Acute childhood idiopathic thrombocytopenic purpura: AIEOP consensus guidelines for diagnosis and treatment. Associazione Italiana di Ematologia e Oncologia Pediatrica.

BACKGROUND AND OBJECTIVE: A recent evaluation carried out by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) about practice management of acute childhood idiopathic thrombocytopenic purpura (ITP) revealed a remarkable difference of behaviors among the different AIEOP centers. A need for common practice guidelines for this frequent illness arose from this observation. Our aim was to make the diagnosis and treatment of childhood ITP uniform. In the future we will evaluate the influence of these guidelines on practice behaviors. DATA SOURCES AND METHODS: Our main reference was the 1996 document produced by the American Society of Hematology (ASH). Their recommendations were updated with information from literature searched for in the MEDLINE database (June 1996-October 1998); search terms included: thrombocytopenia, ITP, diagnosis, therapy, children. The computerized search retrieved 83 articles. DATA EXTRACTION: the scientific validity of the literature was evaluated by a panel of members using published guidelines. The strength of the evidence was assessed using level of evidence criteria. Only data from level I and level II studies were taken in account. Only one study out of the 83 retrieved articles met these selection criteria and it was considered in addition to the 11 out of 581 articles selected in the ASH ITP guidelines. This preliminary work pointed out each issue about ITP not addressed by clinical studies and all participants in a Consensus Conference expressed their opinion about these issues. RESULTS: Diagnosis is essentially based on history, physical examination, a complete blood count and an examination of the peripheral blood smear. Treatment is recommended taking into account the clinical picture and number of platelets. The main difference between these guidelines and those from ASH are: AIEOP guidelines rely on the opinion of the members of the consensus conference, ASH ones on a panel of experts; therapeutic options include only products available in Italy; the indications to treatment rely more on clinical picture than on platelet number. INTERPRETATION AND CONCLUSIONS: These are explicitly developed, evidence-based practice guidelines to assist Italian pediatricians in making decisions about diagnosis and appropriate health care for patients with acute childhood ITP.

Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associzione Italiana Emato-Oncologia Pediatrica.

The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.

Autologous bone marrow transplantation for extramedullary relapse in childhood leukemia. The AIEOP Group and the FONOP. Italian Association of Pediatric Hemato/Oncology.

The role of autologous bone marrow transplantation (ABMT) in childhood ALL after an isolated extramedullary (IE) relapse is controversial. Between December 1984 and November 1995, 52 children underwent ABMT because of an IE relapse. The data were stored in the AIEOP-BMT Registry. Thirty four children were transplanted in 2nd CR; eighteen > 2nd CR. The median duration of 1st CR was 24 (range 3-69) and 18 (range 3-59) months, respectively. The median interval from last CR to ABMT was 6 (range 1-28) and 3 (range 1-81) months, respectively. The 5 year EFS for patients transplanted in 2nd CR was 67.7%, while the 3 year EFS for patients in > 2nd CR was 16.7%. In conclusion, ABMT was an effective treatment in early IE relapse only if performed in 2nd CR.

Myeloablative therapy and bone marrow rescue in advanced neuroblastoma. Report from the Italian Bone Marrow Transplant Registry. Italian Association of Pediatric Hematology-Oncology, BMT Group.

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

[Early and late anthracycline-induced cardiotoxicity in childhood: non-invasive evaluation of contractility in 116 patients]. / Cardiotossicità precoce e tardiva da antracicline in età pediatrica: valutazione non invasiva dello stato contrattile in 116 pazienti.

In order to evaluate the incidence and the characteristics of anthracycline-induced cardiotoxicity we studied 116 children treated with anthracyclines with echocardiography, by using load dependent and independent indexes of contractility (respectively: 1-shortening fraction of the left ventricle (D%), velocity of circumpherential shortening (VCF), telesystolic wall stress (Ses) and 2-the regression curves between D% and Ses VCF and Ses). Eighty-six were off therapy, and 30 were evaluated during induction and reinduction. Off therapy patients had a D% lower than that of controls (37.5 +/- 5.7 vs 41.3 +/- 5.0, p<0.001), but it was clearly depressed only in 8% of them. VCF was also lower than in controls (1.7% +/- 0.5 vs 2.0 +/- 0.6, p<0.001), but in no patient it was clearly depressed. Ses was higher than in controls (63.8 +/- 20.6 vs 44.5 +/- 10.5, p<0.001) and elevated in 47% of them; it was positively related to the dose of anthracyclines administered (r = 0.25, p<0.05). The regression curves between D% and Ses and VCF and Ses showed a depressed contractility in off therapy patients. Dilated cardiomyopathy was present only in 1 of them (1.16%) and regional hypokinesia in 3 (3.5%). Children studied during the acute phase had normal D%, VCF, Ses and regional wall motion during the all period of study. These results indicate that 1) anthracycline-induced cardiotoxicity in childhood is mostly a late event, 2) a long term follow-up of these patients is necessary, 3) the use of Ses and of load independent indexes, more than that of D% and VCF, is mandatory to detect the cardiac damage.

