty-five GR2- and 315 GR3-patients received 4 and 6 COPP/ABV + IFRT, respectively. The 63 GR1 patients spared from radiotherapy had 15-year survival and EFS of 100 and 84.5%, respectively. The GR2 and GR3 15-year FFP were 84.7 and 78.6%, respectively. No different prognosis for patients in CR or PR evaluated during and after chemotherapy was observed. In conclusion, low-risk patients in CR may be successfully treated with radiation-free, low-intensity chemotherapy. Good, but less satisfactory, results were registered in GR2 and GR3. Response evaluated with CI is not a prognostic factor, but permits identification of low-risk patients who can avoid radiotherapy.

Abdomen/pelvis computed tomography in staging of pediatric Hodgkin Lymphoma: is it always necessary?

The purpose of the study was to determine if abdomen/pelvis computed tomography (CT) can be safety omitted in the initial staging of a subgroup of children affected by Hodgkin Lymphoma (HL). Every participating center of A.I.E.O.P (Associazione Italiana di Ematologia ed Oncologia Pediatrica) sent local staging reports of 18F-fluorodeoxyglucose positron emission tomography (PET) and abdominal ultrasound (US) along with digital images of staging abdomen/pelvis CT to the investigation center where the CT scans were evaluated by an experienced pediatric radiologist. The local radiologist who performed the US was unaware of local CT and PET reports (both carried out after US), and the reviewer radiologist examining the CT images was unaware of local US, PET and CT reports. A new abdominal staging of 123 patients performed on the basis of local US report, local PET report, and centralized CT report was then compared to a simpler staging based on local US and PET. No additional lesion was discovered by CT in patients with abdomen/pelvis negativity in both US and PET or isolated spleen positivity in US (or US and PET), and so it seems that in the initial staging, abdomen/pelvis CT can be safety omitted in about 1/2 to 2/3 of children diagnosed with HL.

The prognostic value of biological markers in paediatric Hodgkin lymphoma.

BACKGROUND: Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. PATIENTS AND METHODS: By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. RESULTS: On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. CONCLUSION: Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

Plasma cell-free DNA in paediatric lymphomas.

BACKGROUND: Extracellular circulating DNA (cfDNA) can be found in small amounts in plasma of healthy individuals. Increased levels of cfDNA have been reported in patients with cancer of breast, cervix, colon, liver and it was shown that cfDNA can originate from both tumour and non-tumour cells. OBJECTIVES: Levels of cfDNA of a large series of children with lymphoma were evaluated and analyzed in relation with clinical characteristics. METHODS: plasma cfDNA levels obtained at diagnosis in 201 paediatric lymphoma patients [43 Hodgkin lymphomas (HL), 45 anaplastic large cell lymphomas (ALCL), 88 Burkitt lymphomas (BL), 17 lymphoblastic (LBL), 8 diffuse large B cell lymphoma (DLBCL)] and 15 healthy individuals were determined using a quantitative PCR assay for POLR2 gene and, in addition, for NPM-ALK fusion gene in ALCL patients. Wilcoxon rank sum test was used to compare plasma levels among different patient subgroups and controls and to analyze relationship between levels of cfDNA and clinical characteristics. RESULTS: Levels of cfDNA in lymphoma patients were significantly higher compared with controls (p<0.0001). CfDNA was associated with median age (p=0.01) in HL, and with stage in ALCL (p=0.01). In HL patients high cfDNA levels were correlated with poor prognosis (p=0.03). In ALCL we found that most of the cfDNA (77%) was non-tumor DNA. CONCLUSION: level of plasma cfDNA might constitute an important non-invasive tool at diagnosis in lymphoma patients' management; in particular in patients with HL, cfDNA seems to be a promising prognostic biomarker.

Postchemotherapy PET evaluation correlates with patient outcome in paediatric Hodgkin's disease.

AIM: To evaluate the role of postchemotherapy FDG PET and compare it with other predictive factors in paediatric Hodgkin's disease (HD). MATERIALS AND METHODS: In this retrospective study, 98 paediatric patients with HD (enrolled in eight Italian centres) were analysed. Their mean age was 13.8 years (range 5-19 years). A PET scan was performed at the end of chemotherapy and reported as positive or negative on the basis of visual and/or semiquantitative analysis. True outcome was defined as remission or disease on the basis of combined criteria (clinical, instrumental and/or histological) with a mean follow-up period of 25 months. Statistical analyses were performed for the postchemotherapy PET results and other potential predictive factors (age cut-off, stage, presence of bulky masses and therapeutic group) with respect to patient outcome and progression-free survival (PFS). RESULTS: Overall the patients had a mean PFS of 23.5 months (range 4-46 months): 87 achieved remission (88.8%) and 11 showed disease. Of the 98 patients, 17 were positive on postchemotherapy PET . Seven patients (41%) showed disease during follow-up, and relapse occurred in only four out of the 81 patients who were negative on PET (p = 0.0001). Kaplan-Meier analysis demonstrated significant correlations between PFS and the postchemotherapy PET result (p = 0.0001) and a cut-off age at diagnosis of 13.3 years (p = 0.0337), whereas disease stage (p = 0.7404), therapeutic group (p = 0.5240) and presence of bulky masses (p = 0.2208) were not significantly correlated with PFS. Multivariate analysis confirmed a statistically significant correlation with PFS only for the postchemotherapy PET findings (p = 0.0009). CONCLUSION: In paediatric HD, age at diagnosis and postchemotherapy PET results are the main predictors of patient outcome and PFS, with FDG PET being the only independent predictive factor for PFS.

Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis.

Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-gamma (IFNgamma) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the 'anti-inflammatory profile' determined by the intermediate producer genotype IFNgamma +874A/T (P = 0.029) and the high-producer genotypes IL-4 -590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.