[Show abstract][Hide abstract] ABSTRACT: No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).Bone Marrow Transplantation advance online publication, 15 April 2013; doi:10.1038/bmt.2013.41.
Bone marrow transplantation 04/2013; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The main limit of umbilical cord blood hematopoietic stem cell transplantation is a more difficult engraftment related to the number of cells infused per kilogram of recipient body weight. This limit makes the cord blood a suboptimal source of hematopoietic stem cells for transplantation in case of difficult engraftment situations. Direct intrabone cord blood (CB) injection has been recently investigated as a solution to cell dose problem in the adults population, but there is a lack of data concerning this approach in pediatric patients. Here, we describe 5 pediatric patients undergoing intrabone cord blood transplantation (IBCBT) for different diseases characterized by a high risk of posttransplant graft failure. The conditioning regimen differed according to the disease, whereas the GvHD prophylaxis consisted of cyclosporine, mycophenolate, and ATG. The median numbers of total nucleated cells infused and CD34(+) cells were 3.3 × 10(7)/kg, 2 × 10(5)/kg. All the patients showed complete hematological recovery and complete donor engraftment. No patient had secondary graft failure, whereas 1 patient relapsed 6 months after IBCBT. No patient died of transplant-related complications. Our results show that IBCBT is safe and feasible in pediatrics as well, and suggest that IBCBT might be an attractive option to overcome some limits of umbilical cord blood hematopoietic stem cell transplantation.
Journal of Pediatric Hematology/Oncology 02/2012; 34(5):359-63. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months.
Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion.
The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months.
Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.
Annals of Oncology 11/2011; 23(7):1899-905. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic Lateral Sclerosis is a progressive fatal neurodegenerative disease that targets motor neurons. Its origin is unknown but a main role of reactive astrogliosis and microglia activation in the pathogenesis has been recently demonstrated. Surrounding neurons with healthy adjoining cells completely stops motor neuron death in some cases. Hence stem cell transplantation might represent a promising therapeutic strategy. In this study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion. No significant differences between donors or patients were observed. The patients received intraspinal injections of autologous MSCs at the thoracic level and monitored for 4 years. No significant acute or late side effects were evidenced. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. Four patients show a significant slowing down of the linear decline of the forced vital capacity and of the ALS-FRS score. Our results seem to demonstrate that MSCs represent a good chance for stem cell cell-based therapy in ALS and that intraspinal injection of MSCs is safe also in the long term. A new phase 1 study is carried out to verify these data in a larger number of patients.
Journal of the Neurological Sciences 03/2008; 265(1-2):78-83. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our study was aimed to evaluate the feasibility and safety of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored amyotrophic lateral sclerosis (ALS) patients.
Seven patients affected by definite ALS were enrolled in the study and two patients were treated for compassionate use and monitored for at least 3 years. Bone marrow was collected from the posterior iliac crest according to the standard procedure and MSCs were expanded ex vivo according to Pittenger's protocol. The cells were suspended in 2 ml autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.
The in vitro expanded MSCs did not show any bacterial o fungal contamination, hemopoietic cell contamination, chromosomic alterations and early cellular senescence. No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation and leg sensory dysesthesia, both reversible after a mean period of 6 weeks. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. A significant slowing down of the linear decline of the forced vital capacity was evident in four patients 36 months after MSCs transplantation.
Our results demonstrate that direct injection of autologous expanded MSCs into the spinal cord of ALS patients is safe, with no significant acute or late toxicity, and well tolerated. The clinical results seem to be encouraging.
Neurological Research 08/2006; 28(5):523-6. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A large number of patients affected by acute myeloid leukemia (AML) achieve complete remission following induction chemotherapy based on high-dose aracytin and anthracyclines. However, a postremission consolidation treatment appears to be essential to maintain the remission status. Sixteen patients with newly diagnosed AML received induction chemotherapy according to the AIEOP LAM 92P/Mod protocol. All patients were HLA-typed, and if no donor was identified within the family, patients underwent autologous stem cell transplantation (autoSCT) with mafosfamide-purged bone marrow. Patients with very high-risk AML (cytogenetics with t(9;22), hyperleukocytosis (540x10(9)/L), and AML-M7 with trilineage myelodysplasia) underwent unrelated donor transplantation. One patient relapsed before autoSCT. Eleven patients underwent autoSCT with purged bone marrow, 3 patients underwent unrelated donor transplantation (UD), and 1 patient underwent HLA-identical, matched familiar donor transplantation (MFD). All patients achieved complete remission following one course. No treatment-related deaths occurred during first-line treatment. The median interval between diagnosis and transplant was 175 days (129-277). Three patients relapsed following autoSCT; none relapsed after alloSCT. Taking stem cell transplantation as the starting point, overall survival was 93%, disease-free survival (according to the chosen treatment) was 80%, the relapse rate was 20%, and transplant-related mortality was 0%.
