High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation.

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

SCT for Wilms' tumour.

Thanks to advances in treatment, approximately 85-90% of patients suffering from Wilms' tumour are now cured. However, success rate after relapse is significantly lower, ranging from 25 to 45%. Several different re-induction approaches, more or less intensive according to first-line therapy and characteristics of relapse, have been proposed. A number of adverse prognostic factors related to a bad outcome after relapse have been identified and are used as inclusion criteria for entering in a programme including high-dose chemotherapy (HCT). HCT followed by autologous haematopoietic stem cell rescue has been used in small numbers of patients worldwide and promising results have been reported. Information from the European Group for Blood and Marrow Transplantation Database regarding more than 300 transplants have been gathered. In addition, literature data on rescue therapy and HCT will be discussed, such as recent treatment proposals currently under discussion within European and US cooperative groups.

Myeloablative therapy and unpurged autologous bone marrow transplantation for poor-prognosis neuroblastoma: report of 34 cases.

From October 1984 to November 1987, 34 patients aged from 1 year 1 month to 7 years 7 months with resistant or relapsed neuroblastoma (NB) (group 1, 10 patients), unselected disseminated NB (group 2, 14 patients), or selected disseminated NB (group 3, 10 patients) received myeloablative therapy (MAT) followed by unpurged autologous bone marrow transplantation (ABMT) at the end of an intensive protocol, which included high-dose chemotherapy and surgery to the primary tumor. Median time from diagnosis to MAT and ABMT was 6 months (5 months from last relapse to MAT and ABMT in the relapsed patients). The MAT regimen included vincristine, fractionated total body irradiation (TBI), and melphalan. Seventeen patients were grafted in complete remission (CR), five in very good partial remission (VGPR), 10 in partial remission (PR), and two in progressive disease (PD). The acute toxic death rate was 2.9%. The overall progression-free survival was 29%. The median progression-free survival was 20 months for the 17 patients grafted in CR, 6 months for the five patients grafted in VGPR, and 12 months for the 10 patients grafted in PR.

Evolving role of myeloablative chemotherapy in the treatment of childhood brain tumours.

Primary brain tumours, a heterogeneous group of cancer that constitute the second most common cancer in childhood, were historically treated with neurosurgical resection and radiation therapy. Chemotherapy has proven to be beneficial for some histological types, which has since led to exploration of the role of high-dose chemotherapy and haematopoietic stem cell rescue. Patients with high-grade glial tumours, primitive neuroectodermal tumours and high-risk medulloblastoma usually fare poorly. The indicators of bad prognosis are metastatic status, extent of resection and age. Children <3 years at diagnosis carry worse prognosis. Rare cancers such as ependymoblastoma, atypical teratoid rhabdoid tumour and choroid plexus carcinoma have a dismal prognosis regardless of the above-mentioned indicators. The use of myeloablative therapy (MAT) has been investigated to improve the rate of long-term DFS, as well as to reduce and delay in the youngest children the use of the craniospinal irradiation associated with unacceptable late effects. We will overview the literature regarding patients with 'good and uncertain indications' to MAT. Ependymoma and brain stem tumours, for which the available data discourage the use of MAT, are excluded. Finally, we will summarize a single Institution experience (Giannina Gaslini Children's Hospital, Genoa) with MAT in the period 1997-2003.

Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients.

Bone marrow transplant (BMT) relies on the engraftment of donor hemopoietic precursors in the host marrow space. Colony forming units-fibroblasts (CFU-f), the precursor compartment for the osteogenic lineage, are essential to hemopoietic stem cell survival, proliferation and differentiation. We have studied CFU-f in donors (aged 5 months to 62 years) and in patients who had received allogeneic BMT (aged 2 months to 63 years). In donor marrows we found an inverse correlation between CFU-f frequency and age. In BMT recipients CFU-f frequencies were reduced by 60%-90% (p < 0.05) and the numbers did not recover up to 12 years after transplant. Stromal reconstitution to normal levels was found only in patients < 5 years old. In all patients studied CFU-f post-BMT were of host origin. Patients with low CFU-f levels displayed also a decreased bone mineral density (p < 0.05) and significantly reduced levels of long-term culture-initiating cells (LTC-IC) (p < 0.05). Our study demonstrates that the marrow stromal microenvironment is seriously and irreversibly damaged after BMT. Donor cells do not contribute to reconstitute the marrow microenvironment, whose residual CFU-fs remain of host origin.

Severe neurologic complications after hematopoietic stem cell transplantation in children.