Second malignant tumors after elective end of therapy for a first cancer in childhood: a multicenter study in Italy.

To evaluate the incidence of second malignant tumors in a cohort of subjects previously treated for childhood cancer, we analyzed data from the Off-Therapy Registry (OTR) of the Italian Association of Pediatric Hematology/Oncology, which collects information on children treated for Hodgkin's disease, non-Hodgkin's lymphoma, Wilms' tumor, acute lymphoblastic leukemia (ALL) and acute non-lymphatic leukemia and who had been removed from treatment in the absence of clinical signs of disease, i.e. the off-therapy stage. Second malignant tumors (SMT), diagnosed before December 31, 1988, were identified through a special enquiry to the 36 institutions cooperating in the registry. Observed cases were compared to expected numbers estimated from age- and sex-specific incidence rates derived from the Cancer Registry of the Province of Varese. In a total of 3,310 study subjects, 27 SMTs have been registered. The Cumulative Risk (CR) of SMT was 2.9% 15 years after the end of treatment and the Standard Incidence Ratio (SIR) was 10.8. The ALL sub-cohort had the highest risk of SMT (SIR 13.6) and 9 cases of CNS tumor occurred in this group (SIR 58.9). All 9 had received prophylactic cranial radiotherapy (CRT) and 5 had been treated on one protocol, characterized by low-dose intrathecal methotrexate (IT MTX) given monthly for 2 years after CRT. The Off-Therapy Registry has unique criteria for inclusion; direct comparisons with similar studies are therefore somewhat problematic. However, our data suggest that the risk of SMT in childhood ALL cancer survivors may be greater than previously reported, and that CNS tumors are the most common SMT in this group. The administration schedule of IT MTX may be an important risk factor.

[Use of cyclosporin and verapamil in association with chemotherapy in the treatment of pediatric patients with advanced-stage neoplasms. A pilot study]. / Impiego della ciclosporina e del verapamile in associazione a chemioterapici nel trattamento di pazienti pediatrici con neoplasia in fase avanzata. Studio pilota.

Multidrug resistance represents one of the most important factors that may lead to a therapeutic failure in some patients affected by malignancies. One of the best known mechanisms is linked to the genic amplification or the overproduction of a membrane glycoprotein, GP170, that is the product of the gene MDR1. The existence of drugs (calcium blockers, cyclosporine, tamoxifen, reserpine, quinidine) able to bind themselves to gp170 and to paralyze its activity in vitro is well known. We studied 20 pediatric patients (median age 9 years) affected by acute lymphoblastic leukemia (ALL), osteosarcoma, neuroblastoma and medulloblastoma, in advanced stage of disease. We employed in all cases the association of cytostatics with verapamil (50-70 mg/m2 i.v.) and cyclosporine (5-8 mg/kg i.v.) with different infusion schedules. In leukemias we administered vincristine (1.5 mg/m2), and daunomycin (40 mg/m2), in solid tumors VP16 (150 mg/m2) and adriamycin (60 mg/m2). Seventy-two therapeutic courses were performed: 39 in ALL, 16 in osteosarcoma, 16 in neuroblastoma and 1 in medulloblastoma. On the whole 5 complete remissions were achieved in ALL patients and 1 in an osteosarcoma patient. We did not observe a significant myelosuppression during treatment, therefore few infectious complications occurred; furthermore electrocardiographic changes have been mild and promptly resolved after temporary discontinuation of verapamil infusion. Our data suggest a synergy of verapamil and cyclosporine in the inhibition of multidrug resistance induced by gp170, without the occurrence of heavy toxicity. The results obtained in ALL patients are encouraging., especially in view of a possible subsequent bone marrow transplantation, while in solid tumors they are not as satisfying.

Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Italian Cooperative Group for Neuroblastoma.

PURPOSE: To define factors that influence outcome in children with localized but unresectable neuroblastoma by retrospective investigation of response to therapy and outcome in 21 Italian institutions. PATIENTS AND METHODS: Of 145 assessable children diagnosed between 1979 and 1990, 77 were treated between 1979 and 1984 with three consecutive standard-dose (SD) protocols, and 68 between 1985 and 1990 with a high-dose (HD) protocol. All protocols included chemotherapy, followed by resection of primary tumor if feasible. If at least partial resection was achieved, consolidation therapy followed, except that from 1985 onward, patients considered disease-free following surgery received no further treatment. RESULTS: Ninety-four of 145 patients (65%) achieved a complete response (CR) or partial response (PR) with chemotherapy and 75 (52%) subsequently underwent complete resection of the primary tumor. Eighty-one patients are alive (73 without disease, eight with disease), 63 have died, and one is lost to follow-up. The 5-year overall survival (OS) rate is 55% and progression-free survival (PFS) rate 50%. Both OS and PFS correlated with response to chemotherapy, removal of primary tumor, HD therapy, and serum lactate dehydrogenase (LDH) levels. Infants (< 1 year), independent of primary tumor site, and children aged 1 to 15 years with a nonabdominal primary tumor, did better compared with children aged 1 to 15 years with an abdominal primary tumor (PFS, 72% and 64% v 30%; P < .001 and < .01, respectively). Outcome of this last group improved with the HD protocol (PFS, 40% v 23%; P = .01). CONCLUSION: In children with unresectable neuroblastoma, risk categories can be defined by age and primary tumor site. HD chemotherapy should be investigated for the poor-risk category age 1 to 15 years with an abdominal primary tumor.