Pediatric Hematology and Oncology 01/2005; 22(7):597-608. · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Outcome data were analyzed for 27 patients who were affected with recurrent or newly diagnosed high-risk brain tumors and who underwent high-dose chemotherapy with triethylenethiophosphoramide (thiotepa) and etoposide in addition to autologous stem cell transplantation between May 1992 and September 2002.
Fifteen males and 12 females (median age, 11 years) were included in the study. Twelve patients had newly diagnosed high-risk brain tumors, and 15 patients had recurrent brain tumors. The conditioning regimen consisted of thiotepa 900 mg/m2 and etoposide 1500 mg/m2 over 3 days starting on Day -5. Stem cell rescue was performed using bone marrow (BM) in 8 patients, peripheral blood stem cells (PBSCs) in 18 patients, and BM and PBSCs in 1 patient.
For the BM group, neutrophil (PMN) engraftment was achieved on Day +14 (median value), whereas platelet (PLT) engraftment was achieved on Day +68 (median value). One patient did not achieve PLT engraftment. For the PBSC group, the PMN engraftment was achieved on Day +10.0 (median value), and the PLT engraftment was achieved on Day +15.5 (median value). Transplantation-related toxicity (evaluated using the Bearman score) included Grade 2-3 mucositis in 16 patients, Grade 1 kidney toxicity in 6 patients, Grade 1 liver toxicity in 6 patients, and Grade 2 liver toxicity in 1 patient. Transplantation-related mortality was observed in 1 patient (3.6%), who died of Candida pneumonia. The 3-year overall survival (OS) rate was 44.6%, and the 3-year event-free survival (EFS) rate was 31%. There was a statistically significant difference in OS and EFS rates for patients who underwent ASCT and achieved complete remission compared with patients who had measurable disease.
The results of the current study suggest that high-dose chemotherapy followed by ASCT may be beneficial for patients who achieve complete remission before ASCT, whereas for other patients, new strategies are required.
Cancer 06/2004; 100(10):2215-21. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with relapsed acute myeloid leukemia following autograft have a poor prognosis. The possibility of allograft is frequently time-limited, as the disease reappears before a stem cell donor can be found in the worldwide registries. Cord blood transplantation is a new therapeutic approach, since cord blood units are rapidly available. The authors show how a relapsed chemotherapy-refractory patient was successful transplanted with a mismatched cord blood unit after reduced-intensity conditioning. Twenty-three months after transplantation, the child is in continuous complete remission and has full donor chimerism and no signs of chronic graft-versus-host disease.
Journal of Pediatric Hematology/Oncology 03/2004; 26(2):98-100. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic bone marrow transplantation (BMT) is a widely accepted therapeutic approach in homozygous beta-thalassemia. However, the majority of patients do not have a genotypically identical donor within the family. This prompted us to conduct a pilot study to investigate the feasibility of matched unrelated bone marrow transplantation in thalassemia. The major drawback was the high risk of immunologic and transplant-related complications, mainly graft-versus-host disease (GvHD) and graft failure.
Our aim was to reduce this risk through careful selection of donor/recipient pairs. HLA haplotypes that show a high linkage disequilibrium among their class I, class II and class III alleles are considered extended or ancestral haplotypes.
These haplotypes are conserved and can be shared by apparently unrelated individuals. Our study shows that matching for these haplotypes significantly improves the outcome of unrelated bone marrow transplantation in thalassemia. In fact, results were comparable to those obtained in transplants using HLA-identifical family donors.
Better results were obtained in patients with lesser iron overload and when the donor shared an identity for the DPB1 alleles.
[Show abstract][Hide abstract] ABSTRACT: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive, alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper is to report on 520 patients below 19 years of age undergoing UD BMT in 31 Italian centers between September 1989 and December 2001, and to focus on the results achieved in the 423 patients grafted before December 2000.
In 1989 the Italian Bone Marrow Transplant Group (GITMO) and the Italian Association for Pediatric Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor Registry (IBMDR) to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B typed volunteer donors had been cumulatively registered and 3,411 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 520 UD BMTs were performed in patients below 19 years of age before December 2001. Since 1999 more than 90% of the patients < or = 14 years old, and more than 50% of the patients 15-18 years old undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases donors were found in the IBMDR, and in 50% they were found in 14 other Registries. The average time from search activation to transplant was 6 months for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7 months.