OBJECTIVE: To describe and evaluate the incidence and risk factors of severe neurologic events (SNE) in pediatric recipients of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) for hematologic or nonhematologic diseases. METHODS: Retrospective analysis of 272 consecutive children admitted to the G. Gaslini Children's Research Institute and given HSCT (70 from unrelated donors, 115 from related donors, and 87 autologous) between June 1985 and January 2001. RESULTS: Thirty-seven children (13.6%) developed SNE after a median of 90 days (range, 5 days to 8.8 years) after HSCT. Cyclosporine A (CSA) neurotoxicity was the most frequent SNE (n = 21), followed by irradiation or chemotherapy injury (n = 7), CNS infections (n = 7), cerebrovascular events (n = 3), and immune-mediated etiology SNE (n = 2). Eleven patients (30%) died because of the neurologic complications. Type of HSCT, treatment with total body irradiation (TBI), acute graft-vs-host disease (GvHD), GvHD >grade 2, and treatment with CSA were associated with a significant increased risk of SNE. CONCLUSIONS: Severe neurologic complications are frequent (14%) among children receiving HSCT, causing 8.5% of deaths after transplant. Transplant from allogeneic donor, especially if unrelated, the development of severe acute GvHD grade >2, and the use of TBI in the preparative regimen are the main risk factors for such complications.

Survival after cytomegalovirus pneumonia in two children receiving autologous peripheral blood progenitor cell transplantation (PBPCT).

Cytomegalovirus (CMV) pneumonia is a very rare but often fatal complication of autologous bone marrow or peripheral blood progenitor cell transplantation. Diagnosis is usually made by means of CMV antigenemia which is strongly predictive of CMV disease. We describe two cases of PBPC transplantation who survived after CMV pneumonia which was diagnosed only by bronchoalveolar lavage in the absence of CMV-antigenemia.

Late graft failure 8 years after first bone marrow transplantation for severe acquired aplastic anemia.

A 14-year-old patient with acquired very severe aplastic anemia (VSAA) underwent bone marrow transplantation (BMT) from his HLA-identical brother. Preparative therapy was cyclophosphamide (CY) 200 mg/kg over 4 days. GVHD prophylaxis was with cyclosporin A (CsA) for a year. After an 8 year follow-up during which the patient was well with normal blood counts, graft failure occurred. At this time marrow chimerism studies demonstrated that 85% of hemopoiesis was of recipient origin. The patient was re-engrafted from the same donor after conditioning with CY 200 mg/kg over 4 days plus rabbit antithymocyte globulin (ATG) 3.5 mg/kg/day for 3 days. After 140 days follow-up he has a normal blood count. The possible causes of the graft failure are discussed. This case demonstrates that, although rarely, very late graft failure may occur after BMT for AA and highlights the need for long-term monitoring even in apparently successfully transplanted patients.

Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry.

The European BMT Solid Tumour Registry (EBMT-STR) received reports from 21 European transplant centers on 63 patients (50 Ewing's sarcomas and 13 peripheral neuroectodermal tumours) in first (n = 32) or second CR (n = 31) consolidated with megatherapy and BM and/or PSC rescue between December 1982 and November 1992. There were 31 males and 32 females with a median age of 12 years (range 1-30 years) at megatherapy. The median follow-up time since megatherapy is 4 years (range 1 month to 10 years), Thirty-two patients with metastatic disease at diagnosis (22 had metastases to the bone and/or bone marrow) and consolidated in CR1 reached an actuarial event-free survival (EFS) of 21% at 5 years. Thirty one patients in CR2 achieved an actuarial EFS of 32% at 5 years. Favourable outcome was limited to relapse patients with localised disease at initial diagnosis. Distant relapse had a more favourable prognosis than local failure. Analysis of the different megatherapy strategies could not identify a significantly superior approach, nor is there convincing evidence in favour of double graft procedures. From the above results it appears that consolidation treatment by megatherapy contributes to improved EFS rates in high-risk patients compared with historical experience. Major questions for the future to be addressed prior to randomised studies include agreement on the definition of high-risk patients and the most efficient megatherapy procedure.

Mesial temporal sclerosis--a late complication in four allogeneic pediatric recipients with persistent seizures after an acute episode of cyclosporine-A neurotoxicity.

Mesial temporal sclerosis (MTS) is a common finding in patients with intractable temporal lobe epilepsy (TLE). In this report, we retrospectively reviewed the neuroimaging results of four children who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and who developed recurrent, partial, intractable seizures following a first event caused by cyclosporine-A (CSA) neurotoxicity. Neuroradiologic findings of MTS were demonstrated in all these patients. We suggest that MTS may be a consequence of CSA neurotoxicity, which induces repeated seizures, associated with other predisposing conditions, as well as being a consequence of the underlying disease and its treatment, and of severe graft-versus-host disease (GvHD).

Bone marrow transplantation in childhood: a report from the AIEOP-BMT group registry.

