Roberta Burnelli

Phase I study of high‐dose thiotepa with busulfan, etoposide, and autologous stem cell support in children with disseminated solid tumors

BACKGROUND The aim of this phase I study was to define the maximum tolerated dose (MTD) of thiotepa (TT), administered with busulfan (BU) 480 mg/m(2) and etoposide 2,400 mg/m(2), followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (APBSCT) support in children with solid tumors either disseminated at diagnosis or after relapse. PROCEDURE Nineteen patients, between 2 and 16 years of age, received a high-dose chemotherapy regimen including escalating doses of TT starting from 150 mg/m(2). Subsequent dose escalation was determined by a modified Fibonacci scheme. Whenever one patient at one dosage level showed a grade III or grade IV reversible toxicity, additional patients were admitted (one by one) up to a maximum number of 6. Upon observing grade III or IV reversible toxicity in two or more systems, in 3 of the 6 patients, no further escalation was performed, and the corresponding dosage was taken as the MTD. WHO criteria were adopted to assess grade of toxicity. RESULTS All patients had hematological recovery; and neutrophils and platelet engraftment were observed after median times of 12 and 29 days from stem cell infusion, respectively. The MTD of TT was determined to be 750 mg/ m(2). At this level, 3 of 6 patients experienced grade III mucositis and/or grade III gastrointestinal toxicity. No patient died of treatment-related toxicity. CONCLUSIONS A dose of 750 mg/m(2) TT is the MTD when it is associated with BU 480 mg/m(2) and etoposide 2, 400 mg/m(2). This ablative regimen represents a feasible and tolerable combination for high-dose chemotherapy followed by hematopoietic stem cell rescue (HSCR). Phase II studies in children with poor-prognosis solid tumors are required to evaluate the effectiveness of this treatment.

Long‐term results of high‐dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long‐term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long‐term results of high‐dose IM (340 mg/m2/d) in CML patients in chronic phase (CP‐CML) aged <18 years at diagnosis. A total of 47 CP‐CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91·5% of the evaluable patients at a median time of 6 months. BCR‐ABL1 International Scale ≤ 0·1% (major molecular response; MMR) and ≤0·01% (molecular response; MR) at 12 months were 66·6% and 33%, respectively. During follow‐up, MMR and MR were achieved in 78·6% and 61% of children, respectively. IM was safely discontinued in 3 long‐term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression‐free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow‐up of 52 months (range 3–146), all patients are alive. High‐dose IM is a long‐term effective therapy in children and adolescents with CP‐CML.

Primary Renal Soft Tissue Sarcoma in Children

OBJECTIVE To describe clinical and treatment characteristics of renal soft tissue sarcomas in children, we analyzed a series of patients enrolled in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee (STSC). METHODS From 1979 to 2011, 2138 patients with soft tissue sarcomas were registered in different STSC protocols, and 12 had a renal sarcoma: 7 primitive peripheral neuroectodermal tumors, 2 undifferentiated sarcomas, 1 rhabdomyosarcoma, 1 desmoplastic small round cell tumor, and 1 kaposiform hemangioendothelioma. Treatment included conservative surgery, chemotherapy according to the guidelines of the protocols, and radiotherapy for high-risk patients. RESULTS Nephrectomy was performed in 11 children resulting in a complete tumor resection in 7. In 4 patients, macroscopical (1) or microscopic (3) tumor residuals remained postoperatively. Tumorectomy was performed in patients with congenital renal agenesis. All patients received chemotherapy. Seven patients also received postoperative radiotherapy. Overall, 9 patients are alive in first complete remission with a median follow-up of 6.1 years (range, 1.3-21.1 years). Two of the 7 patients with primitive peripheral neuroectodermal tumors (pPNETs) died after an early relapse: 1 had metastatic disease at diagnosis and the other was initially misdiagnosed with Wilms tumor (WT). One child with desmoplastic small round cell tumor (DSRCT) is alive with disease. Two patients developed signs of ifosfamide-related nephrotoxicity. CONCLUSION In our analysis, pPNET is the most common type of renal soft tissue sarcoma (STS). Prognosis seems satisfactory with the adoption of an aggressive multidisciplinary approach, especially when complete tumor resection is possible. The replacement of ifosfamide with cyclophosphamide could be considered after nephrectomy.

Childhood Non-Hodgkin's Lymphoma and “Leukemia-Lymphoma Syndrome”: Long-Term Results with the Modified LSA2-L2 Protocol

From June 1976 to December 1984, 48 previously untreated children with non-Hodgkins lymphoma (NHL) were treated according to the LSA2-L2 protocol, modified by inclusion of cranial irradiation for patients in stage III and stage IV disease. According to the staging system proposed by Wollner, 4 patients were in stage I, 8 in stage II, 11 in stage III, 8 in stage IVA (less than or equal to 25% blasts in the bone marrow), 15 in stage IVB (greater than 25% blasts in the bone marrow), and 2 in stage IV central nervous system disease. The complete remission rate was 95.8%. The relapse-free survival (RFS) rate of 46 complete responders was 76% after a median observation time of 47+ months. Only 1 of 35 high-risk responder patients developed CNS relapse after prophylactic treatment. Clinical stages were related to the RFS: 100% in stage I-II vs. 69% in stage III-IV. All 8 patients in stage IV were alive without evidence of disease with a median observation time of 59+ months. Fifteen patients in stage IVB who had leukemia-lymphoma syndrome attained 59% RFS with a median observation time of 39+ months. After a median observation time of 38+ months, 29 of 37 patients are off therapy. The results emphasize the value of both the histologic and immunologic features and the stage of disease in predicting the outcome of NHL in children. The LSA2-L2 regimen appears to be a very effective protocol for children with lymphoblastic lymphoma, although it may be less efficacious for patients with large bone marrow involvement.