Actuarial 100-day transplant-related mortality (TRM) was 32% in patients grafted between 1989 and 1997, and 21% for patients grafted after 1998 (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD. The rate of disease-free survival at three years was 37% for patients with acute lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic syndrome patients, 59% for patients with inborn errors, and 51% for patients with CML.
We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. Results show a positive trend after 1998, mainly due to a decrease in transplant-related-mortality.
[Show abstract][Hide abstract] ABSTRACT: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse.
Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT.
Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%.
HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.
Journal of Clinical Oncology 05/2002; 20(8):2150-6. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) has emerged as one of the main transplant-related complications over the last 15 years. The current study defines the incidence and the risk factors for the occurrence of TTP in 131 consecutive leukemic children who were transplanted between January 1994 and December 1997 at four Italian pediatric centers. Patients with ALL (101), AML (21), MDS (9), underwent an HLA-identical sibling BMT (82) or an HLA-identical unrelated BMT (49), receiving a conditioning regimen consisting of high-dose chemotherapy in 24 patients and of F-TBI combined with high-dose chemotherapy in 107 patients. The diagnosis of TTP was retrospectively evaluated on the basis of parallel criteria. TTP treatment varied according to the protocol of each treatment center. Twenty-eight of 131 patients (21.4%) developed TTP at a median of 46 days (range 21-80) after BMT. Multivariate analysis demonstrated that the risk of TTP was higher in patients who underwent unrelated BMT (P value = 0.02). Acute GVHD, stage of disease at BMT, conditioning with TBI, gender, age, did not appear to be associated with the occurrence of TTP. As to the outcome, TTP resolved in 19 patients while in nine it was the principal cause of death (32.1%). In patients with TTP, LDH peak value was the only statistically significant factor (P = 0.001) related to severe TTP. In conclusion, our experience demonstrates that leukemic children undergoing BMT, especially from an unrelated donor, should be carefully assessed for TTP which appears to be a severe and relatively common transplant-related complication when strict diagnostic criteria are applied.
Bone Marrow Transplantation 12/2000; 26(9):1005-9. · 3.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of the present study was to analyze the characteristics of infectious complications occurring during the first 100 days after bone marrow transplantation (BMT) in a cohort of 123 pediatric patients with hematological malignancies (n = 73), solid tumors (n = 32) and nonmalignant disorders (n = 18). Fifty-eight patients received allogeneic grafts, and 65 patients an autologous transplant. Fever developed in 107 (87%) children; 82% of infectious complications occurred during the neutropenic period. Documented infection developed in 33 (31%) patients, while 74 (69%) patients had possible infection (i.e. fever of unknown origin). The incidence of bacteremia was 21%, and gram-positive cocci were the predominant pathogens; non-bacteremic microbiologically documented infection developed in 6% of patients; clinically evident infection developed in 4% of subjects. The incidence of primary febrile episodes was not significantly different between autologous and allogeneic BMT (86% vs 88%); nor did the median number of days to the onset of fever (5 days in both groups) or the median duration of fever (5 days in both groups) differ. In contrast, the frequency of secondary febrile episodes was significantly higher (P = 0.0001) in allogeneic BMT recipients (40%) than in autologous recipients (15%). The mortality rate due to infections was 2/36 (5%) for matched sibling donor BMT, and 1/13 (8%) for matched unrelated donor BMT. No deaths occurred in the 65 patients who were autografted. Invasive fungal infections accounted for 2 of the 3 infectious deaths. In conclusion, the majority of children undergoing BMT experienced at least one infectious episode; allogeneic BMT recipients were at high risk of developing secondary febrile episodes, but the overall mortality rate due to infection in the first 100 days after transplantation was low.