A multicenter cooperative group has been activated in Italy in 1986, with the aim of focusing on the following issues: to standardize perspectively the approach to bone marrow transplantation (BMT) in pediatric centers granting the recommendations of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP); to study effects and toxicity of preparative regimens to BMT; to evaluate the special features of BMT in children, such as clinical management, care and late effects, as peculiar issues of a pediatric setting. Indeed, one of the major aims of the group is to attempt to address in the most appropriate ways, such as in children only and at a nation-wide level, the most crucial questions about the real role of BMT, taking advantage from the fact that most of the children with cancer undergoing BMT in Italy have been treated homogeneously before transplant, i.e. according to AIEOP protocols (70%). Accordingly, specific information were recorded by means of problem oriented forms, aimed to generate a full registry. The registry has been collecting the experiences of 10 pediatric hematology and oncology centers where children eligible for BMT were registered and/or where BMT was performed. This paper was meant both to summarize the 4 years activity of the registry and to analyze what we have learnt so far, as well as what may be suggested to design our future strategies by presently available although retrospective data. It is concluded that the pediatric BMT registry we set up appears useful and of growing interest and potential relevance.

ABMT for children AML: Italian experience. GITMO-AIEOP Groups.

We report data from an Italian survey on ABMT in 93 AML children less than 14 years in 1st or 2nd remission performed in 15 Centers. Different conditioning regimens have been employed: BAVC, an original schedule of chemotherapy; TBI plus Cy and/or other drugs (TBI + CHT); other high dose chemotherapy schedules (HD CHT). 62 patients have been transplanted in 1st CR; 38 have been conditioned with BAVC, 16 with TBI + CHT and 8 with HD CHT. Relapses were 21 in the BAVC group (DFS = 35% at 66 months), 5 in the TBI group (DFS = 61% at 48 months) and 5 in the HD CHT group; overall DFS is 39% at 66 months. 31 patients have been transplanted in 2nd CR; 14 were conditioned with BAVC and 16 with TBI + CHT; 6 patients relapsed in the first group, DFS is 56% at 50 months; in the second group 2 early deaths and 3 relapses occurred, DFS is 65% at 65 months. 1 patient in 2nd CR, conditioned with HD CHT, died during aplasia. Overall DFS is 59% at 65 months. Although no final conclusions concerning ABMT in AML children may be drawn from this retrospective study because of heterogeneity of population and methods, results obtained in 2nd CR are clearly better to those obtained with standard chemotherapy alone, confirming the role of ABMT in this high risk category of patients.

Low CD4 lymphocyte count in a patient with P. carinii pneumonia after autologous bone marrow transplantation.

Authors report a case of P. carinii pneumonia in a child with 5% CD4 lymphocytes (absolute number 5/microliters) after autologous bone marrow transplantation followed by pulmonary irradiation. Serial evaluation of CD4 lymphocyte count or percentage or, at least, detection of significant and persistent lymphopenia could be useful for detecting a high risk of developing P. carinii pneumonia.

Phase II study of recombinant human granulocyte colony-stimulating factor in children undergoing bone marrow transplantation.

Twenty-three children with congenital or acquired hematological disorders and 8 children with solid tumors received filgrastim at a dose of 5 micrograms/Kg by a daily 2-hour infusion following allogeneic (18 cases) or autologous (13 cases) bone marrow transplantation (group I). The results were compared with those of a disease, age and type of transplant matched cohort of 31 children treated in the same institution who did not receive the growth factor (group II). Filgrastim treatment was started within 24 hours of completion of the marrow infusion and lasted for 21 consecutive days or until the absolute neutrophil count reached 10 x 10(9)/l for 3 consecutive days. Twelve variables were evaluated prospectively in Group I and retrospectively in Group II. Myeloid reconstitution with peripheral granulocyte counts > 0.5 x 10(9)/L was achieved at a median time of 13 days in group I and of 14 days in group II (p = ns). Platelet recovery to > 50 x 10(9)/L was slower in group I (43 vs 30 days: p < .05). Median time to last platelet and red blood cell infusion was higher in group I (33 vs 18 days for platelets, p < .05; 45 vs 25 for red blood cells, p < .005). Filgrastim-treated children undergoing autologous BMT had fewer days of fever (6 vs 10 days, p < .05). There was no significant toxicity ascribable to filgrastim. Clinically and microbiologically documented infections, days of antibiotic therapy, duration of total parenteral nutrition and median time in hospital were similar in both groups. We conclude that in children undergoing autologous BMT for malignancies, filgrastim significantly reduced the number of febrile days. Similar benefits were not observed in children undergoing allogeneic BMT. Children receiving filgrastim experienced a delay in erythrocyte and platelet recovery. A prospective randomized study is required to better define the cost-benefit of filgrastim in children undergoing autologous or allogeneic BMT.

Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma.

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.

Fatal pneumopathy in children after bone marrow transplantation--report from the Italian Registry. Italian Association of Pediatric Hematology-Oncology BMT Group.