Outcome after cessation of therapy in childhood acute lymphoblastic leukaemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP).

A total of 2192 children with acute lymphoblastic leukaemia who had reached cessation of therapy in complete remission were followed for a median time of 52 months after treatment suspension. Of the 485 relapses observed, 62.3% occurred in the first year off therapy and 68.9% involved the bone marrow. Eight relapses were reported more than 5 years (62-143 months) after treatment withdrawal. Males fared worse than females consistently, experiencing 1.5 times more relapses (P < 0.0001). Thirteen patients died in continuous complete remission, 5 because of non-neoplastic central nervous system complications. There were 11 second solid malignancies, 8 of them in the central nervous system; 9 subjects presented an haematopoietic malignancy after ALL. The projected event-free survival at 8 years is 73%. Twenty-two of the 171 young adults (age > 20 years) were married and 16 have had 21 healthy children. Twenty-four per cent of patients experienced an unfavourable event. Relapses accounted for 93% of failures. Central nervous system late effects and second malignancies were the major causes of non-leukaemic morbidity and mortality.

[Cellular and molecular therapy in severe combined immunodeficiencies]. / Terapia cellulare e molecolare delle immunodeficienze combinate gravi.

Severe combined immunodeficiencies are usually fatal diseases unless affected children are admitted to protective isolation unit or unless the underlying immunological defect is treated by transplanting bone marrow from an healthy donor. The patients present, with early onset, life-threatening infections from fungal, viral or bacterial agents. Since only a minority of patients has an HLA-identical donor, recently other strategies have been devised including bone marrow transplantation from donors other than HLA-identical within the family or from HLA-non identical family members or from HLA-matched unrelated donors included in the International Bone Marrow Volunteers' Registry. In these cases, in order to realize this approach the "purging" of T-cells of the HLA-non identical donor bone marrow is necessary. Overall survival after HLA-identical BMT is 76%, when all BMT of the European multicenter analysis are considered, while in BMT from non-identical donors is 56%. Recently particular cases of SCID caused by enzyme deficiency, such as adenosine-deaminase (ADA), have been treated by molecular therapy with administration of polyethylene glycol (PEG) conjugated ADA: PEG protects from degradation and inhibits clearance of the enzyme. This approach, already realized in 15 children, allows reconstitution of cellular and humoral immunity, as demonstrated by one case treated by our group.

Treatment of advanced neuroblastoma with I-131 meta-iodobenzylguanidine.

From February 1986 to December 1988, 31 children with advanced pretreated neuroblastoma were treated with 131-I meta-Iodobenzylguanidine (131-MIBG). Thirteen children had been resistant to first-line therapy, three had suffered a local relapse, and fourteen had suffered a disseminated relapse without over bone marrow infiltration. One child was treated initially because of resistance to first-line therapy, and subsequently for a local relapse. A total of 72 courses of 131-MIBG was administered, with doses ranging from 2.8 to 6.0 GBq (median, 3.7 GBq). One child received five courses, two four courses, 13 three courses, four two courses, and 12 one course of 131-MIBG. The most common toxic effect was thrombocytopenia, with a platelet level of less than 50,000/cmm occurring after 19 of 60 evaluable courses. A leukocyte count less than 1000/cmm was seen only once. There were six major responses (two complete) lasting 4 to 9 months, and two minor responses lasting longer than 38 and 44 months. Responses were seen more commonly in children whose only lesion was a residual primary tumor and in children who had not been pretreated who experienced disseminated relapse. Further studies of the role of 131-I meta-Iodobenzylguanidine in treatment of neuroblastoma are needed.

Prevention of perinatally transmitted hepatitis B virus infection by hepatitis B immunoglobulin immunoprophylaxis: an account of 201 newborn babies of hepatitis Bs antigen carrier mothers.

Of 5,327 pregnant women who were screened between July 1981 and July 1983, 5.2% were found to be hepatitis Bs antigen (HBsAg) carriers. This high percentage of carriers accentuates the importance of vertical transmission of hepatitis B virus in our area. In view of this we sought to verify the effectiveness of hyperimmune immunoglobulins in the prevention of infection. We studied 201 babies born to HBsAg-positive mothers. These babies had regular checkups until 12 months of age. One hundred forty-nine received prophylactic hyperimmune globulin (two to seven doses according to risk ranking), while 52 did not. A higher percentage of infection was found in the babies who had no prophylaxis (25%) than in the babies who had prophylaxis (7.4%). Furthermore, hepatitis appeared earlier (from the 2nd to the 6th month) in the babies who had no prophylaxis than in the babies who had prophylaxis (from the 9th to the 12th month). No infection was observed during prophylaxis or up to 6 months.