Supportive Care Cancer 08/1999; 7(4):253-9. · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An Italian-Scandinavian treatment and research protocol with high-dose chemotherapy and double peripheral blood stem cell (PBSC) transplantation has been designed in an attempt to improve overall results of children with metastatic osteosarcoma (OST). Six patients, aged 12-17 years, underwent PBSC mobilization with CY 4 g/m2 and VP-16 600 mg/m2 followed by G-CSF (n = 4 with recurrent disease) or ifosfamide 15 g/m2 plus G-CSF (n = 2 with synchronous metastases). The target dose of CD34+ cells for two transplant procedures was 8 x 10(6)/kg or more; conditioning regimen for both the grafts consisted of carboplatin 375 mg/m2/day for 4 days and VP16 450 mg/m2/day for 4 days. The first transplant was planned 2-4 weeks after the mobilization, the second transplant 4-6 weeks after the first graft. In three patients a single course of CY-VP16 mobilised a total number of CD34+ sufficient for two transplants; in the patient who did not obtain the target dose of CD34+ cells a bone marrow harvest was added. In the two other children high-dose ifosfamide failed to achieve the required CD34+ number: one patient underwent a single transplant procedure, one patient was successfully mobilized with doxorubicin 90 mg/m2 plus G-CSF. Patients underwent a median of two collections (range 2-4). Leukapheresis resulted in the collection of a median of 8.9 CD34+ cells/kg (range 1.3-14.8). The median time to granulocyte count recovery to more than 0.5 x 10(9)/l was 10 days (range 9-14 days) after the first graft and 11 days (range 10-12 days) after the second graft, respectively. Platelets recovered to 50 x 10(9)/l at a median of 11 (range 10-30 days) and 13 days (range 10-28) respectively after the first and the second graft. Conditioning regimen was well tolerated in all patients with mild extra haematological toxicity, also following the second transplant. Two patients grafted with metastases at diagnosis are alive and disease free 3 and 7 months from the transplant. One of the four patients transplanted for recurrent disease developed pulmonary metastases 2 months after the procedure; one patient is alive with significant reduction of tumor mass 1 month after the first transplant, one patient is alive without evidence of disease 9 months from the second transplant and one after a complete metastasectomy (tumor necrosis >90%) which followed the second transplant. With the limits of the small number of cases and the short follow-up, these preliminary results show that this approach may be promising for the treatment of patients with metastatic OST who currently are not cured by conventional-dose regimens.
[Show abstract][Hide abstract] ABSTRACT: Between February 1995 and August 1997, 11 children (eight males, three females) aged 4-16 years (median 7 years) underwent allogeneic PBPC transplantation for treatment of hematological disorders. Seven patients with acute leukemia (n = 5 ALL, n = 1 AML) or lymphoma (n = 1) received primary allogeneic PBPC transplantation, four patients received a second allotransplantation for graft failure (n = 1 AML, n = 1 sickle cell anemia) or disease recurrence (n = 1 ALL, n = 1 MDS). Five donors were HLA-identical siblings, five were 0-1 antigen mismatched family members and one was a matched unrelated donor. Donors received G-CSF 10-12 microg/kg/day for 3-7 days, and underwent one or two leukaphereses. The median cell yield per donor expressed per kg of recipient body weight was as follows: mononucleated cells 10.8 x 10(8)/kg (range 4.7-21.2); CD34+ cells 8.6 x 10(6)/kg (range 3.2-22); CD3+ cells 3.7 x 10(8)/kg (range 2.7-7.5). All patients achieved an ANC >0.5 x 10(9)/l after a median of 12 days (11-18). An unsupported platelet count >50 x 10(9)/l was reached 15 days (13-21) after PBPC transplantation; four patients failed to reach this threshold. Acute GVHD (aGVHD) grades II to IV occurred in eight (73%) patients: seven of them experienced grade III-IV aGVHD. Seven patients evaluable for chronic GVHD (cGVHD) were scored as absent in five, limited in one and extensive in one patient. As of September 1997, six patients (55 %) were alive between 60 and 938 days post-transplant (median follow-up 274 days); four patients with malignancy were alive in CR after primary allotransplantation, two patients were alive after a second PBPC transplant. Five patients have died with the main causes of death being aGVHD (n = 3), ARDS (n = 1), relapse of the underlying disease (n = 1). In conclusion, despite the limited number of patients, these preliminary results indicate that PBPC may be considered as an alternative to bone marrow for allografting also in children.
[Show abstract][Hide abstract] ABSTRACT: A 4-year-old boy with acute myeloid leukemia developed acute myositis associated with refractory thrombocytopenia one month after autologous bone marrow transplantation (BMT). Clinical, electromyographic and biohumoral features were consistent with the diagnosis of myositis. The patient responded to corticosteroids, and 39 months after BMT he is in complete remission and has regained good muscle function. Although we could not determine with certainty the specific pathophysiologic mechanism of this complication, it should be pointed out that acute myositis can occur in the early post-BMT period.
[Show abstract][Hide abstract] ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a frequent complication of allogeneic bone marrow transplantation (BMT). Thalidomide was found to have immunosuppressive properties and it has been used in a limited number of children with cGVHD. We report our experience with refractory and/or high-risk cGVHD in 14 children. Six children showed complete clinical response to thalidomide in a median time of 2 months. Four children had partial responses and four failed. Side-effects were usually mild (somnolence, constipation) and only two patients developed sensory peripheral neuropathy. An increased incidence of infectious complications attributable to thalidomide was not observed. Nine out of 10 responding patients are alive 49-111 months post-BMT. Thalidomide can be effective particularly in children with prevailing mucocutaneous cGVHD. All patients should be carefully monitored to detect peripheral neuropathy early.
Bone Marrow Transplantation 03/1998; 21(6):577-81. · 3.54 Impact Factor