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.

Neurological presentation of Hodgkin lymphoma in the Italian Association of Pediatric Hematology and Oncology LH-2004 protocol

Neurological symptoms can represent the first clinical manifestation of central nervous system (CNS) involvement in Hodgkin lymphoma (HL). Because of its rarity, it is often misunderstood for other pathological processes. We report two cases of pediatric CNS HL, presenting with neurological symptoms at diagnosis. We have also reviewed the literature and few cases are reported, only 19 of them concerning children. In both primary and metastatic CNS HL, all patients complained of neurological symptoms at presentation. Despite it being uncommon, physicians should regard the possibility of CNS localization in all children affected by HL presenting with neurological signs and/or symptoms.

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

Abstract 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.

Early response does not predict outcome in children and adolescents with chronic myeloid leukaemia treated with high‐dose imatinib

The achievement of early response has been shown to predict a significantly better outcome in adults with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with either imatinib (IM) or second-generation tyrosine kinase inhibitors (TKIs) (Branford et al, 2012; Hanfstein et al, 2012; Marin et al, 2012; Jain et al, 2013; Jabbour et al, 2014). Recently, early molecular response (EMR) was also reported to predict a better outcome in 40 CP-CML children treated with IM at a standard dose (260 mg/m/day) (Millot et al, 2014). We hereby analysed the predictive value of the BCR-ABL1 transcript levels at 3 months in terms of responses and outcome in a cohort of children and adolescents with CP-CML treated with high-dose IM at 11 Italian centres. This study (CMLPetit-01) was approved by the Institutional Ethics Committees. From March 2001 to March 2014, 53 patients younger than 18 years of age with a newly diagnosed CML in CP were treated with IM at a dose of 340 mg/m/day. Cytogenetics and quantitative reverse transcription polymerase chain reaction (qPCR) analysis were planned on bone marrow (BM) every 3 months and qPCR on peripheral blood (PB) monthly, as previously described (Giona et al, 2015). Haematological and cytogenetic response (CyR) criteria were defined according to the European LeukaemiaNet recommendations (Baccarani et al, 2009). Major molecular response (MMR) was defined as ≤0 1% BCR-ABL1 according to the International Scale (IS), while molecular response (MR) was considered as ≤0 01% BCR-ABL1 IS. Complete molecular response (CMR) was used to indicate levels of disease ≤0 0032% BCR-ABL1 IS or undetectable. Transcript levels ≤10% and ≤1% BCR-ABL1 IS at 3 months after starting IM were defined as EMR and deep EMR, respectively. Forty-four CP-CML patients (27 males, 17 females; median age: 11 years, range 3 to 15) who had available BCR-ABL1 levels at 3 months and had been followed for at least 12 months were included in this analysis. Overall, 92 5%, 85%, 56% and 39% of patients achieved a complete CyR (CCyR), MMR, MR and CMR after a median time of 6 2 (range 3 5–8 6), 13 4 (range 9 4–19 7), 14 9 (range 10 1– 24 1) and 15 (range 10 1–24 8) months, respectively. Three months after the start of IM, BCR-ABL1 transcript levels >10% IS were detected in 9/44 (20 5%) patients, whereas 18/ 44 (41%) and 17/44 (38 5%) patients had BCR-ABL1 IS of

Classical pediatric Hodgkin lymphoma in very young patients: the Italian experience

Abstract Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.

Italian Multicenter Study on Accuracy of 18F-FDG PET/CT in Assessing Bone Marrow Involvement in Pediatric Hodgkin Lymphoma

&NA; The present study investigated the utility of fluorine‐18 (18F) fluoro‐2‐deoxy‐d‐glucose (FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in newly diagnosed pediatric Hodgkin lymphoma (HL). 18F‐FDG PET/CT shows high diagnostic performance in evaluating BMI in pediatric HL. BMB should be ideally reserved for patients with doubtful 18F‐FDG PET/CT BMI findings. Introduction: The present study investigated the utility of fluorine‐18 (18F) fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in newly diagnosed pediatric Hodgkin lymphoma (HL). Patients and Methods: A total of 224 pediatric patients with HL underwent 18F‐FDG PET/CT at staging. BMB or follow‐up imaging was used as the standard of reference for the evaluation of BMI. Results: 18F‐FDG PET/CT was negative for BMI in 193 cases. Of the 193 patients, the findings for 16 were originally reported as doubtful and later interpreted as negative for BMI, with negative findings on follow‐up imaging and BMB. At BMB, 1 of the 16 patients (6.25%) had BMI. Of the 193 patients, 192 (99.48%) had negative BMB findings. Thus, the 18F‐FDG PET/CT findings were truly negative for 192 patients and falsely negative for 1 patient for BMI. Conclusion: 18F‐FDG PET/CT showed high diagnostic performance in the evaluation of BMI in pediatric HL. Thus, BMB should be ideally reserved for patients presenting with doubtful 18F‐FDG PET/CT findings for BMI.