We have examined data reported in the AIEOP-BMT Registry in order to determine the incidence, causes and risk factors for fatal pneumopathy after bone marrow transplantation in a pediatric population. Overall, in the Registry 1134 children are reported, 531 of whom received an autologous BMT, 468 allomatched BMT, eight syngeneic, 75 mismatched, 29 unrelated and 23 peripheral blood progenitor cells as rescue after myeloablative therapy in the period 1983-1993. 198 patients out of 1134 (17%) died of transplant-related causes and 86 of them died of pulmonary complications: 12 were recorded as fungal pneumonia, eight bacterial, four bacterial and fungal, six viral, two Pneumocystis carinii pneumonia, 12 ARDS, 13 interstitial, 29 unspecified 'respiratory failure'. Multivariate analysis showed that only type of graft and presence or absence of Pneumocystis carinii prophylaxis influence the cumulative incidence of fatal pneumonia. After autologous BMTs only Pneumocystis carinii prophylaxis was significant in multivariate analysis. After allogeneic BMTs multivariate analysis showed that BMT type, Pneumocystis carinii prophylaxis and GVHD grade seem to maintain their influence on cumulative incidence of fatal pneumonia. After BMT the incidence of fatal pneumopathy in children is low (9%), but it represents the second cause of death after primary disease. Pneumocysti carinii prophylaxis should also be given after autologous BMT.

Bloodstream infections can develop late (after day 100) and/or in the absence of neutropenia in children receiving allogeneic bone marrow transplantation.

We retrospectively evaluated the incidence and time from transplantation of bloodstream infections occurring in children receiving bone marrow transplant (BMT) at G Gaslini Children's Hospital between September 1984 and December 1997. During this period the incidence was 35% after allogeneic and 26% after autologous BMT (P=0.08). Among these episodes, 38% after allogeneic BMT and 90% after autologous BMT were detected in the presence of neutropenia within the first 30 days from reinfusion (P < 0.001). Incidence of catheter-related bloodstream infections was 40% after allogeneic and 8% after autologous BMT (P < 0.001). Bloodstream infections in the absence of neutropenia were 55% after allogeneic BMT vs 10% after autologous BMT (P < 0.001) and occurred later after reinfusion (mean 199 vs 41 days, P <0.001). Among the episodes occurring after allogeneic BMT and in the absence of neutropenia, 61% were related to the presence of a central venous catheter, 15% were related to the presence of GVHD, but 23% were not associated with any of major risk factors for infection. Finally, 38% of episodes following allogeneic BMT were detected after day 100 vs 1% after autologous BMT. We concluded that patients receiving allogeneic BMT experience a high incidence of bloodstream infections in the absence of neutropenia and that a significant proportion of these episodes is not clearly associated with well known risk factors such as GVHD or central venous catheters. Moreover, many episodes develop a long time after the transplantation procedure. Therefore, any febrile episode following allogeneic BMT even late and/or in the absence of neutropenia should be intensively managed.

Fiberoptic bronchoscopy and bronchoalveolar lavage for the evaluation of pulmonary infiltrates after BMT in children.

Thirty-one fiberoptic bronchoscopies and BAL performed within 4 days after the appearance of pulmonary infiltrates in 28 children who received BMT were reviewed. A causative agent was identified in 67% of patients with diffuse infiltrates (Cytomegalovirus in 8 cases, Pneumocystis carinii in 4) and in 31% of those with localized infiltrates (Aspergillus in 2, bacteria in 2). No relevant side effect was reported. The results obtained from cytological and microbiological testing provided relevant informations for the management of most cases, regardless to the identification of a specific pathogen. We conclude that BAL is a safe diagnostic procedure that should be considered early after the onset of pulmonary complications in BMT recipients.

Long-term follow-up of two children with a variant of mild autosomal recessive osteopetrosis undergoing bone marrow transplantation.

Malignant autosomal recessive (AR) osteopetrosis represents an absolute indication for bone marrow transplantation (BMT). Over the last 15 years, almost 100 BMTs for osteopetrosis have been reported. The median age at transplant of most patients is 4 months. Very few cases of mild AR osteopetrosis have been described. Here, we report the good outcome of two cases of mild AR osteopetrosis with a follow-up of 5 and 6 years, respectively, after an HLA-identical sibling transplant undergone at 5 and 12 years of age, respectively. At the time of BMT, severe visual impairment was present in both children. Bone biopsy demonstrated hypermineralization with virtual obliteration of the medullary spaces, rare microfoci of hematopoiesis and marked deficiency in osteoclastic activity. Successful engraftment was complicated by hypercalcemia, controlled by a combination of bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. Following BMT, radiological and histological findings showed extensive bone resorption with marked augmentation of the osteoclasts in normalized marrow. No improvement was observed in visual acuity, despite complete remodeling of skeletal abnormalities. We conclude that allogeneic BMT is the only chance of curing mild AR osteopetrosis.

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.